Estudio clínico Fase III Para Evaluar la Eficacia terapéutica en Pacientes Mexicanos Con Dislipidemia Mediante el Uso vía Oral de L-Carnitina + Atorvastatina Comparado Con Atorvastatina
Phase: PHASE3
Conditions: Dyslipidemias, Cardiovascular Risk Factor
Sponsor: Laboratorios Grossman, S.A.

 
 
 
 
 
 
 
 
 
Title: 
“PHASE 
III 
CLINICAL 
STUDY 
TO 
EVALUATE 
THE 
THERAPEUTIC EFFICACY IN MEXICAN PATIENTS WITH 
DYSLIPIDEMIA THROUGH THE ORAL ROUTE USE OF L-
CARNITINE 
+ 
ATORVASTATIN 
COMPARED 
WITH 
ATORVASTATIN.” 
Investigational product: 
Posology indications: 
Type of study: 
Atorvastatin 10mg/Carnitine 500mg 
Dyslipidemias of the total hypercholesterolemia type, LDL 
lipoprotein 
hypercholesterolemia, 
hypoalphalipoproteinemia, 
hypertriglyceridemia. 
Phase III clinical assay, experimental randomized with two other 
multi-center, longitudinal treatment groups, to evaluate the 
therapeutic efficacy in the dyslipidemias of Mexican adults. 
Code of study: 
GMX-001-2017 
Clinical phase of study: 
Phase III Study 
Sponsor: 
Valeant Pharmaceuticals International. 
Calzada de Tlalpan 2021 
Col Parque San Andrés 
México D.F. 
C.P. 04040 
Elaboration and 
Coordination: 
Dr. Ventura Aguirre Rojas. Medical and Regulatory Director for 
Mexico and Latin America, Valeant Pharmaceuticals International 
Dr. Francisco Javier Figueroa Vallejo. Coordinator of Clinical 
Studies for Mexico and Latin America, Valeant Pharmaceuticals 
International 
Elaboration date: 
August 3, 2017. 
Version Number: 
02. 
Amendment Number : 
0. 

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CONFIDENTIALITY AGREEMENT 
 
 
 
The information contained in this document, especially the non-
published data, 
is property of 
Valeant Pharmaceuticals 
International (or is controlled by it). 
 
This document is provided confidentially to investigator, 
potential investigator or consultant, for its revision and/or 
revision by its workgroup, and in the event of revision by the 
Ethics Institutional Review Board. 
 
It is understood that this information shall not be made known to 
third parties, without written authorization from 
Valeant 
Pharmaceuticals International, with the exception and in the 
necessary extension to obtain the informed consent of the 
participants to whom the medicine will be administered. 

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SIGNATURE PAGE FOR AUTHORIZATION BY THE SPONSOR 
 
 
 
Valeant Pharmaceuticals International is committed to perform the study according 
to what is stipulated in this protocol, in conformity with the existing guidelines of the 
Regulations for the human research of the General Health Law, COFEPRIS, the 
Good Clinical Practices (GCP), the Helsinki Declaration and the International 
Conference on Harmonization (ICH). 
 
 
 
Dr. Ventura Aguirre Rojas 
 
Medical and Regulatory Director of Mexico and Latin America 
 
 
 
 
 
Signature:   
 
Date: 
/ 
/ 
 
DD 
MMM 
YYYY 
 
 
 
 
 
 
Dr. Francisco Javier Figueroa Vallejo 
 
Clinical Research Coordinator of Mexico and Latin America 
 
 
 
 
 
Signature:   
 
Date: 
/ 
/ 
 
DD 
MMM 
YYYY 
 
 
 
 
M.C. Cesar Alik Pedrajo Zenteno 
 
Pharmacovigilance Manager of Latin America 
 
 
 
 
 
Signature:   
 
Date: 
/ 
/ 
 
DD 
MMM 
YYYY 

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SIGNATURE PAGE FOR APPROVAL OF PROTOCOL BY THE PRINCIPAL 
INVESTIGATOR 
 
Complete name (in 
print): 
 
 
Location of the site for 
the research: 
 
 
Address          (street, 
number, 
colony, 
municipality, 
state 
and Z.C.): 
 
 
 
 
Fixed Telephone: 
 
 
Mobile Telephone: 
 
 
E-mail: 
 
 
 
I have read this protocol and I commit myself to carry out the study according to 
what is stipulated in it, in conformance with prevailing guidelines of the Regulation 
for human research of the General Health Law, COFEPRIS, Good Clinical 
Practices (GCP), the Helsinki Declaration and the International Conference for 
Harmonization (ICH). 
 
Any deviation from this protocol shall be agreed in writing, previous analysis, 
between the Sponsor and me. 
 
I agree that I or the person designated by me, will inform completely to all 
participating patients in this study about the pertinent details and purpose of the 
study before they accept to participate in the study in conformance to what is 
established in the GCP and in the requirements of the regulatory authorities. 
 
I shall be responsible of preserving the format of informed consent of each patient 
in the study file and of providing each patient with a faithful copy of the signed 
original of its informed consent format. 
 
 
 
Name and signature: 
 
 
 
Date: 
/ 
/ 
DD 
MMM 
YYYY 

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Table of Contents 
INTRODUCTION 
8 
1. 
DEFINITIONS 
11 
2. 
SYMBOLS AND ABBREVIATIONS 
19 
3. 
THEORIC FRAME 
    21 
   Lipids  
21 
   Dyslipidemias  
22 
   Cardiovascular risk factors  
32 
3.3.1. 
Non-modifiable cardiovascular risk factors 
32 
3.3.2. 
Modifiable cardiovascular risk factors  
33 
4. 
PRESENTATION OF PROBLEM 
33 
5. 
HISTORY 
55 
6. 
JUSTIFICATION 
65 
7. 
HYPOTHESIS 
71 
   Main hypothesis:  
71 
   Secondary hypothesis:  
71 
8. 
OBJECTIVES 
71 
   General Objectives:  
71 
8.1.1. 
Evaluate the therapeutic efficacy in Mexican adults with dyslipidemia through the oral route 
use of  L-carnitine + atorvastatin in comparison to the use of Atorvastatin, posterior to six months of 
treatment de treatment                                                                                                               71                     
8.1.2. 
Evaluate the safety of the medicines being studied.  
71 
   Specific Objectives:  
72 
8.2.1. 
Evaluate the diminishing of LDL Cholesterol in Mexican adults with dyslipidemia through 
the use of oral route  of L-carnitine   + atorvastatin in comparison with the use of Atorvastatin, after 
six months of treatment                                                                                                                               72 
8.2.2. 
Evaluate the diminishing of non-HDL Cholesterol in Mexican adults with dyslipidemia 
through the use of oral route  of L-carnitine   + atorvastatin in comparison with the use of 
Atorvastatin, after six months of treatment                                                                                              72                              
8.2.3. 
Evaluate the variability of the serum levels of Total Cholesterol in Mexican adults with 
dyslipidemia through the use of oral route L-carnitine + atorvastatin in comparison with the use  
of Atorvastatin, after six months of treatment with Atorvastatin 
72 
8.2.4. 
Evaluate the variability of serum levels of Triglycerides in Mexican adults with dyslipidemia 
through the use of oral route  L-carnitine + atorvastatin in comparison with the use of 
Atorvastatin, after six months of treatment.  
72 
8.2.5. 
Evaluate the variability of serum levels of HDL Cholesterol in Mexican adults with 
dyslipidemia through the use of oral route  L-carnitine + atorvastatin in comparison with the use 
of Atorvastatin, after six months of treatment.  
72 
8.2.6. 
Evaluate incidence, prevalence and progression of related serious and non-serious adverse 
events through the oral route administration of L-carnitine + atorvastatin in comparison with the 
use of Atorvastatin, after six months of treatment in the subjects participating in the study         72  

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Premises of the study: 
72 
9. 
DESIGN OF THE STUDY 
73 
selection of the study population 
74 
9.1.1. 
Inclusion Criteria. 
74 
9.1.2. 
Exclusion Criteria. 
75 
9.1.3. 
Early Termination Criteria. 
77 
Estimate of the sample size. 
78 
Assignation of treatment and treatment groups 
80 
9.3.1. 
Experimental Group: 
81 
9.3.2. 
Control Group with Active: 
81 
Processes to perform during the study: 
82 
9.4.1. 
Recruitment of patients 
82 
9.4.2. 
Process of Informed Consent 
82 
9.4.3. 
Assignation of subject identification code 
84 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4.4. 
Basal visit, day 0. Revision of inclusion and exclusion criteria, formulation of clinical 
history, physical exploration, laboratory tests and inclusion of participants. 
85 
3.1. 
Blood Biometry without differential and Glycosylated Hemoglobin. 
89 
3.2. 
Blood Chemistry to evaluate: CT, C-LDL, C-HDL, TG, C-no HDL, Glucose, Urea, 
Creatinine, Uric Acid, ALT, AST and CPK. 
89 
9.4.5. 
Basal visit day 0, assigning of treatment 
89 
9.4.6. 
Telephone call posterior to basal visit, day 7 +/- 2 days 
90 
9.4.7. 
Visit 1, day 30 +/- 3 days with respect to complete basal visit 
90 
9.4.8. 
Telephone calls, posterior to visit 1, days 37 (+/- 3) and 60 (+/- 3) 
92 
9.4.9. 
Visit 2, day 90 +/- 5 days from complete basal visit 
92 
9.4.10. Telephone calls posterior to visit 2, days 97 (+/- 3), 120 (+/- 5) and 150 (+/- 5)  
94 
9.4.11. Visit 3, day 180 +/- 7 days with respect to complete basal visit (Final Visit) 
94 
1.1. 
Blood Biometry without differential and Glycosylated Hemoglobin. 
95 
1.2. 
 Blood Chemistry to evaluate: CT, C-LDL, C-HDL, TG, C-no HDL, Glucose, Urea, 
Creatinine, Uric Acid, ALT, AST and CPK. 
95 
9.4.12. Summary of the processes to perform by the investigation subjects during their 
participation in the study . 
96 
9.4.13. Patients to Sieve to comply with Sample Size 
101 
9.4.14. Procedures based on study groups 
103 
9.4.15. Visits not stipulated by protocol 
105 
9.4.16. Capture and processing of data 
105 
9.4.17. Statistical analysis and interpretation of the information 
106 
10. 
STUDY OBSERVATIONS. 
107 
 Medicine  
107 
10.1.1. Dose 
107 
10.1.2. Labeling of medicine. 
108 
10.1.3. Banned medicines. 
109 
10.1.4. Medicine Inventory 
112 
10.1.5. Medicine storage 
113 
Taking and processing of laboratory samples 
                        114 
Study registry, case report forms and source document 
                        116 
Efficacy criteria 
                        117 
10.4.1. Success 
                        117 
Safety criteria. 
                        117 
11. 
SAFETY 
                        118 
Adverse events 
                        118 
11.1.1. Classification of adverse events, suspicion of adverse reaction and the adverse reactions 

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of the medicines:  
119 
11.1.2. Quality of the obtained information  
121 
11.1.3. Causality  
121 
11.1.4. Special conditions  
123 
 Report of the adverse events  
123 
 Follow-up of adverse events  
124 
 Data for notification of serious adverse events  
124 
 Adverse events expected for the medicine under study  
125 
11.5.1. Atorvastatin  
125 
11.5.2. L-Carnitine  
132 
12. 
ADMINISTRATIVE ASPECTS OF THE STUDY  
135 
 Confidentiality  
135 
 Data withholding   
135 
 Authorization of the protocol by the Committee of Ethics in Investigations and the Institutional 
Review Board                                                                                                                                      136 
 
 Authorization of protocol by the Federal Commission for Protection against Health Risks 
(COFEPRIS)  
137 
 Start of the study  
138 
13. 
DURATION OF THE STUDY  
138 
14. 
MONITORING OF THE STUDY  
138 
 Responsibilities during monitoring  
139 
 Monitoring reports  
141 
15. 
AUDITS  
142 
16. 
NON-COMPLIANCE  
143 
17. 
SUSPENSION OF STUDY  
143 
18. 
DEVIATIONS FROM PROTOCOL  
144 
19. 
AMMENDMENTS  
145 
20. 
ETHICAL ASPECTS  
145 
21. 
MATERIAL RESOURCES AND FINANCING  
146 
BIBLIOGRAPHIC REFERENCES  
148 
LEGISLATIVE ANNEX  
161 
ANNEX 1. ESCALA DE GLOBORISK  
162 
 ANNEX 2. CONTROL CARD OF TREATMENT OF PARTICIPANT BASAL VISIT  
163 
 ANNEX 3. CONTROL CARD OF TREATMENT OF PARTICIPANT VISIT 1  
168 
 ANNEX 4. CONTROL CARD OF TREATMENT OF PARTICIPANT VISIT 2  
175 
 ANNEX 5. FORMAT FOR THE EVALUATION OF CAUSALITY  
184 

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SUMMARY 
 
General 
objectives: 
Evaluate the therapeutic efficacy in Mexican adults with 
dyslipidemia through the oral route use of L-carnitine + 
atorvastatin in comparison with the use of Atorvastatin, after six 
months of treatment. 
Evaluate the safety of the medicines under study. 
Hypothesis: 
The combined use of L-carnitine   +   atorvastatin   offers 
therapeutic superiority with respect to the use of atorvastatin as 
treatment to reduce the percentage of C-LDL in patients with 
dyslipidemia. 
The combination of L-carnitine + atorvastatin shows fewer 
incidences in the presence of adverse events attributable to the 
medicine in comparison to the use of atorvastatin as mono-
therapy, in the treatment of dyslipidemia patients. 
Design: 
Phase III clinical assay, experimental randomized with two 
treatment, multi-centered, longitudinal, to evaluate the 
therapeutic efficacy in dyslipidemias of Mexican adults. 
Material and Methods: 
Sample Size 
120 subjects will be included. 
Inclusion Criteria Mexicans between 35 and 75 years of age. 
Gender indistinct. 
Patient with abnormal lipid profile considered as serum levels 
of C-LDL of 100mg/dl or greater obtained by laboratory 
parameters. 
Not  
under 
pharmacologic 
treatment 
to 
handle 
their 
dyslipidemia or accepting to suspend their current treatment 
and be evaluated for their inclusion in the next 3 weeks starting 
on the day of the initial evaluation. 
Women in fertile stage with a safe, hormonal-free family 
planning method. A safe planning method includes surgical 
methods in women, intrauterine device that doesn’t release 
progestines and use of preservative in all their sexual relations. 
Women in fertile stage who don’t wish to become pregnant 
during their participation in the study. 
Post-menopause women or with hysterectomy history. 
Have a fixed and/or mobile telephone and accept to receive 
calls from the site for study processes. 
Grant their duly informed consent. 
Exclusion 
Criteria 
Subject lacking the mental capacity to understand the 
processes which imply their participation in the study and thus,  

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not capable of granting their participation in a voluntary 
manner. 
History of hypersensitivity to the medicines being studied. 
Daily intake of at least 240ml of grape juice or sporadic 
ingestion of 1 liter. 
Potentially fertile women without a safe family planning method, 
who wish to become pregnant during the study, are already 
pregnant or in lactation period. 
Having on Globorisk scale for Mexicans, or as an associated 
risk factor, a high stratification for cardiovascular risk. 
Basal laboratory values with elevation of ALT 1.5 times larger 
than the upper limit considered normal according to international 
units. 
Basal laboratory values with elevation of CPK not attributable 
to physical activity. 
Subjects who are under anti-coagulant treatment, suffer from 
coagulation 
disorders, 
or 
any 
circumstance 
which 
contraindicates the taking of a blood. 
History of acute myocardial infarction, unstable angina, some 
confirmed coronopathy, arrhythmias, congestive cardiac failure 
or cerebrovascular disease. 
History of muscular conditions of the genetic type or of 
rhabdomyolysis in patient or first degree relative. 
History or diagnose of congenital hepatic disorders, chronic 
infection by hepatitis virus, hepatitis with fatty liver, alcoholic 
hepatitis, primary biliary cirrhosis, primary sclerosis, cholangitis  
or hepatic failure. 
History or diagnose of congenital renal disorders, chronic renal 
failure, acute renal damage or nephritic syndrome. 
History of infection by Human Immunodeficiency Virus. 
History of Acute or Chronic Pancreatitis. 
History of the following endocrine diseases: non-controlled 
Diabetes Mellitus, lipodystrophy, thyroid disorders, Cushing 
Syndrome and/or Polycystic Ovary Syndrome. 
Diseases which compromise immunity such as Systemic Lupus 
Erythematous, 
Rheumatoid 
Arthritis, 
Antiphospholipid 
Antibodies Syndrome or Psoriasis. 
Diseases by deposit such as Gaucher Disease, disease by 
glycogen deposit, Tay-Sachs juvenile disease or Niemann Pick 
Disease. 
Diagnose of Kawasaki Disease, Werner Syndrome, intermittent 
acute Porphyria, Idiopathic Hyperkalemia or Klinefelter 
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Suffer from Idiopathic Hyperkalemia, Klinefelter Syndrome, 
Werner Syndrome, Kawasaki Disease or Porphyria.  
History of epilepsy. 
History or diagnose of alcoholism.  
Intake of more than 20g of alcohol per day. 
User of marihuana. 
User of illegal drugs. 
Intake of medicines with pharmacologic interaction which 
increase or decrease the efficacy of L-Carnitine and/or 
atorvastatin or alter the lipids in blood such as:  
Macrolide 
antibiotics: 
Erythromycin, 
Telithromycin 
and 
Clarithromycin. Azole anti-fungi: Ketoconazole, Itraconazole, 
Fluconazole 
and 
Nefazodone. 
Quercetin, 
Amiodarone, 
Aprepitant, Cimetidine, Ciprofloxacin, Cyclosporine, Diltiazem, 
Imatinib, Echinacea, Enoxacin, Ergotamine, Metronidazole, 
Mifepristone, Tofisopam, Gestodene, Verapamil, Mibefradil, 
Fluoxetine, 
Phenobarbital, 
Carbamazepine, 
Phenytoin, 
Rifampin, 
Modafinil, 
Glucocorticoids, 
Felbamate, 
Rosiglitazone, 
Griseofulvin, 
Pioglitazone, 
Gemfibrozil, 
Clofibrate, Fenofibrate, Niacin, Nefazodone, Cholestyramine, 
Colchicine, Colestipol, Primidone, Topiramate, Troglitazone, 
Rifabutin, 
Digoxin, 
Thiazides, 
anabolic 
Steroids, 
Progestogens, Estrogens, Danazol, Amiodarone, fibric Acid, 
docosahexaenoic acid, Isotretinoine, Immunosuppressives, 
protease inhibitors of HIV or of the Hepatitis C Virus, Inhibitors of 
the co-transport of sodium-glucose, Tamoxifen, Raloxifene, 
non-selective Beta 
blockers, biliary acid sequestrants, 
asparginase, Sirolimus and Interferon. 
Patients who have been diagnosed with terminal conditions. 
Patients with recent Cancer diagnose or undergoing any type 
of therapy for same. Patients who have suffered skin cancer not 
of the melanoma type and have been cured and haven’t been on 
treatment for at least 1 year before the start of their participation 
in the study may enter. 
Patients under lipid lowering treatment and who, because of 
their clinical condition aren’t candidates to the period of lavage 
or detoxification; or well reject same. 
Been participating in another clinical trial or having concluded 
their participation in the 30 days previous to beginning their 
participation in this study. 
Any other which, at the Investigator’s criteria, puts at risk the 
safety of the participant and/or interferes with the results of the 
study. 

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Medicine 
L-Carnitine, Atorvastatin 
Dose 
L-Carnitine 1 g + Atorvastatin 20 mg daily for 6 months and 
Atorvastatin 20 mg daily for 6 months 
Efficacy criteria: The efficacy of the combined treatment vs. atorvastatin in 
mono-therapy for dyslipidemia will be compared, through 
evaluation of the variability of the biochemical parameters at the 
start and end of the study. 

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INTRODUCTION 
 
 
Cardiovascular diseases constitute the first cause of mortality in Mexico and the 
world; in 2012 they caused 46% of non-transmissible secondary deaths and 37% 
in premature deaths in persons under 70 years of age; situations that were 
potentially reversible  with an adequate handling of prevention. For the year 2030 
a mortality of 22.2 million persons is projected, according to data from the World 
Health Organization in 2014. [1] 
 
This overall view sets us on the way to act on the factors that may determine the 
risk of suffering cardiovascular diseases; for this, primary and secondary 
prevention strategies have to be used, which modify morbidity and mortality. In 
this area, dyslipidemias have a wide terrain, for they form part of the modifiable 
cardiovascular risk factors; being the main identified modifiable factor. [L1] This 
correction is linked to a cost-effective benefit in population older than 20 years, 
becoming its prevention and handling a necessity. [2, L1] Besides, a favorable effect 
has been proven in the diminishing of tension figures secondary to the decrease 
of figures of fatty acids in serum. [L1, L2] 
 
Furthermore, dyslipidemias have been associated as a risk factor for the 
acquisition of type 2 Diabetes Mellitus (significant cause of mortality at national 
and global level) and arthrosclerosis; the latter pathology plays a central role in 
three of the five main causes of death in Mexico. [L1] 
 
Certain strategies necessary for underscoring the problem of interest have been 
identified, with an integral focus which rises from the changes in lifestyle; the 
exception are the dyslipidemias of genetic origin or of primary origin. Another 
impact strategy is the secondary prevention, done in populations with high 
cardiovascular risk; with a predominantly clinical focus, aimed at early detection 
and opportune treatment of the dyslipidemias to avoid a disease by alteration of 
fatty acids. The outline of nutritional and pharmacologic treatment of patients with 
dyslipidemias is based on the serum levels of lipids, in function of the 
cardiovascular risk level and certain particular recommendations, [2] being able to 
continue with this pairing of treatment as a manner of keeping the lipids level 
below the limited parameters according to the established cardiovascular risk 
level. 
 
The statins are a pharmacologic group used in the correction of serum levels of 
lipids which are found altered in dyslipidemias, available since 1987, broadly 
described and well-tolerated.  [3]   Their use is recommendable in the primary and 

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secondary prevention of the dyslipidemias. [2, 4] 
 
Identified secondary reactions have been attributed to them that in special 
situations limit their use. [5] But at the same time, with the previous identification 
of the factors that make the patients prone to suffering these reactions and due to 
their low frequency, they keep on being used and are the most adequate 
management to treat the dyslipidemias, with an approach to benefit in the 
decrease of the cardiovascular risk. [6] 
 
Even so, in this protocol the possibility of finding a therapeutic alternative with a 
greater efficacy and a better safety profile is proposed, adding the L-carnitine, 
which counts with a repertory of evidence that sustains the safety and therapeutic 
efficacy in dyslipidemia patients. [7] 
 
In this study, the necessary elements to sustain the performance of the study in a 
Mexican population will be approached in an integral manner with an objective 
focus. To lead to the efficacious comprehension of the study protocol definition and 
abbreviations are included, which will be set in the posterior section. In the 
theoretical frame the basic concepts of the alterations of lipids in Mexicans will be 
explained; besides, the argumentation of dyslipidemias will be led based on the 
antecedents and the therapy used as an interrogative derived from previous 
studies, indicating the relation of the themes, sub-themes or variables. 
 
It is transcendent to know the magnitude, relevance and impact of the 
interrogative in study, how a therapy adequate to the patient who courses with 
dyslipidemias may have a new expectative of treatment that is efficacious and 
safe, for which the necessary argumentation is recurred to situate the necessity 
of the study. 
 
In the proposed hypothesis the postulate of proving the therapeutic efficacy of L-
carnitine + atorvastatin in comparison to atorvastatin arises, for which overall and 
specific objectives are proposed that Valeant Pharmaceuticals International 
through their department of Clinical Research considers of special interest in this 
protocol study.  Nonetheless, there exist premises of the study, which will be 
considered in compliance in temporality and convenience of Valeant 
Pharmaceuticals International during the study, not being a primordial part of study 
object but that, may include the generation of new investigations focused on the 
therapeutics of dyslipidemias and associated factors for the benefit of the Mexican 
population. 

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The methodology used describes the procedures and tools that will help in the 
fulfillment of the research, following a structure of logical ordination for a study of 
experimental nature with clinical object, through the collection of data from the 
adequate sources. A study of the therapeutic efficacy of the product under 
research for dyslipidemias is proposed, with exploratory goals and longitudinal 
interventions and random assignation of treatments blind to the observer; 
localizing this study as a clinical assay of therapeutic superiority. The criteria for 
the selection of patients are focused on allocating for the population that has the 
condition a treatment that has therapeutic benefits and foresees the incidence of 
adverse events related with the investigational product and the active control, as 
well as the foreseeables not related with the investigational product. In the 
progression of the protocol the methods for data gathering and the analysis 
processing of same are described. 
 
In this document is included a chronogram that mentions the times to follow 
previous to the inclusion of the participants, during and posterior to the conclusion 
of their participation in the study; besides the processes that will be carried out 
with the documentation generated during and after the study. 
 
This protocol forms part of the Clincal Trials of Valeant Pharmaceuticals 
International, a responsible pharmaceutical company, concerned for watching the 
autonomy, beneficence and justice of the subjects of investigation; for which it 
was developed and was designed to proceed in the most ethical way possible in 
the handling of the participants and the documentation generated from these, 
having as a reference for their compliance the criteria established in the Helsinki 
Declaration, the Guides of Good Clinical Practices and others stipulated by the 
International Conference for Harmonization (ICH), not leaving aside what’s 
contained in local regulations. 
 
Since this protocol is designed to be carried out in Mexican population, it is written 
so that its content and the processes stemming from it in the investigation comply 
according to the Normativity and existing requirements by the Federal Commission 
for the Protection of Sanitary Risks (COFEPRIS). At the same time, it shall 
develop in concordance to the Mexican Official Norms, NOM-012-SSA3-2012 
that establishes the criteria for the execution of human research projects for health 
in human beings, NOM- 004-SSA3-2012 of the clinical file, The Regulation of the 
general health law in matters of human research, General Health Law DOF 27-
01-2017, Regulations of the Federal Commission for the Protection against Health 
Risks; making use of these of an enunciate character but not limitative, for there 
could be recourse to another existing normativity in favor of the adequate  
execution of the Clinical Study. 

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1. 
DEFINITIONS 
 
 
 
Physical Activity: the motor acts performed by persons, as part of their daily 
and/or programmed (exercise) activities. 
 
Anorexia: no food ingestion. 
 
Apolipoproteins: proteins of the lipoprotein surface that, besides providing 
stability to the lipid particles, direct their metabolic destiny. 
 
Rheumatoid Arthritis: chronic inflammatory disease, self-immune and systemic 
of unknown etiology; its main target organ is the synovial membrane. 
 
Arthrosclerosis: is a disease that initially affects the intima of distribution 
arteries, with endothelial damage and inflammation, which is characterized by 
deposits of lipids and proliferation of fibrous tissue, with capacity to obstruct the 
vessel’s lumen either by growth of the plaque or by rupture and thrombosis. It is 
the most frequent complication of the association of Diabetes, Arterial 
Hypertension and Hypercholesterolemia, with an exponential increase when 
associated to smoking. 
 
Audit: A systematic and independent exam of the activities and documents 
related with the study to determine if the evaluated activities were executed and 
the data was registered, analyzed and reported with accuracy in accordance to 
the protocol, standard procedures of operation of the sponsor, Guidelines of Good 
Clinical Practices and the applicable regulatory requirements. 
 
Fasting: the abstinence of caloric ingestion, for a determinate period of time. For 
the determination of lipids it will have to be from 9 to 12 hours. 
 
Cases with known diagnose of dyslipidemia under treatment: the set of 
people with known diagnose of dyslipidemias which course with controlled levels 
of triglycerides, total cholesterol, C-HDL, C-no HDL or C-LDL in response to the 
treatment or continue uncontrolled despite treatment. 
 
Cholesterol: the steroid molecule, formed by four hydro carbonated rings plus an 
aliphatic chain of eight carbon atoms in the C-17 and one OH in the C-3 of the A 
ring. Although from the chemical point of view it is an alcohol, it possesses 
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Cholesterol HDL (C-HDL, High Density Lipoprotein): is the concentration of 
cholesterol contained in the high-density lipoproteins. The HDL participates in the 
reverse transport of cholesterol, that is, from the tissues to the liver for their 
excretion or recycling. They are lipoproteins that contain Apo A-I and float at larger 
densities compared with the lipoproteins that contain the Apo B, due to their high 
protein content. For this they are known as high-density lipoproteins. 
 
Cholesterol LDL (C-LDL, Low Density Lipoprotein): is the concentration of 
cholesterol contained in the low-density lipoproteins; transport cholesterol to the 
tissues, its elevation favors the appearance of arthrosclerosis and therefore, of 
cardiovascular problems. 
 
Cholesterol Not-HDL: is all the cholesterol that isn’t transported by the Cholesterol 
HDL and is potentially atherogenic.  The use of non-HDL cholesterol (C-Non-
HDL) as a tool to evaluate the risk of death by cardiovascular disease. The C-
Non-HDL is defined as the difference between the total cholesterol value and the 
cholesterol of the HDL (C-no-HDL= CT - C-HDL), and comprises the fractions of 
lipoproteins: LDL, IDL, and VLDL, and includes highly atherogenic particles like 
the remnants of VLDL and Lp (a). 
 
Acute renal damage: is a syndrome characterized by the sudden and sustained 
decrease of the glomerular filtrate, the diuresis or both and the consequent 
increase of nitrogenized products in blood. 
 
Diabetes mellitus: is a chronic-degenerative systemic disease of a 
heterogeneous character, with variable degrees of hereditary predisposition and 
with the participation of diverse ambient factors, and which is characterized by 
chronic hypoglycemia due to the deficiency in the production or action of insulin, 
which affects the intermediate metabolism of carbohydrates, proteins and fats. 
 
Diet: the set of foods that are consumed each day. 
 
Healthy diet: the set of natural and prepared foods which are consumed each 
day with balance, variety and sufficiency in calories, proteins, carbohydrates, fats, 
vitamins, fiber and micronutrients, as well as the ingestion of water, to have an 
adequate corporal nutrition which translates in and adequate nutritional state for 
the age and gender. 
 
Dyslipidemias: the alteration of the normal concentration of lipids in blood. 

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Source documents: Documents, data and original registries (for example, 
hospital registries, clinical sheets, laboratory notes, memoranda, diaries of the 
subjects or verification lists of evaluation, registries of delivery from pharmacy, 
data registered by automated instruments, certified copies or transcriptions after 
being verified as exact copies, micro-files, photographic negatives, magnetic 
means or microfilm, x-rays, expedients of the subjects and registries preserved 
in the pharmacy, in the laboratories  and in the medical-technical departments 
involved in the clinical study). 
 
Education for Health: the process of teaching-learning of attitudes in the general 
population that allows, through the exchange and analysis of the information, to 
develop abilities and change attitudes with the purpose of inducing behaviors to 
avoid overweight, obesity, sedentary lifestyle, stress, smoking and the excessive 
consumption of alcohol, as well as the factors of lifestyle which propitiate the 
development of dyslipidemias and which are acquired with an attitude contrary to 
the observance of individual, familiar and collective health. 
 
 
Peripheral arterial disease: 
is one of the clinical manifestations of 
arthrosclerosis characterized by stenosis or obstruction of the arterial lumen due 
to plaques of atheroma originated in the intima which affects the abdominal aorta 
and its terminal branches. 
 
Premature 
cardiovascular 
disease: 
the 
onset 
of 
manifestations 
of 
cardiovascular disease in men under 55 or women under 65. 
 
Statins: pharmacologic group utilized as a lipid-lowering agent with effect over the 
inhibition of the enzyme HMG-CoA reductase. 
 
Healthy lifestyles: refers to behaviors that diminish the risk of contracting 
disease such as: correct feeding, adequate control and treatment of tensions and 
negative emotions: good exercise, sleep and distraction regime; the control and 
avoidance in the abuse of substances such as caffeine, nicotine and alcohol; a 
correct distribution and use of time. 
 
Clinical file: the set of written, graphic and imaging documents or of any other 
nature, in which the health personnel shall make the registries, annotations and 
certifications correspondent to their intervention, with arrangement adherence to 
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Cerebral vascular event: presence of neurologic symptoms which have an 
abrupt onset such as headache, nausea, vomit, deterioration of vigil, aphasia or 
hemiparesis, and which are corroborated with an image study. 
 
Risk factor: the attribute or exposition of a person, population or environment, 
that are associated to the probability of the occurrence of an event. 
 
Fibrates: pharmacologic group for the treatment of dyslipidemias with action on 
the receptor of peroxisomal proliferators. 
 
Tumor necrosis factor: is a protein of the group of cytokines released by the 
cells of the immune system that intervene in the inflammation and the apoptosis. 
 
Unsaturated fats: these are found in foods of vegetable origin like vegetable oils 
(olive, sunflower or corn oil). Also in dry fruits (nuts, almonds, etc.) and in seeds 
(sesame, sunflower, flax). These are liquid fats at ambient temperature. According 
to the number of double links they present, they are classified as: 
 
- Monounsaturated (one sole double link): the most representative is oleic acid 
present mainly in olive oil and other fats of vegetable origin like seed oils 
(sunflower seed oil, colza oil). They are also found in nuts, almonds and 
avocados. The substitution of saturated fats for unsaturated fats in the diet 
contributes to maintaining normal levels of blood cholesterol. Oleic acid is an 
unsaturated fat. 
 
- Polyunsaturated (two or more double links): These are essential for our 
organism because they can’t be synthetized and must be supplied through the daily 
diet to regulate metabolic processes of the cardiovascular, immune and pulmonary 
systems, among others. They are present in foods of vegetable and animal origin. 
There exist two families within these: Omega 3 and Omega 6. 
 
Saturated fats: these are found in foods of animal origin like meats, sausages, milk 
and derivatives (cheese, ice-creams). These are fats that solidify at ambient 
temperature. They can also be found in oils of vegetable origin like coconut or palm 
oils (which are consumed through industrial pastries, salty aperitifs and transformed 
products). 
 
Trans fats: these are unsaturated fats that are formed in the industrial processing 
of some foods known as hydrogenation, during which they change their 
configuration and pass from being unsaturated fats to saturated fats, becoming 
solid fats. They are found in fried foods, snacks, baked products (cakes, rolls, 
cookies) and prepared foods. The consumption of Trans fat  

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acids causes in the organism an effect more negative than saturated fats since it 
increases the levels of C-LDL and triglycerides and also reduces the C-HDL in 
blood. 
 
Family hypercholesterolemia: is the dyslipidemia associated to a larger risk of 
arthrosclerosis, is the entity in which the main abnormality is the elevation of C-
LDL as consequence of the mutations of the gen of the receptor LDL, of the apoB 
or of the proprotein gen convertase subtilisin  kexin  9  (PcsK9). There are two 
forms, the heterozygotes and the homozygotes; their transmission may be 
dominant or recessive autosomal. It is characterized for having levels of total 
cholesterol greater than 400mg/dL. The corneal arch and the sinewy xanthomas 
are characteristic of this pathology. 
 
Polygenic Hypercholesterolemia: is the entity in which the elevations of C-LDL 
are superior to 160 mg/dL and <190mg/dL and characteristically xanthomas aren’t 
present. Diagnose is established when at least one first-degree relative has C-
LDL above 160 mg/dL. 
 
Hyperglycemia: elevation of glucose above 100mg/dl. 
 
Combined Family Hyperlipidemia: is the entity which manifests with different 
phenotypes, with constant fluctuations in the lipid profile, absence of xanthomas, 
Apo B > percentile 90 demographic, family or personal history of premature 
ischemic cardiopathy, have a relative with hypertriglyceridemia, a relative with 
hypercholesterolemia and a relative with both dyslipidemias, association with 
Metabolic Syndrome. 
 
Systemic arterial hypertension: is a syndrome of multiple etiologies 
characterized by the persistent elevation of arterial pressure figures ≥ 140/90 ml/Hg. 
 
Endogenous familial hypertriglyceridemia: the entity in which there is 
triglyceride values greater than 200 mg/dL, with C-LDL normal or low. The levels 
of C-HDL are diminished and normal levels of Apo B, coexist in patients with type 
2 Diabetes. 
 
Hypertriglyceridemia: abnormal elevation of triglycerides in blood, greater than 
150mg/dl. 
 
Hypoalphalipoproteinemia: abnormal descent of type HDL cholesterol in blood 
less than 40mg/dl. 

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Lipid-lowering agents: the medicines that reduce the lipid levels in blood. 
 
Hypothyroidism: common endocrine disease, caused by and inadequate action 
of thyroid hormones, mainly by diminishment in their synthesis and secretion and 
occasionally by peripheral resistance to thyroid hormones. 
 
Corporal mass index (CMI): is the corporal weight divided by the height squared 
(Kg/m2). 
 
Chronic renal failure: diminishment in renal function, expressed by a glomerular 
rate of filtration less than 60 ml/min/1.73m2 or as the presence of renal damage 
(histologic alterations, albuminuria, proteinuria, alterations of the urinary sediment 
or alterations in image tests) in a persistent manner during at least 3 months. 
 
Insulin deficiency: deficiency in the secretion of insulin by the pancreas causes 
hyperglycemia. 
 
Investigator: A person responsible for the conduction of the clinical study at the 
site where the study is done. If the study is conducted by a group of individuals 
the investigator is the leader responsible for the group and shall be called main 
investigator. 
 
Systemic Lupus Erythematous: a disease that is self-immune, inflammatory, 
chronic and of unknown etiology, which is characterized by the presence of 
multiple antibodies and a wide spectrum of clinical manifestations in different 
organs and systems, among which the skin, joints, kidney, lung, central nervous 
system, serous membranes and other systems stand out. 
 
Myalgia: presence of muscular pain. 
Myoglobinuria: presence of myoglobin in urine. 
Myonecrosis: death of muscular tissue. 
Myositis: presence of muscular inflammation. 
Monitoring: The act of supervising the process of a clinical study and assuring 
that it is conducted, registered and reported according to the protocol, Standard 
Operative Procedures, Guidelines of Good Clinical Practices and the applicable 
regulatory requirements. 

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Obesity: CMI equal to or greater than 30 in adults. 
 
Sponsor: An individual, company, institution or organization responsible of 
initiating/managing/controlling and/or financing a clinical study. 
 
Placebo: inert substance from a pharmacologic point of view. 
 
Person at risk: a person with one or several factors that could develop a 
dyslipidemia. 
 
Corporal weight: according to the Corporal Mass Index (Kg/m2), to the next 
classification: Corporal mass index >18.5 and <24.9 normal weight, Corporal 
mass index > 25 and < 29.9 overweight, corporal mass index > 30 obesity. 
 
Pre-diabetes: a person with an intermediate metabolic state between normal 
state and Diabetes. The term pre-diabetes is applied in cases of Abnormal Fasting 
Glucose (AFG), as well as in cases of Intolerance to Glucose (ITG). 
 
Primary prevention: set of activities done by the health personnel, by the 
community or by governments to prevent or delay the onset of a determinate 
condition. 
 
Secondary prevention: activity that tries to delay the recurrence or death by a 
disease. 
 
Cardiovascular disease: term that refers to al vascular diseases caused by 
arthrosclerosis. 
 
First attention level: the attention units that constitute the entry to health 
services; they are primordially oriented to the promotion of health, prevention, 
detection, diagnose, early treatment and control of most prevalent diseases. 
 
Reactive protein C: circulating plasmatic protein that increases its levels in 
response to inflammation. 
 
Psoriasis: chronic condition that is inflammatory, systemic, with a genetic etiology 
and that may be modified by environmental factors. It is characterized by the 
presence of scales, erythematous patches, papules and plaques that are 
frequently itchy and often manifest in bone projections. 

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Chylomicrons: Lipoprotein isolated through ultracentrifugation of plasma, 
characterized by low density and large diameter. 
 
Rhabdomyolysis: disorder characterized by the de-structuring and posterior 
necrosis of the skeletal muscle. 
 
Resistance to insulin: is the decrease of the action of this hormone in muscular, 
hepatic and adipose tissues. 
 
Cardiovascular risk: probability of presenting a death by cardiovascular event 
within 10 years. 
 
Second level attention: the units that addresses health problems that due to their 
complexity can’t be solved in the first attention level. 
 
Cushing syndrome: Hormonal disorder caused by excess of exposure to 
cortisol. 
 
Anti-phospholipid antibodies syndrome: pro-thrombotic, self-immune and 
systemic disease characterized by the association of venous and/or arterial 
thrombosis, recurrent fetal loss, often accompanied by mild to moderate 
thrombocytopenia and elevated titles of anti-phospholipid antibodies. 
 
Metabolic syndrome: the set of biochemical, physiological and anthropometric 
abnormalities, that occur simultaneously and may produce or be linked to the 
resistance to insulin and/or overweight or central obesity, that increase the risk of 
developing Diabetes mellitus, cardiovascular disease or both. Its fundamental 
components are: abdominal obesity, pre-Diabetes or type 2 Diabetes mellitus, 
arterial 
hypertension 
or 
frontier 
arterial 
pressure, 
dyslipidemia 
(hypertriglyceridemia and/or low HDL). 
 
Nephritic syndrome: common endocrine disease, caused by inadequate action 
of the thyroid hormones, mainly by decrease in their synthesis and secretion and 
occasionally by peripheral resistance to thyroid hormones. 
 
Smoking: is the addiction to tobacco or other products of tobacco. 
 
Triglycerides: are the molecules of glycerol, esterified by three fatty acids. It is 
the main form of energy storage in the organism. Also called triacylglycerols. 

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Ubiquinone: also called Coenzyme Q10; is a 1,4-benzoquinona, where the Q 
refers to the chemical group quinone, and the 10 refers to the number of subunits 
of the chemical product isoprenyl in its tail. 
 
Tendinous xanthomas: these are the subcutaneous lipid deposits, in form of 
protuberances, located mainly in the Achilles’ tendon or in the tendons of the 
extensor muscles of the hands, associated to the elevation of serum cholesterol. 
 
Tuberous xanthomas:  are the subcutaneous lipid deposits located on knees 
and elbows, associated to dysbetalipoproteinemia. 
 
 
 
 
2. 
SYMBOLS AND ABBREVIATIONS 
 
 
 
ALT: Alanine aminotransferase 
APO B: Apolipoprotein B  
APO CII: Apolipoprotein CII 
AST: Aspartate aminotransferase 
 
AUC: Area Under the Curve 
 
C-HDL: Cholesterol of high density lipoproteins 
 C-LDL: Cholesterol of low density lipoproteins 
 C-No-HDL: Cholesterol no HDL 
CPK: Creatinine phosphokinase 
 
CT: Cholesterol total 
 
ENSANUT: Health and Nutrition National Survey 
 
g: Grams 
 
HMG-CoA: Hydroxymethyl-glutaryl-coenzyme A 
 
IL-6: Interleukin 6 
 
IL-1: Interleukin 1 

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CMI: Corporal Mass Index 
CH: Carbohydrates 
 Kcal: Kilocalorie 
Kg/m2: Kilograms per meters (height) squared 
 
LDL: Low-density lipoproteins 
 
MCP-1: Monocyte 1 Chemoattractive lipoproteins  
 
mg: Milligram 
 
mg/day: Milligrams per day 
mg/dl: Milligrams per deciliter 
mg/kg: Milligrams per kilogram 
mmHg: Millimeters of mercury 
NCEP: National Cholesterol Education Program 
 
MON: Mexican Official Norm 
 
PCSK9: Proprotein convertase subtilisin/kexin type 9 
PPAR: Peroxisomal proliferator receptors 
 TG: Triglycerides 
TNF: -Tumor Necrosis Factor 
 
VLDL: Very Low Density Lipoproteins 
 
%: Percentage 
 
>: Grater than 
 
<: Less than 
 
>: Greater than or equal to 
 
<: Less than or equal to 
 
°C: Degrees Centigrade 

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3. 
THEORETICAL FRAMEWORK 
 
 
     Lipids 
 
 
Lipids are a group of immediate principles, very heterogeneous from the 
molecular point of view, but they maintain a common characteristic: they are 
soluble in inorganic solvents and insoluble in an aqueous medium. They 
participate in diverse organic functions as structures in the cellular wall, energetic 
deposits, structure of hormones and cellular signaling. According to their 
composition they are classified in simple lipids and complex lipids. The simple 
lipids contain only carbon, hydrogen and oxygen; in this group are included fatty 
acids, acylglycerols, waxes and cholesterol. The complex lipids contain carbon, 
hydrogen, oxygen and besides phosphorus and/or nitrogen and/or sulphur; some 
examples are phospholipids and sphingolipids. [8] 
 
Within the lipids of interest in this study are found the Total Cholesterol, high 
density Cholesterol (HDL), low density Cholesterol (LDL) and triglycerides. 
 
Cholesterol has a molecular structure derived from cyclopentone cholesterol 
Cyclopentanoperhydrophenanthrene (sterane), with polar head (hydroxyl group) 
and a-polar tail. It is found present in the cells of vertebrate animals, is an essential 
component of plasmatic membranes and precursor of lipoproteins, biliary salts, 
vitamin D and hormones (sexual and corticosteroids). Because of their 
hydrophobic character, in blood it is transported by lipoproteins and, at cellular 
level, can be found forming part of the membranes or in the cytoplasm, previous 
esterification with a fatty acid, for the excess of free cholesterol is toxic for the cell. 
The accumulation of intracellular esterified cholesterol is harmful to man, favoring 
the development of arteriosclerotic lesions [9] 
 
More than half of cholesterol is obtained from the diet, known as exogenous 
cholesterol; the rest is synthetized inside the organism and is known as 
endogenous cholesterol. It isn’t possible to completely metabolize cholesterol and 
since its accumulation is deleterious, it isn’t surprising that its homeostasis is 
subject to complex and fine mechanisms of regulation. 
 
From Cholesterol, proteins are derived that have the name lipoproteins, are 
subcellular spherical structures evolutionarily developed for the transport of lipids, 
insoluble in the bloodstream. They are composed by a polar cover and a nucleus; 
the polar cover contains apolipoproteins, phospholipids and free 
 
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cholesterol; in the nucleus are found the hydrophobic elements (esters of 
cholesterol and triglycerides). Through ultracentrifugation 4 major classes of 
plasmatic lipoproteins have been isolated that vary in size, density and protein 
and lipid composition. These are chylomicrons (CM), very low density lipoproteins 
(VLDL), low density lipoproteins (LDL) and high density lipoproteins (HDL). [10, 11] 
The VLDL are lipoproteins rich in triglycerides (TG) and cholesterol, are in charge 
of endogenous transport of lipids from the place of hepatic synthesis to the 
peripheral tissues. They are considered atherogenic particles, especially those of 
smaller size. The C-LDL lipoproteins are the final product of the metabolism of the 
VLDL, and are considered highly atherogenic. [10] 
 
The C-HDL lipoproteins originate in the precursors which come from the liver, 
intestine and the catabolism of other lipoproteins. They are the protagonists of the 
reverse transport of cholesterol from the peripheral tissues to the liver for their 
biliary elimination. Therefore, they are considered as anti-atherogenic particles. 
[12] 
 
The apolipoproteins are proteins of the lipoprotein surface which besides 
providing stability to the lipid particles, aid in their metabolic destiny. Denominated 
with letters of the alphabet, the most important are A, B, C and E. The 
apolipoproteins A type I and type II (Apo AI and Apo AII), are the most abundant 
in plasma, are synthetized in the liver and are structural components of the HDL, 
although they are also found in the chylomicrons. The apolipoproteins B 
correspond to types 48 and 100 (Apo B48 y Apo B100). The first one is from 
intestinal synthesis and exclusive of chylomicrons, the second one is from hepatic 
synthesis and of VLDL and LDL. Besides, the Apo B100 is ligand of the receptor 
of LDL (LDLR). the apolipoproteins type I, type II and type III (Apo CI, CII and CIII), 
are present in all particles and are fundamental in the hydrolysis of its 
triglycerides; finally, the apolipoprotein E is of pervasive synthesis (liver, 
astrocytes, macrophages, etc.), in not very abundant but is present in all 
lipoproteins, inclusively in the LDL. [10] 
 
 
 
 
     Dyslipidemias 
 
 
The abnormal metabolism of lipids (dyslipidemia) plays a crucial role in the onset 
of cardiovascular disease due to the arthrosclerosis and thrombosis of the wall of 
arterial vessels. The metabolism of lipids may be altered in different paths, favoring 
changes in the concentration or function of the plasmatic lipoproteins. When other 
factors of cardiovascular risk are added to this such as 

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hypertension, smoking diabetes, metabolic syndrome and chronic inflammation, 
it predisposes the subject to an early start of atherosclerosis. The dyslipidemia is 
usually asymptomatic; the majority of patients are identified only during a routine 
revision or following control for having presented a cardiovascular event. [13] 
 
The common characteristic of dyslipidemias is having abnormal concentrations of 
serum lipoproteins. Typically, elevated plasmatic concentrations of triglycerides 
(TG), total cholesterol (TC) are observed, also low levels of lipoproteins derived 
from high density cholesterol (C-HDL) and prevalence of lipoproteins derived from 
low density cholesterol (C-LDL). The alteration of the serum profile of lipids in their 
different lipoprotein fractions leads to an increase in the risk of cardiovascular 
disease; this being the main cause of mortality secondary to dyslipidemias. 
Besides, dyslipidemias are the most frequent modifiable cardiovascular risk 
factor. [2] 
 
The lipoprotein alteration associated to cardiovascular risk is attributed to C-LDL, 
lipoprotein that has replaced total cholesterol as primary measurement for the risk 
of atherogenic lipoproteins and remains as the most used measurement as 
objective of the treatment. [14,15] It has been identified that not only the levels of C-
LDL increase the Cardiovascular Risk, but that also proteins rich in TG and 
lipoprotein remnant are atherogenic;  known as Cholesterol No HDL (C-No HDL). 
[4, 6] 
 
Notwithstanding the aforementioned associations, it is recommendable to 
measure other lipids in blood for an integral diagnose. These lipids include CT, 
TG and C-HDL.[14] 
 
There exist detailed descriptions which date back to 1993-1994 in the National 
Survey of Chronic Diseases where a sample amount of 15,607 adults was 
available, between 20 and 69 years of age, residents in 417 urban areas of 
Mexico. Reference values were obtained of TC 182.7 + 40mg/dl, LDL 116.6+ 
36mg/dl, HDL 38.3+ 9.5mg/dl and TG 213.4 +158mg/dl, with a larger 
prevalence of hypertriglyceridemia (42.3%) and hypoalphalipoproteinemia (61%). 
The TC was found high in 27.1%. [17] There are other precedents that speak of the 
prevalence of dyslipidemias located among the Mexican population, in the study 
CARMELA where Mexico was included, showing a prevalence of little more than 
50% in persons over 20 years of age. [18] 
 
The most frequent dyslipidemias in Mexicans are the decrease of C-HDL and 
hypertriglyceridemia; [19] finding figures of up to 58.9% of prevalence for 
hypoalphalipoproteinemia, which place it as the most predominant dyslipidemia.[20] 

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In turn, dyslipidemias are classified as primary and secondary; the first group is 
constituted by disorders characterized by defects in the enzymes, receptors or 
metabolites that participate in the synthesis and elimination of the lipoproteins; the 
most frequent is familial hypercholesterolemia, followed by combined familial 
hyperlipidemia, dysbetalipoproteinemia and familial hypertriglyceridemia.[13] The 
second group includes the alterations in the lipids, consequence of diseases and 
use of some drugs. [19,21] 
 
Hereunder are more comments with respect to the primary and secondary factors. 
 
A. Primary 
 
 
The primary errors of the lipid metabolism include: 
 
 
a) Familial Endogenous Hypertriglyceridemia. 
b) Combined Familial Hyperlipemia (CFH). 
c) Familial Hypercholesterolemia (FH). 
i. 
Classic Familial Hypercholesterolemia (FH1). 
ii. 
Familial Defective Apo B (FDB). 
iii. 
Mutations in the PCSK9 gen (Protein Convertase Subtilisin/Kexin 
type 9; FH3). 
iv. 
Deficiency of cholesterol 7-a-hydroxylase (CYP7A1). 
v. 
Recessive Autosomal Hypercholesterolemia (RAH). 
 
 
a) Endogenous Familial Hypertriglyceridemia. Dominant autosomal 
disorder of variable penetration; some sporadic cases have been 
described. The defect hasn’t been defined yet and it is thought that it 
could be the presence of common polymorphic variants located in 
introns of the gene if lipase lipoprotein (LPL), in the promoter of Apo CIII 
and/or the alleles 2 and 4 of the gene Apo E; the presence of these 
variants may be expressed phenotypically with hypertriglyceridemia 
when some precipitating factors coexist such as obesity, alcoholism, fat 
diet, smoking, etc. The interaction gene/environment is therefore very 
important. A prevalence of 1% has been estimated in the general 
population and a 5% among the survivors of an acute heart attack. It is 
considered that the metabolic disorder is due to the increase of the 
synthesis of VLDL, associated or not to defective lipolysis and some 
authors postulate that the subjacent pathogenic element is the insulin-
resistance. It usually expresses after puberty and courses with 
hypertriglyceridemia between 200 and 700 mg/dl (phenotype IV), at 
expense of VLDL of a larger size but not increased in number, so the 
levels of plasmatic Apo B are located within normality. On the other 
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denominated “phenotype B” (small and dense LDL particles). In 
homozygotes for the mutation c.433C>T of the gene Apo AV a 
phenotype V may appear with chylomicronemia in fasting and levels of 
plasmatic triglycerides superior to 1000 mg/dl. The impact of this disorder 
over the risk of cardiovascular disease among those who suffer from it 
is controversial and seems conditioned by the levels of C-HDL and/or the 
existence of the phenotype B. Some variants of Apo E (E3/3, E4/3 or 
E4/2), polymorphisms in Apo CIII (Sstl, S2, -455T>C, -482C>T, 
homozygotes -455C) and variants of Apo AV (a5*2/A5*3) confer a larger 
risk. There are values of triglycerides greater than 200mg/dl, C-LDL 
normal or low, C-HDL diminished and coexists in patient of type 2 
Diabetes. [2, L1] 
 
 
b) Combined Familial Hyperlipemia (CFH): the study of extensive 
genealogic trees of affected families has led to consider it as a dominant 
autosomal hereditary disorder with an elevated penetration and 
heterogeneous and unknown genetic bases, to the point of questioning 
if it is a sole entity. In this sense, the CFH has been related with some 
polymorphisms of the gene of LPL. The presence of these 
polymorphisms leads to a reduction in the activity among 30-50% of the 
cases. Also, CFH has been related with polymorphisms in the gene Apo 
CIII. It has prevalence in the population estimated at 1-2%. The 
pathogenesis is complex and isn’t totally clear either, but its known that 
there is a hyper flow of free fatty acids to the liver, consequence of bad 
digestion in the adipose tissue where a low activity of the acylation 
stimulating proteins (ASP Acyl-Stimulating Protein) has been shown, 
and of the lipase sensitive to hormones (HSL Hormone Sensitive 
Lipase). This defect causes an increase in hepatic synthesis of Apo B 
and a consequent increase in the production of VLDL particles that are 
of a smaller size than those present in healthy subjects or with Familial 
Hypertriglyceridemia. In their metabolism these particles produce the 
highly atherogenic small and dense LDLs (phenotype B). A defective 
lipolysis may or may not be associated. The affected individuals present 
dyslipidemia starting from puberty, being characteristic the inter-
individual  phenotypic variability among members of the same family and 
inter-individual, throughout life, , as a response to diet modifications, in 
physical activity or weight, and to exogenous factors (alcohol and/or 
drugs). Isolated hypercholesterolemia may appear at the expense of 
LDL or phenotype IIA (less frequent), hypertriglyceridemia (200-500 
mg/dl) by increase of VLDL particles 
 
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(phenotype IV) or mixed hyperlipemia due to increase in both C-LDL and 
VLDL (phenotype IIb), characteristic of the disorder. It is frequent that 
there are low levels of C-HDL and elevated concentrations of Apo B, 
above the demographic 90 percentile. [2, L1] 
 
 
c) Familial Hypercholesterolemia (FH): We understand as monogenic 
familial hypercholesterolemia (FH) a set of disorders of lipid metabolism 
of a hereditary character, characterized by hypercholesterolemia at 
expense of C-LDL, since an early age in life and an elevated incidence of 
precocious atherosclerotic cardiovascular disease. To date, 5 hereditary 
disorders have been identified as cause of familial hypercholesterolemia, 
the most frequent of them in Mexicans is the classic familial 
hypercholesterolemia (FH1). [17] Although in other populations it has been 
observed that the greater prevalence courses with combined familial 
hypercholesterolemia 
(disorder 
of 
mixed 
hyperlipidemia 
and 
hypertriglyceridemia). [17] In prevalence range it is followed by Apo B 
defective familial (BDF or FH2), being the most rare that caused by 
mutations of the gene PCSK9 (Proprotein Convertase Subitilisin/Kexin 
type 9; HF3), the deficiency of cholesterol 7 to hydroxylase (CYP7A1) 
or the Recessive Autosomal Hypercholesterolemia (RAH). The elevation 
of C-LDL is a consequence of mutations of the gene of receptor LDL, of 
apoB or of the gene PCSK9. [2, 17, 22, L1 ] 
 
 
i. 
Classic 
Familial 
Hypercholesterolemia 
(FH1): 
dominant 
autosomal hereditary disorder due to mutations in the gene that 
codifies the receptor of low density lipoproteins (LDLR), located in 
chromosome 19p13.2, where normally 18 exons codify the 5 
dominions of said protein. The defect may affect the synthesis of the 
receptor, its transport to the cellular surface, the union to 
lipoproteins, internalization or even its recycling, conditioning the 
defective elimination of C-LDL particles in blood. [23] This causes 
levels of TC larger than 300mg/dl, C-LDL larger than 190mg/dl and 
sinewy xanthomas. [17] 
 
 
To date, more than 1000 mutations have been described globally. 
Therefore its distribution is universal, with a prevalence of 1/500 
subjects for the heterozygote form and 1/1, 000,000 for the 
homozygote. The characteristic and pathognomonic clinical trait, 
although not so frequent is the presence of sinewy and cutaneous  
 
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xanthomas. Furthermore, xanthelasmas and corneal arch may 
appear, although they aren’t so specific. Patients with FH have C-
LDL values at double or triple of what’s observed in the general 
population, oscillating between 190 and 400 mg/dl; the triglycerides 
generally show normal values although in some cases they might be 
elevated. The certainty diagnose approximates the binomial genetic 
defect-functional alteration, that is, known or new mutation and 
hypercholesterolemia. 
There 
is 
no 
unanimity 
among 
the 
international scientific community to determine which should be the 
unequivocal clinical criteria for the diagnose of FH, although the 
most widespread are the criteria of the Dutch MEDPED, having 
estimated for a score of at least 8 points (certainty diagnose), a 
sensitivity of 41% and a specificity of 88%. [24] Neither is the cutting 
point of greater sensitivity known to use the determination of C-LDL 
as the exclusive diagnostic tool, for although its values are greater 
in subjects with FH than in the general population, the interval 
overlaps between both populations, especially in young subjects 
where the sieving of cases of FH would have a greater benefit. The 
natural history of FH is intimately linked to the development of 
cardiovascular disease for the main cause of death in these patients 
is ischemic cardiopathy; 50% of women and 85% of untreated men 
will suffer a coronary event before age 65 (10% of the cases of 
ischemic cardiopathy in some countries) therefore, the value and 
extension of the remaining factors of classic cardiovascular risk isn’t 
comparable to that of the general population. [25] 
 
 
Classic familial hypercholesterolemia is catalogued as the 
hyperlipidemia that has the greatest association with Cardiovascular 
Risk. [19] 
 
 
ii. 
Familial Defective Apo (FDB): Dominant autosomal defect. Four 
simple polymorphisms of nucleotides have been recognized (SNPs 
single nucleotide polymorphisms), in the gene ApoB located in the 
chromosome 2, associated to functional defects. This genetic 
defect of the Caucasian race dates back 6000-7000 years and has 
been linked to the existence of Celtic villages, which at the time 
dwelled in central Europe. In this line it hasn’t been possible to 
identify it in Japanese or Israelis. In Europe it implies from 2 to 5% 
of primary hypercholesterolemias with prevalence in 
 
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the variable general population that oscillates between 1/500-700, 
clearly larger in Switzerland (1/210). In Spain, a prevalence of 2.8 
cases /100,000 habitants had been estimated after identifying the 
first family. As a result of the publishing of the first data of the 
Spanish Registry of Familial Hypercholesterolemia, a prevalence of 
1.4% 
was 
appreciated 
among 
subjects 
with 
primary 
hypercholesterolemia (13/913). [26] The defect provokes a reduction 
in the elimination of circulating C-LDL particles of 20- 30%. 
Nonetheless there is a regulation to the increase of reverse transport 
of cholesterol and of the activity of the C-LDL receptor that 
determines an increase in hepatic capture of VLDL remnants and a 
lesser conversion of these to C-LDL. Although in the presence of an 
adequate environmental and genetic substrate it may result in a 
clinical syndrome that is indistinguishable from FH, it often presents 
with a more favorable phenotype: a lesser prevalence of xanthomas 
and corneal arch, inferior total cholesterol and LDL levels and 
greater levels of HDL, with a more delayed cardiovascular disease. 
[27] 
 
 
iii. 
Mutation 
in 
the 
gene 
PCSK9 
(Protein 
Convertase 
Subtilisin/Kexin type 9; HF3): PCSK9 is a serinprotease of hepatic 
and intestinal location, belonging to the secreting subtilase  families 
that intervene in the homeostasis of cholesterol, favoring the 
catabolism of LDLR and preventing their recycling in the cellular 
surface. Therefore, its activity diminishes the amount of LDLR and 
increases the plasmatic concentrations of C-LDL. The gene that 
codifies the protein is localized in chromosome 1 (1p32.3) and 
mutations have been describe in it with opposing functional 
response, that is, gain or loss of function. [28] Since the year 2003 
the mutations with gain in function have been related with the 
phenotype of FH implying 2-3% of patients clinically diagnosed with 
FH without mutations detected in the genes LDLR or Apo B. The 
levels of C-LDL are somewhat lower than in FH1although there is 
still a high cardiovascular risk that can’t be controlled, even with the 
best response to treatment.[29] 
 
 
iv. 
Deficiency 
of 
cholesterol 
7--hydroxylase 
(CYP7A1): 
Cholesterol 7--hydroxylase is an enzyme that belongs to the 
superfamily of cytochrome P450 that catalyzes the first step in the 
hepatic synthesis of biliary acids. Polymorphisms in the gene that 
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of FH following a same pattern of dominant autosomal heredity. In 
these patients the levels of C-LDL are somewhat lower than in classic 
FH and there is often Hypertriglyceridemia. The disorder presents 
predisposition for atherosclerotic cardiovascular disease and 
cholelithiasis. The poor response to treatment with statins is 
characteristic. [27] 
 
 
v. 
Recessive Autosomal Hypercholesterolemia (RAH): is very 
exceptional, since there exist about 50 described cases. It follows a 
pattern of recessive autosomal heredity, being characteristic in the 
progenitors the consanguinity and the absence of lipid alterations. 
The defect resides in mutations of the gene LDLRAP1 (locus 1p35) 
that codifies an adaptor protein that is necessary for the internalization 
and posterior recycling of the LDLRs. Mutations with a loss of function 
provoke a diminishment of LDLR and thus, an increase in plasmatic 
concentrations of total cholesterol, C-LDL and even triglycerides 
(VLDL and remnants are eliminated with difficulty). Precocious 
cardiovascular disease and a good response to statins are 
characteristic. [30] 
 
 
B. Secondary 
 
It may appear isolated or associated to a primary dyslipidemia. In a study 
formed by a cohort of 824 patients referred for dyslipidemia evaluation, it 
was found that  28% had one or more potential causes of dyslipidemia; 
the most common causes were alcohol consumption (10%) and non-
controlled diabetes mellitus (8%).[31] 
 
a) Poorly-controlled type 2 Diabetes mellitus: may course with 
hypertriglyceridemia due to an increase in the synthesis of VLDL and/or 
decrease of its catabolism due to a lesser activity of the LPL. A 
dysbetalipoproteinemia may also be triggered in genetically predisposed 
subjects (Apo E2/E2) by the accumulation of intermediate density 
lipoproteinemia (Intermediate Low Density Lipoproteins, IDL). In turn, a 
relation with the diminishment of C-HDL is observed. [32, L3] 
 
 
b) Obesity: is related with the hyper production of VLDL and consequently 
of C-LDL. Hypertriglyceridemia or mixed dyslipidemia may also appear. 
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c) Anorexia: on occasions hypercholesterolemia is present. [2, L1] 
 
 
d) Hypothyroidism: there exists an association in presenting elevations in 
total cholesterol with the presence of hypothyroidism in  a 56%; [17] as a 
consequence of the decrease in hepatic activity of the LDLR an increase 
of C-LDL is produced (phenotype IIa). A phenotype IIb may also appear 
due to an accumulation of VLDL. On individuals with isoform Apo E2/2 
the existence of hypothyroidism triggers a dysbetalipoproteinemia. 
Substitute hormonal treatment corrects the associated lipid alterations; 
otherwise, a subjacent primary dyslipidemia may be suspect. [2, L1] 
 
e) Cushing Syndrome: it may produce hypertriglyceridemia caused by an 
increase in hepatic synthesis of VLDL (phenotype IV) or a mixed 
hyperlipemia caused by an increase in the conversion of VLDL to C-LDL 
through activation of the lipoprotein lipase. [L1] 
 
 
f) Nephrotic syndrome: Often, an increase of Total Cholesterol, 
triglycerides and apolipoprotein B which guards close relation with 
proteinuria, may be produced. These alterations contribute to the 
development and progression of cardiovascular disease and renal 
damage. [33] 
 
g) Chronic renal failure: is characterized by the elevation of triglycerides 
and the presence of low levels of C-HDL, with fewer changes in stages 1 
and 2 of chronic renal disease, in serum levels of TC and C-LDL. [34] 
 
 
h) Hepatic disorders: Hepatitis with fatty liver may produce mild 
hypertriglyceridemia caused by hypo activity of hepatic lipase (HL) and 
a defect in the elimination of chylomicrons and VLDL. In cholestasis, a 
decrease of the enzyme lecithin cholesterol acyl transferase (LCAT) with 
hypercholesterolemia at the expense of lipoproteins (LDL normal or low) 
is present. Other alterations which are related as secondary causes of 
dyslipidemias are primary biliary cirrhosis, primary sclerosis cholangitis 
(associated to ulcerous colitis in 90%) and the malformation of the biliary 
conducts. [2, L1] 
 
 
i) Pancreatic diseases: acute pancreatitis is found if it results in 
insulinopenia, hyperglycemia and systemic inflammatory response; due 
to the secondary decrease of said hormone, important in the metabolic 
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j) Human Immunodeficiency Virus: patients who have this virus, show 
inferior levels of CT, C-LDL and C-HDL with hypertriglyceridemia. [35] 
 
 
k) Autoimmune diseases: it has been observed that patients who course 
with rheumatoid arthritis, systemic lupus erythematous, Antiphospholipid 
antibodies syndrome and psoriasis have a greater frequency of 
arthrosclerosis 
caused 
by 
combined 
hypercholesterolemia 
and 
cardiovascular morbidity and mortality rates which are elevated with 
respect to the population in general. [36] 
 
 
l) Other diseases: it has been reported that in diseases by deposit 
(Diseases by deposit of glycogen, Gaucher disease, Tay-Sachs juvenile 
disease and Niemann Pick disease) course with variable abnormalities in 
the metabolism of lipids.[2, 37] Besides the previous, alterations of lipids 
are observed in idiopathic Hyperkalemia, Klinefelter Syndrome, Werner 
Syndrome, Kawasaki Disease and intermittent acute Porfiria. [37] 
 
 
m) Recreational drugs: an alteration in the lipid profile is observed in 
specific in the increase of triglycerides in subjects who used alcohol and 
marihuana. [33] 
 
 
n) Hormonal pharmacotherapy that may elevate C-LDL: anabolic 
steroids, glucocorticoids, progestin and danazol. [33] 
 
 
o) Cardiometabolic pharmacotherapy that may elevate 
C-LDL: 
amiodarone, thiazide diuretics, thiazide diuretics, rosiglitazone, fibric 
acid, docosahexaenoic acid. [33] 
 
 
p) Other pharmacotherapies that may elevate C-LDL: Isotretinoin, 
Immunosuppressors (Cyclosporine) and inhibitors of the co-transport of 
sodium-glucose. [33] 
 
 
q) Hormonal pharmacotherapy that increases the TG: oral estrogens, 
oral contraceptives,  glucocorticoids, tamoxifen and raloxifene.[33] 
 
 
r) Cardiometabolic pharmacotherapy that increases TG: Non-selective 
Beta-blockers, thiazide diuretics and sequestrants of biliary acids.[33]

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s) Antineoplastic pharmacotherapy that increases TG: L- asparginase 
and cyclophosphamide. [33] 
 
 
t) Other pharmacotherapies that increase TG: retinoids, inhibitors of 
protease, immunoactive agents, cyclosporine, sirolimus and interferon. 
[33] 
 
 
 
     Cardiovascular risk factors 
 
 
Cardiovascular diseases constitute a serious world public health for being the first 
cause of morbidity-mortality at global level. [1] Besides, this place in the ranking 
has been maintained for more than 10 years. [38] 
 
Cardiovascular risk is defined as the probability of presenting death by 
cardiovascular event within 10 years. [39] 
 
A direct relation is seen with arthrosclerosis, progressive pathologic process, 
related with age and of a marked inflammatory component that affects arteries of 
medium and large caliber, characterized by the deposit of lipoproteins in the sub 
endothelial space which form a plaque of atheroma (basic lesion) and for 
presenting acute complication in the form of cardiovascular accidents (ictus, 
angina, acute heart attack). [40] The pathologic findings reveal that the vascular 
intima is filled with caseous cellular detritus, rich in lipids which form plaques; said 
plaques are surrounded by active macrophages that contain inclusions of lipids 
and surrounding cells of proliferating stroma. [41] 
 
The development of said disease is promoted by several risk factors, 
denominated cardiovascular risk factors; some are modifiable and subject to 
preventive measures, others are not modifiable. [42] Cardiovascular risk is defined 
as the probability of a clinical event (cardiovascular death) which happens to a 
person in a period of 10 years. [42] 
 
 
 
 
3.3.1. Non-modifiable Cardiovascular Risk Factors 
 
 
 
 Age. In men, being older than 45 years, and in women, being older than 
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 Gender, being born male. 
 Race 
 History of premature ischemic cardiopathy, in men younger than 55 and 
in women younger than 65. 
 
 
 
3.3.2. Modifiable Cardiovascular Risk Factors 
 
 
 
 Dyslipidemia 
 Systemic arterial hypertension 
 Diabetes Mellitus 
 Smoking 
 Obesity 
 
 
 
In subjects from 20 to 79 years of age who don’t have clinical history of associated 
cardiovascular disease, international guides suggest as a first step measuring the 
associated cardiovascular risk factors. If they have a minor risk (-7.5%) than 10 
years, the factors have to be evaluated every 4 to 6 years. If the patient is between 
40 and 79 years old estimate the risk to 10 years in a formal manner. [39] 
 
In the approach of the problem, lipids will be addressed as a favorable factor of 
cardiovascular risk among other pertinent considerations. 
 
 
 
 
4. 
APPROACH OF THE PROBLEM 
 
 
 
From the results of great epidemiologic studies (Framingham Heart Study, 
Multiple Risk Factor Intervention Trial (MRFIT), etc.) cardiovascular risk factors 
(smoking, hypercholesterolemia, diabetes mellitus and/or arterial hypertension) 
were identified, and finally the binomial arthrosclerosis-cardiovascular accidents 
is established. Since then, total cholesterol, C- LDL, C-HDL and plasmatic 
triglycerides have been related in a greater or lesser measure with the 
development 
of 
atherosclerotic 
cardiovascular 
disease, 
representing 
approximately a 50% of the demographic attributable risk. [43] Thus, the abnormal 
metabolism of lipids, dyslipidemia, plays a crucial role in the pathogenesis of 
cardiovascular diseases. This may present alterations in different ways, favoring 
changes in the concentration or function of the 

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plasmatic lipoproteins. When other cardiovascular risk factors are added to this, 
such as systemic arterial hypertension, smoking, diabetes, metabolic syndrome 
and chronic inflammation, it predisposes the individual to and early onset of 
arthrosclerosis. [41] 
 
The Mexican population has a high prevalence of deaths in adults caused by 
cardiovascular events. Data from the year 2015 reported mortality associated to 
cardiovascular events in adults by reason of 292 cases for every 100,000 
habitants; combined with the poor forecast in the quality of life of the survivors, 
since some shall require long-term health care and their working capacity will be 
affected in a negative manner. Besides, in our country, it has been possible to 
reduce only 1% of deaths secondary to cardiovascular disease, compared to a 
48% reduction in developed countries. [44] 
 
In our country, the average values of cholesterol present significant differences 
between the different socio-economic levels of the populations. There is a greater 
prevalence of hypercholesterolemia in medium and high socio-economic strata, 
in the population in northern Mexico and a relation with the presentation of this 
alteration at an older age has been seen. According to a study from 2007, the 
global prevalence of hypercholesterolemia in Mexico was 23.6%, lower than that 
reported in the United States of America (39%) and higher than that of Japan; the 
authors emphasized that this dyslipidemia is determined by two factors: genetic 
predisposition and diet. [45] 
 
The National Survey of Health and Nutrition (ENSANUT), gathers data throughout 
Mexico about health and nutrition determinants in each sector of demographic 
health and makes a comparative between genders.  As part of the ENSANUT 
done in 2006, the values of Total Cholesterol in serum were studied in adult 
Mexican population with a sample size of 4,040. A prevalence of 43.6% was found 
for individuals with total cholesterol in serum registries greater than 200mg/dl. [20] 
This same year, the Mexican Institute of Social Security (IMSS) made a study with 
a larger sample than that of ENSANUT (20,062 vs. 4,040); the prevalence found 
was 12.4% for men and 13.8% for women. [46] 
 
In past years, a study was made to know more about the factors of the metabolic 
syndrome for Latin America; Mexico ventured in said study called CARMELA, 
from which arose an analysis attuned to the serum profile found in the included 
population. For this caption 833 men and 889 women were studied (48.4% and 
51.6% respectively) from 25 to 64 years of age. The results 

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gave a media for serum levels of TC of 202.9mg/dl; it was shown that in groups 
of an older age the blood level of TC was greater (188.5mg/dl in the group of  25-
34 years vs. 216.5mg/dl for the group from 55 to 64 years). According to gender, 
the average values of TC were larger for men with 204.3mg/dl, compared to the 
media of 201.6mg/dl found in women. For the C-LDL, type of cholesterol whose 
values are used as cardiovascular risk predictors, the average value was 
118.7mg/dl; with this a correlation was found (just like with the TC) in presenting 
blood levels of C-LDL more elevated in the group of older age (127.2mg/dl vs. 
109mg/dl in the population of 25-34 years). C-HDL, known as the type of 
cholesterol that should present figures greater than 40mg/dl as benefic against 
the cardiovascular risk, showed average values of 49.2mg/dl. The average values 
of triglycerides were found at 183.9mg/dl, having a significant increase in the 
younger age group in comparison with the older age group with 159mg/dl (25-24 
years) to 200.6mg/dl (55 to 64 years). [18] 
 
With respect to the question, which is the most frequent dyslipidemia in the adult 
Mexican population? 2 have been placed as the main ones; the first one is the 
decrease of HDL type cholesterol and the second one is the increase of 
triglycerides. [19] The ENSANUT 2006 found that up to 58.9% of the adult Mexican 
population courses with figures of C-HDL lower than 40mg/dl, entering into the 
group of those who suffer hypoalphalipoproteinemia. [20] There are studies that 
indicate that 24.3% of the Mexican population between 20 to 69 years with 
residence in cities presents TG values of 200mg/dl or more, this being greater 
than that described in other ethnic groups. [45] 
 
There are precedents that mention that even in children high figures of cholesterol 
and triglycerides in blood have been detected, which has been attributed to the 
massive commercialization of processed foods, the changes in alimentary 
regimes and the abuse of foods rich in animal fats. In some cases it has been 
detected that a change of 100 mg of cholesterol in the diet for every 1000 
kilocalories modifies in 12 mg/dl the concentration of cholesterol in blood. [47] 
 
On the other side according to the data reported in the ENSANUT 2012, in Mexico 
there is a prevalence of overweight or obesity of 73% for women and 69.4% for 
men, factor which correlates with the serum levels of lipids. In this year 49.9% of 
the population included referred that tests had been done to determine the levels 
of total cholesterol in serum, where 37% had a normal cholesterol result and 13% 
a result of Total Cholesterol equal to or greater than 200mg/dl. [48] 

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Chart 1. Lipid levels recommended by the Adult 
Treatment Panel III 
LIPIDS 
Levels (mg//dl) 
Category 
< 200 
Desirable 
≥ 240 
High 
< 100 
100 - 129 
Optimal 
 
Desirable 
CHOLESTEROL LDL 
130-159 
High level 
160-189 
High 
≥ 190 
Very high 
CHOLESTEROL HDL 
< 40 
Los 
≥ 60 
High 
 
Demographic studies and studies of intervention with different hypolipemia 
therapies have shown a direct, gradual and continuous relation between plasmatic 
cholesterol and cardiovascular morbidity and mortality. In the MRFIT study, for 
example, it was observed that values of cholesterolemia greater than 200 mg/dl 
increased the risk of coronary accidents in an exponential manner. [49] In turn, in a 
study published in the year 2006 by the magazine Circulation, the risk of morbidity-
mortality by cardiovascular disease secondary to serum levels of total cholesterol, 
was estimated at 38.7% for men 50 years or older if their levels in blood were 
greater than 180mg/dl and elevates to 64.6%, with figures equal to or greater 
than 240mg/dl. In women, the associated risk is less, with figures of 19.4% with 
serum levels of TC greater than 180mg/dl and 48% with figures equal to or greater 
than 240mg/dl. [50] 
 
The consensus of experts of the National Association of Lipids in the United 
States of America in its Chapter III for detection, evaluation and treatment of 
Cholesterol in Adults, estimated the limit levels in concentrations of serum lipids. 
These estimations are found contained in the following chart: [L1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TOTAL 
CHOLESTEROL  
200-239 
High limit 

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< 150 
Desirable 
150 – 199 
High limit 
200 – 499 
High 
≥ 500
Very high 
< 100 -190 
Depending on 
cardiovascular 
risk 
 
 
 
 
 
TRIGLYCERIDES 
 
 
 
 
 
CHOLESTEROL NO 
HDL 
 
 
 
 
Nowadays, it is known that the lipoprotein C-LDL shows a greater correlation with 
the risk of developing a cardiovascular disease associated to dyslipidemias; thus, 
it has replaced TC as the primary measure of risk for atherogenic lipoproteins and 
remains as the most used measurement as objective of treatment. [14, 15] So, it is 
known that the increase of 30mg/dl of C-LDL increases in 30% the risk of 
ischemic cardiopathy. In turn, if C-LDL levels are maintained between 77 and 
116mg/dl, there is a decrease of 40 to 50% in the risk of presenting a heart attack, 
revascularization or a cerebral event of the ischemic type. [51] Besides, an alarming 
data which has been found in countries with high incomes is that the C-LDL with 
serum levels above 147mg/dl is responsible for more than half of cardiovascular 
diseases. [52] For its part, the Framingham study showed that subjects with serum 
levels of C-LDL greater than 160mg/dl, indistinctly between men or women, 
develop 1.5 times more cardiovascular diseases, in comparison with the subjects 
who have levels of C-LDL below 130mg/dl in serum. [15] For the relation between 
levels of C-LDL and atherosclerosis, it has been found that an increase of 39mg/dl 
of C-LDL increases in 40% the risk of presenting a cardiovascular event and 
conversely, reducing 39mg/dl the blood level of C-LDL decreases in 20% the risk 
of the presence of some cardiovascular event. [51] 
 
Due to this relevance the monitoring of the levels of C-LDL and its optimal level, 
is objective to decrease the risk of cardiovascular diseases. The optimal levels in 
the patient have to be handled in a personal capacity according to the 
cardiovascular risk they present. For patients with a very high cardiovascular risk 
the goal is to maintain levels of C-LDL inferior to 70mg/dl, in patients with high 
cardiovascular risk, levels of C-LDL inferior to 100mg/dl are advised and in patients 
with moderate to low risk, the levels must be below 115mg/dl. [4] Then, there are 
2 critical points; on one hand the estimation of the risk of suffering a cardiovascular 
disease, and on the other hand, the estimation of the levels of C- 

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LDL. The identification of both will lead to an adequate primary prevention; 
recommended even in subjects without clinical history of cardiovascular disease, 
the associated cardiovascular risk. For Mexico, there exists a validated multi-
center prospective cohort known as “Globorisk”. Patients from 40 to 84 years 
of age were included, and the follow-up lasted 15 years. The results found a 
prevalence of associated cardiovascular risk of 16% for men and 11% for women. 
In reference to these data, a gauged equation was developed for Mexicans in the 
estimation of cardiovascular risk; besides adding other models of Framingham 
and SCORE. The result established a correlation of cardiovascular risk to 10 for 
Mexicans, where all those who have a probability over 10% of risk of occurrence 
of some cardiovascular event in 10 years, were graded as a very high risk: [53] 
 
 
 
 
 

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So then, it is necessary to estimate through the Globorisk scale modified for 
Mexicans the cardiovascular risk of our population. The second important point is 
the calculation of C-LDL, which if it isn’t obtained from laboratory parameters, may 
use the Friedewald formula, as long as the reported values of triglycerides in blood 
are below 400mg/dl. The Friedewald formula is: C-LDL = CT – (C-HDL + TG/5). 
[53] 
 
According to the cardiovascular risk, it is suggested to evaluate it in patients older 
than 40 years if they present one of the following: History of cardiovascular 
disease at a premature age, familial hyperlipidemia, smoking, systemic arterial 
hypertension, diabetes mellitus or elevated concentrations of lipids. Classified as 
a very high cardiovascular risk, someone who has an established cardiovascular   
disease, history of acute heart attack, any type of revascularization, history of 
cerebral event of the ischemic type, diagnose of type 2 diabetes mellitus or type 
1 with damage to white organ (micro albuminuria) or, a calculated risk of Globorisk 
greater than 10% in 10 years. Individuals who classify as a high cardiovascular 
risk will be those who present a cardiovascular risk by the  Globorisk scale of 5 to 
10% in 10 years, moderately elevated risk such as arterial tension > to 
180/110mmHg, dyslipidemia with TC greater than 310mg/dl or primary familial 
dyslipidemia. [4] To classify subjects with moderate cardiovascular risk, they must 
have a Globorisk risk of 1-5% in 10 years, [4] for this being the classification level 
with the different established scales most susceptible to being sieved,  it is 
recommended to complement it in an individualized manner  with risk factors such 
as familial history of premature cardiovascular disease, abdominal obesity (men 
with abdominal perimeter > 94cm and women > 80cm), a sedentary lifestyle and 
the presence of inflammatory chronic disease. [36] In the low risk classification, 
those with a Globorisk value to 10 years below 1%. [4] Caution must be observe in 
the use of the adequate scale for the population to be analyzed; in the case of 
Mexico, the modified Globorisk for this population, with the aforementioned 
parameters. 
 
On the issue of sieving in subjects to discard dyslipidemias; the consensus of 
experts of the National Lipid Association of the United States of America, 
recommends to do it in persons without associated cardiovascular risk factors 
starting form 20 years and to repeat it every 5 years in all those in which initial 
evaluation is normal and the condition of the patient remains stable. The lipids to 
be measured in this sieve must be obtained from peripheral blood and include Total 
Cholesterol, Cholesterol HDL, Cholesterol LDL and the Cholesterol No HDL must 
be calculated, for which the measurement of triglycerides is necessary. [54] The 
updated clinical practice guides of Mexico make the same recommendation.[2] The 
optimal serum levels of C-LDL will be according to the cardiovascular risk factor 
reported by the Globorisk scale for Mexicans, previously  

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mentioned. For the obtention of the blood levels of Cholesterol no HDL (C-No 
HDL) it’s necessary to perform an estimation through the following equation: C-
No HDL = CT – C-HDL. Since it has been observed that this type of proteins rich 
in TG and remnants of lipoproteins are atherogenic, this parameter is relevant in 
the evaluation of cardiovascular risk, although not as much as the levels of C- 
LDL; therefore, it is recommended to maintain as an objective value for C-No HDL 
levels below 100mg/dl in patients with very high cardiovascular risk, below 
130 in patients with high cardiovascular risk and for those who present a 
moderate cardiovascular risk, levels below 145mg/dl. [4] 
 
With the aforementioned data, the following chart which contains the optimal 
levels of lipids in blood was generated: 
 
 
Chart 2. Recommended lipid levels. [4, 6] 
LIPIDS 
Levels (mg//dl) 
Recommendation 
< 70 
In very high 
cardiovascular 
risk 
In high 
CHOLESTEROL LDL 
< 100 
cardiovascular 
risk 
< 115 
In moderate to low 
Cardiovascular 
risk 
CHOLESTEROL NO 
< 100 
In very high 
cardiovascular 
risk 
In high 
HDL 
< 130 
cardiovascular 
risk 
< 145 
In moderate 
cardiovascular 
risk 

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TOTAL CHOLESTEROL 
< 200 
Desirable 
CHOLESTEROL HDL 
> 40
Desirable 
TRIGLYCERIDES 
 
 
 
 
 
 
< 150 
Desirable 
 
 
 
 
Now, levels of C-LDL above 190mg/dl, carry the suspicion that the patient suffers 
from familial hypercholesterolemia; for which the previous exclusion of the 
secondary causes that contribute to the appearance of those figures will be 
necessary. 
Other 
aspects 
to 
consider 
in 
the 
suspicion 
of 
familial 
hypercholesterolemia are: the presence of premature coronary disease (in men, 
younger than 55 years and in women, younger than 65 years) in the case and/or in 
a first degree relative; xanthomas in the patient and/or first degree relative, familial 
history of high levels of serum cholesterol and; with an 80% probability of suffering 
this disease, having levels of C-LDL without treatment at 30 years or more than 
250mg/dl, 220mg/dl from 20 to 29 years or, of 190mg/dl in persons under 20 
years.[55] 
In 
case 
there 
is 
suspicion 
of 
the 
presence 
of 
familial 
hypercholesterolemia, a detailed physical exploration shall be performed; within 
the aspects to consider are: on inspection the presence of xanthomas in tendons 
at any age, being more frequent in the Achilles’ tendon or in the extensor of the 
fingers and less frequently, in the patellar and triceps; presence of corneal arch in 
persons under 45, tuberous xanthomas in persons under 25 and xanthelasma (if 
it is present in persons over 25, it strengthens the suspicion). Despite having the 
knowledge that an intentioned search must be performed of these findings in 
those with suspicion of familial hypercholesterolemia, the majority of these 
subjects don’t present the mentioned findings. [56] 
 
If there is a course with figures of TC greater than 300mg/dl or C-No HDL greater 
than 220mg/dl, there are several conditions to discard, being the most common 
causal etiologies of familial hypercholesterolemia, hypothyroidism, cholestasis 
and nephrotic syndrome. It is unlikely that other primary hyperlipidemias which 
cause isolated hypercholesterolemia, cause concentrations of total cholesterol in 
such magnitudes. The concentrations of cholesterol between 200 to 300mg/dl are 
generally due to an excess in the consumption of saturated fats and/or 
cholesterol, use of drugs (referred in the section of secondary causes of 
dyslipidemias), obesity and other causes described as secondary. [19] 
 
There are several studies which sustain the relation of consumption of Trans fats 
with the increase of TC and -LDL, besides the decrease of C-HDL. It is known 
that in the consumption of excessive fatty acids, the macrophages are the main 
ones, but not the only agents which respond to the change; for lipids are the 

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promoters of the production of inflammatory cytokines in macrophages and at 
hepatic level. On their part, the unsaturated fats and large amounts of saturated 
fats (particularly of long chain), have effects on the increase of TNF and MCP-1, 
IL-6, IL-1 and Protein C Reactive as a secondary hepatic response; joined to the 
contribution in the presentation of obesity diabetes and cardiac damage. Besides, 
it promotes atherosclerotic lesions through an induced cellular death cycle. [41] 
 
The role of triglycerides in the promotion of atherosclerotic cardiovascular disease 
has had variable and inconsistent results in diverse epidemiologic researches. 
Solving this matter isn’t free from problems, first because from a pathogenic point 
of view hypertriglyceridemia must be considered causal to cardiovascular 
diseases in the measure that an increase of atherogenic lipoproteins is reflected 
and that isn’t always so; second because there is a narrow and inverse relation 
between it and the plasmatic levels of HDL with contributions relative to the 
cardiovascular risk of difficult dissection. In recent years and in a consistent 
manner, the measurement of triglyceridemia in postprandial state (2-4 hours 
following intake) has been recognized as a predictor of cardiovascular accidents, 
even after controlling other factors such as HDL. Recently, a post-hoc analysis of 
the assay PROVE IT-TIMI 22 demonstrated that patients that reached fasting 
levels of triglyceridemia lower than 150 mg/dl had a lesser cardiovascular 
morbidity-mortality even among those who had reached figures of LDL inferior to 
70 mg/dl. [57] 
 
Placing Mexico in the overall picture of the problem implied by dyslipidemias as 
the main modifiable cardiovascular risk factor, it is relevant to mention that 
according to the Global Burden Disease, cardiovascular mortality in the last 20 
years has decreased globally in 21%. Although these data are in the context of 
developed countries, for in developing countries there remains an increase in 
mortality attributable to cardiovascular disease. This becomes relevant upon 
recognizing the strategies that developed countries used in comparison with 
undeveloped countries. In the last 60 years, strategies with 2 guidelines were 
implemented in countries with decrease of global risk by cardiovascular disease. 
The first guideline is in the population where public health policies were conducted 
with the objective of reducing the incidence and mortality by cardiovascular 
disease. The second strategic intervention was directly on the subjects, focusing 
on the decrease of probability of future cardiovascular events through the 
appropriate handling of the modifiable risk factors. [58] From this, it can be 
concluded that the primordial and critical step as strategy is the handling 

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of the cardiovascular risk in the clinical stage. With first-contact physicians, the 
evaluation of cardiovascular risk has shown to be useful, with the purpose of 
identifying patients who will benefit most from primary prevention therapies. [59] 
 
Because most dyslipidemias are a silent disease, it is advisable for Mexicans that 
the scrutiny of the cardiovascular risk factors, including serum lipid profile, be 
done starting at age 20 and if result are normal without associated cardiovascular 
risk, which the evaluation of the lipid profile continue every 5 years. [2] This forms 
part of the primary prevention strategies, defined as the set of activities performed 
by the health personnel, community or government to prevent or delay the onset 
of a determined condition. [60] Besides the primary prevention strategies, there are 
secondary prevention strategies that for the particular condition are the 
interventions in patients with known cardiovascular disease and in those who 
gather the conditions that classify them as risky. The objective of this secondary 
prevention is to avoid the recurrence or exacerbations of a cardiovascular disease 
or the complication by use of a specific therapy. It is recognized that this offers a 
greater gain in health and in the cost / effectiveness relation. [32] 
 
Starting from these observation, an integral treatment must be established, which 
consists in a non-pharmacological treatment and a pharmacological one, being 
combined or not. The non-pharmacological treatment must include the education 
for a healthy lifestyle, the promotion of physical activity of the patient, stress 
handling if present, avoid smoking and orient the subject in the diminishing of 
psychosocial risk factors. It is recommended that individuals with high 
cardiovascular risk be subject to a multi-disciplinary intervention (nutrition, 
nursing, psychology), with the aim of integrating the medical resources with the 
criteria to be included as part of the non-pharmacological treatment. [4] 
 
A relation has been seen between loss of weight with a favorable impact in the 
decrease of serum lipids, so it is recommended to install a regime directed to 
combat this factor. Its known that with the weight loss of 3 kilograms of weight, 
triglycerides are reduces on an average value of 15mg/dl; if the patient manages 
to loose from 5 to 8 kg, the C-LDL will be reduced in average levels of 5mg/dl and 
the C-HDL will increase from 2 to 3 mg/dl in average. In patients that present a 
loss of 3 kg, the effect will be observed over TG, C-LDL and C-HDL. In adults who 
suffer from Diabetes mellitus 2 and overweight or obesity, if an 8% weight loss is 
achieved in 1 year or 5.3% in 4 years, the C-HDL will increase in 2mg/dl. [61] 

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Another primary prevention factor that contributes to the loss of weight is the diet 
of the patients who suffer dyslipidemias, and it is considered a cornerstone in the 
handling of this type of population. It is known that certain types of fat in the diet 
directly increase the figures of C-LDL, and these are denominated Trans fats and 
saturated fats. The Trans fats are found in foods such as margarine, vegetable 
lard, fast-foods, industrialized products, fried or baked bread, snacks, cakes, 
cookies and candy. The saturated fats are contained in food products like red 
meats, sausages, butter, coconut oil, cream, milk and cheese. [62] By contrast, it 
has been studied that a DASH diet (Diet Approach to Stop Hypertension) in 
subjects with stable weight and blood levels of TC of 260mg/dl and C-LDL over 
160mg/dl reduces the C-LDL by 11mg/dl and the C-HDL by 4mg/dl. This diet is 
high in vegetables and fruits, potassium, magnesium and calcium; regular in 
whole grains, fish, nuts, protein and fiber and reduced in saturated fats, 
cholesterol, sugars and red meats. [62] It is known that a patient with dyslipidemias 
finds benefit in the correction of the lipid alterations if their meals count with the 
addition or substitution of unsaturated fatty acids; the linoleic acid, 
eicosapentaenoic (EPA) and docosahexaenoic (DHA) are unsaturated fats of 
Omega 3 and 6 that maintain the levels of cholesterol in serum. This type of fatty 
acids are found in soy, sunflower seed oil, dry fruits (nuts), fatty fish like salmon, 
herring, tuna, mackerel, sardine, etc. Therefore, it is recommended to substitute in 
the diet the saturated fats for this type of fats. [63] 
 
The following scheme is advised as a healthy diet for a patient with dyslipidemia: 
 
1. Have and intake of saturated fatty acids below 10% of the total intake of 
energy and replace these for polyunsaturated fatty acids. [4] 
2. That the intake of Trans fats and unsaturated fatty acids are less than 1% 
of the total energy intake. [4] 
3. Consume less than 5 grams of salt per day. [4] 
4. Consume from 30 to 45 grams of fiber each day, preferably of integral 
products. [4] 
5. Consume 200g or more of vegetables per day divided in 2 to 3 portions. [4] 
6. Consume 200g or more of fruits per day divided in 2 to 3 portions. [4] 
7. Consume fish once or twice a week. [4] 
8. Consume 30g of unsalted nuts per day. [4] 
9. Abstain from taking a maximum of 20 g of alcoholic beverages per day for 
men and 10 grams of alcoholic beverages in the case of women. [4] 
10. Abstain from consuming beverages sweetened with sugar. [4] 

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Exercising has a direct impact on C-HDL; studies reveal that walking from 25 to 
30 kilometers per week (which entails an average caloric burning of 1500 to 2000 
kilocalories per week), raises the levels of CHDL in 3.1 to 6 mg/dl. [63] The 
European guides for the prevention of cardiovascular diseases in the clinical 
practice, stratify the physical activity in mild, moderate and intense; according to 
the values of elevation of maximum cardiac frequency (MCF). Mild activity is that in 
which cardiac frequency is maintained with values of 50 to 63% of the MCF and is 
achieved when performing activities such as walking at a speed of 4.7 km/hr. and 
domestic activities. The moderate physical activity maintains a cardiac frequency 
with values of 64 to 76% of the MCF; this objective is reached with activities such 
as walking at speeds of 4.8-6.5 km/hr., bicycling at a speed of 15 km/hr., practicing 
golf, cutting grass, dance, perform aquatic gymnastics, etc. Finally, intense physical 
activity consist of elevating the cardiac frequency from 77 to 93% of the MCF 
through the performance of activities such as running, bicycling at more than 15 
km/hr., do continuous excavations of gardening, swimming, play tennis, etc. 
Healthy adults shall do at least 150 minutes of exercise of moderate intensity per 
week or 75 minutes of intense aerobic exercise in the same time lapse. For patients 
with cardiovascular risk factors who pretend to perform high intensity physical 
activities, it is recommendable to do it under previous clinical evaluation. [4] 
 
In patients with dyslipidemia, as a preventive measure, it is recommended to 
advise the suspension of active and passive tobacco inhaling, as well as inhaling 
of herbal products. [4] 
 
Groups of medicines that route their handling in the decrease of serum lipids are 
found in the pharmacological therapy of dyslipidemias. By their action mechanism, 
they are divided into inhibitors of the Hydroxymethylglutaryl Coenzyme A 
reductase, inhibitors of the absorption of cholesterol, sequestrants of biliary acids 
and inhibitors of the lipoprotein convertase subtilisin/kexin type 9 (PCSK-9). [4] 
 
The inhibitors of HMG-CoA reductase which as a pharmacologic group are known 
as statins, are considered the first line of treatment. They have been available 
since 1987 and have been amply described and well tolerated. [3] This group 
reduces the synthesis of cholesterol at hepatic level, by competitive inhibition of 
the enzyme Hydroxymethylglutaryl coenzyme A reductase. This induces the 
expression of receptor LDL in the surface of the hepatocyte, which results in the 
decrease of circulating LDL, Apo B and triglyceride particles. [4] 

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They are usually classified according to their capacity of reduction in the C-LDL 
of statins of high intensity, moderate intensity and low intensity. The first reduce 
the levels of LDL with a proportion over 50% and these are Atorvastatin at doses 
of 40 to 80 mg/day and Rosuvastatin at doses of 40 mg/day. Moderate intensity 
statins have a percentage of reduction of C-LDL from 30 to 50%, and in this group 
are found Atorvastatin at doses of 10-20 mg/day, Lovastatin at doses of 40 
mg/day, Pitavastatin at doses of 2-4 mg/day, Pravastatin at doses of 40-80 
mg/day, Rosuvastatin at doses of 5-20 mg/day and Simvastatin at doses of 20-80 
mg/day. The last group denominated as low intensity because of its reduction 
percentage, decreases the C-LDL in proportions below 30%; in this group are 
Fluvastatin at doses of 20-40 mg/day, Lovastatin at doses of 20 mg/day, pravastatin 
at doses of 10-20 mg/day and Simvastatin at doses of 10 mg/day. [6] The intensity 
of the treatment shall be guided according to the cardiovascular risk established 
by the Globorisk scale and its correlation with the C-LDL. [4] 
 
In general, the therapy with statins shows a therapeutic effect which carries a 
reduction in the percentage of C-LDL from 20 to 60% with the secondary reduction 
of the morbidity-mortality of cardiovascular events and the decrease in the 
progression of coronary atherosclerosis; reason for which they are considered as 
part of the primary and secondary prevention. [3, 6] Associated to the reduction of 
C-LDL, it has also been observed that the statins maintain a relation with a 
reduction in serum levels of TC in 17 to 41% and a variable improvement in the 
levels of triglycerides and C-HDL. [65, 66] In isolated hypercholesterolemia, it is 
known that the reduction of C-LDL in 40 mg/dl shows an association with the 
reduction of 22% of cardiovascular morbidity-mortality and that in patients managed 
with statins, after a diminishing of C-LDL of 39 mg/dl (1mmol/l) the cardiovascular 
mortality and the non-fatal infarction are reduced from 20 to 25%. [51] In the 
wording of lipoproteins which are related to cardiovascular risk, properties have 
been added to the statins not only in the reduction of C-LDL, but also in the C-No 
HDL, associating its decrease with the reduction of cardiovascular risk. [67] 
 
Among other benefic effects reported by the use of statins are: less endothelial 
dysfunction, increase in the bioavailability of nitric oxide with its ulterior effect on 
the relaxation of vascular musculature, antioxidant properties and inhibition in the 
vascular inflammatory process. [68] 
 
For this reason, in primary prevention, the use of statins is adequate based on the 
calculation of risk established by the Globorisk cardiovascular risk scale for 
Mexicans correlated to the levels of C-LDL. [4] Among the patients who are 
benefited with the use of statins are those that have some cardiovascular disease, 
those who present serum levels of C-LDL equal to or above 190 mg/dl,  

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those who suffer from Diabetes Mellitus and are aged from 40 to 75 years, with 
elevated levels of C-LDL and a high or very high cardiovascular risk and, those 
aged from 40 to 75 years who don’t suffer from Diabetes Mellitus but have a high 
or very high cardiovascular risk . [69] 
 
In patients who course with familial hypercholesterolemia it is recommended to use 
as treatment nutritional therapy and statins of high intensity at the moment of diagnose 
with the subsequent evaluation of cardiovascular risk; for them, a very high risk will 
be denominated if they have a coronary disease or Diabetes Mellitus 2 and high 
with the presence of 1 cardiovascular risk factor. The goals in the treatment depend 
on this stratification; it is paramount for those of very high cardiovascular risk to 
reduce levels of C-LDL below 70mg/dl, below 100mg/dl of C-LDL for those 
classified as high cardiovascular risk and for those that don’t have another 
cardiovascular risk, the therapeutic goals will be of C-LDL inferior to 130mg/dl. [70] 
In subjects older than 21 and younger than 0 with serum levels of C-LDL of 
190mg/dl or more, it isn’t necessary to estimate a scale to evaluate the 
cardiovascular risk to initiate therapy and the use of high-density statins is 
substantiated on the maximum dose tolerated as initial manner. Apart from 
studying the possibility of a genetic alteration (primary hypercholesterolemia) as 
originator of dyslipidemia, and the intent of approaching relatives of said patients 
will be sought to see the possibility, in case that they present the problem, of 
being favored with the therapy. [6] 
 
For individuals from 40 to 75 years without Diabetes Mellitus, the treatment with 
statins must be initiated according to the level of C-LDL and the assessed 
cardiovascular risk. It is recommended to use high-density statins for those who 
have serum concentrations of C-LDL between 100 to 189 mg/dl with very high 
cardiovascular risk. In subjects who course with a moderate cardiovascular risk 
and a dyslipidemia of C-LDL greater than 190, a therapy of statins of moderate 
intensity must be started. [4, L3] 
 
 
In the diabetic patient, special considerations must be taken in the handling of 
statins; hence patients younger than 40 with micro-vascular complications or 
multiple cardiovascular risk factors, will be benefited with the use of moderate to 
high intensity statins. For those who are between 40 to 75 years without 
cardiovascular risk, a treatment based on moderate to high density statins must 
be administered and, for those who present cardiovascular risk factors, the use of 
high intensity statins is suggested. [71, L3] 
 
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In clinical practice, the statin to utilize and the dose shall be adjusted based on 
the individual response of each patient. In patients with moderate cardiovascular 
risk, the goal of primary prevention must be of C-LDL under 115mg/dl and C-No 
HDL below 145mg/dl. In Diabetic patients the goals in primary prevention is of C-
LDL below 100mg/dl and C-No HDL is an alternative goal that doesn’t require 
fasting and is considered as a minor objective of 130mg/dl. [4] See Chart 2. 
 
In patients with moderate risk who don’t reach the goal with a change of lifestyle 
and/or present other factors of cardiovascular risk that can’t be modified such as a 
history of premature cardiovascular disease in first degree relative and inflammatory 
chronic diseases, treatment with statins shall be individualized. [2] 
 
In individuals who have serum levels of triglycerides greater than 200mg/dl, the 
C-No HDL is considered an objective of treatment. [72] 
 
In secondary prevention the use of statins is justified in those with cardiovascular 
disease known as acute myocardial infarction, chest angina, coronary 
revascularization or high risk conditions such as cerebrovascular event, 
peripheral arterial disease, chronic renal disease and diabetes mellitus 2 with 
damage to target organ, which are considered patients of very high cardiovascular 
risk. [32] In turn, in those patients who have high cardiovascular risk and are older 
than 95 years, it is recommended to use as first line high density statins, 
remembering that the goal in patients with very high cardiovascular risk is C-LDL 
less than 70mg/dl and C-No-HDL less than 100mg/dl. [6] 
 
Notwithstanding what’s stated in the previous paragraph, in adults over 75 there 
isn’t enough evidence for the generalized use of statins, since most clinical studies 
exclude adults older than that age. [69] 
 
In persons over 80 who use statins, a higher index of associated falls and fractures 
have been seen in the first 2 years of treatment without a significant reduction in 
cardiovascular diseases, so the therapeutic handling of this age group with statins 
isn’t recommended. [73] 
 
The intolerance to the use of statins is defined by adverse signs or symptoms or 
laboratory abnormalities, in the majority perceived by the patient that interfere in 
their daily activities and lead to the decision of reducing or suspending the therapy 
with statins. [54] In patients who don’t tolerate a low dose of statin, but where it is 
evaluated that the risk/benefit with the therapeutic incursion of some medicine of 
this pharmacologic group is favorable to the benefit of the subject, 
 
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some long half-life statin may be administered as is the case of atorvastatin or 
rosuvastatin with a frequency of once a week, or 2 to 3 times per week. [74] 
 
There are individuals who are found with a predisposed risk to present adverse 
events related with the use of statins; in these groups are found those who course 
with multiple or serious comorbidities, including renal damage and hepatic failure, 
history of previous intolerance to statins by muscular comorbidities, elevation of 
ALT in blood to 3 times the upper limit considered as normal in an unexplainable 
manner (reported in international units), age above 75, have Asian descent, 
history of having suffered a cerebrovascular event of the hemorrhagic type and, 
characteristics proper of the patient or of the concomitant treatment that affect the 
metabolism of statins. [6] 
 
The adverse event that maintains the most relevance in the patients treated with 
statins is myopathy. This includes several entities, but lacks evidence in that it 
initiates with myalgias and progresses to more severe clinical or laboratory 
manifestations associated to myopathy. In these cases, the patient may course 
with myalgia, myopathy, myositis, myonecrosis and myoglobinuria or acute renal 
damage. [5] The reported prevalence of myopathy in those who take statins is of 5 
to 10%, but the risk of rhabdomyolysis is extremely rare. Its presentation is greater 
in older adults of the feminine gender and in those who course with complex 
medical problems or have a history of using multiple medicines. [4] The greater 
presentation in older adults is justified by the sarcopenia (decrease of muscular 
mass) increasing the risk of developing myopathy secondary to the use of statins, 
combined with the fact that the enzymes that metabolize statins may be less 
functional increasing the interaction among drugs. [75] The physiopathology base 
of the onset of myopathy in users of statins resides in that the inhibition of HMG-
CoA reductase furthermore decreases other intermediaries like the dolichols, 
prenylated proteins and electron carrier proteins, hemo A and ubiquinone; these 
form part of complex I and II in the chain of transport of electrons at mitochondrial 
level of the skeletal muscle. The observation of diminished levels of ubiquinone, not 
only in circulation in skeletal muscle of those who are treated with statins, suggests 
that these interfere in mitochondrial function causing a secondary damage in 
muscular morphology. Studies in humans have shown the there is more 
lactate/pyruvate in those who used statins in comparison with the controls. In 
muscular biopsies of some patients, abnormal elevations with deposits of lipids in 
red fibers were found, and also a diminishment in the activity of cytochrome c, 
biomarker of mitochondrial activity at muscular level. Among the different statins, 
atorvastatin and rosuvastatin were the ones found  
 
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With less diminishment in the levels of Coenzyme Q10, even in a meta-analysis 
to that effect, it was found only in one study at doses of 40 mg of Atorvastatin with 
significant reductions of ubiquinone; [76] and in another that used doses of 80 
mg/day, an elevation in muscular sensitivity was seen. [77] Even so, it is concluded 
that these effects are found in patients susceptible to suffer myopathy by statins. 
[78] 
 
In the subjects who course with myopathy, the measurement of Creatine 
phosphokinase (CPK) is recommended, besides being recommended in 
individuals with a risk of presenting muscular adverse events or a familial history 
of intolerance to statins or muscular disorder, it is important to always correlate 
with the clinical presentation and the concomitant therapy in and individualized 
manner. In patients who course with muscular symptoms additional to the 
measurement of CPK, it is recommended to measure the creatine and perform a 
urinalysis with intended search of myoglobin to rule out rhabdomyolysis. At the 
resolution of muscular symptoms, if no rhabdomyolysis existed, then one can 
return to treatment with statins at low doses. If after 2 months of withdrawal of the 
use of statins muscular symptoms or CPK levels don’t improve, then these must 
be considered secondary to other muscular causes. [6] Studies have sustained 
that in the presence of myalgias in patients with treatment based on statins without 
CPK elevation or intolerance, strategies of assay-error may be performed starting 
with low-potency statins at low doses. Also the change of statin used may be an 
option or through the administration of different doses between the days of 
treatment with a gradual increase by tolerance each week. [5] 
 
Since hepatic damage secondary to the use of statins shows an extremely low 
annual incidence, less than 2 cases per million patients, the increase of hepatic 
enzymes associated to the use of statins is an occasional finding in the majority 
of the cases, potentially reversible, for which the routine hepatic enzyme 
measurement isn’t recommended in the patient who uses statins. 
[69] 
Nevertheless, it is recommended to perform biochemical tests that evaluate hepatic 
function in those who present symptoms suggestive of hepatotoxicity such as 
unusual fatigue or weakness, loss of appetite, abdominal pain, choluria and 
jaundice. In turn, it is recommended not to include in clinical studies subjects that 
present basal levels of ALT above 1.5 to 2 times the normal superior limit reported 
in international units. [6] Combined with the non-recommendation of the use of 
statins in patients with hepatic failure or established hepatic cirrhosis. [69] 
 
In patients who suffer chronic renal disease, Atorvastatin and fluvastatin don’t 
require adjustment since their renal excretion is minimal. For Rosuvastatin it is 
 
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recommended to start with 5 mg and use a maximum of 10 mg in those who 
present a glomerular filtration rate lower than 30ml/min, the use of Rosuvastatin 
isn’t recommended for patients undergoing dialysis. [75] 
 
In patients who have HIV, the use of statins must be considered risky, especially 
in those who are under anti-retroviral treatment with protease inhibitors and/or 
non-nucleoside inhibitors of reverse transcriptase. If the benefit is adequate their 
use is justified but the therapy shall be performed with special care and may only 
be used as treatment options Atorvastatin and Rosuvastatin from the group of 
statins. [75] 
 
In the presence of alterations in the state of alertness in subjects who use statins, 
the possibility must the evaluated that these are the causal factor. [69] 
 
It has been debated whether the treatment with statins may have a relation with 
new cases of Diabetes Mellitus; it is known that it is associated to an increase of 
risk to acquire this disease in 9% (Odds ratio of 1.09, Confidence Interval 1.92-
1.17) with low heterogeneity of studies (I2: 11%). It is known that for 1 case of 
diabetes mellitus to be produced in 4 years, the necessary number of patients to 
be treated with statins is 255 subjects; likewise, in this period statins will prevent 
the occurrence of 5.4 events of coronary disease, cardiovascular death or non-
fatal acute infarction of the heart. Therefore, it is not recommended to abandon 
treatment with statins for this cause. [79] 
 
As part of the monitoring in the therapy with statins, it is recommended to perform 
a basal lipemic profile that reports biochemical levels of TC, TG, C-LDL and C- 
HDL, followed by another measurement in the following 4 to 12 weeks of the 
starting pharmacologic treatment and continuing with the same studies every 3 to 
12 months. [6] 
 
Another alternate drug used in the treatment of dyslipidemias is ezetimibe; 
inhibitor of the absorption of cholesterol directed to the protein similar to Niemann- 
Pick C1 (NPC1L1), the polymorphisms which affect NPC1L1 are associated to 
decrease C-LDL and the risk of presenting cardiovascular events. [80] These drugs 
have shown results when combined with the therapy of statins in the reduction of 
the percentage of C-LDL with an additional 24%. In a clinical assay, it was 
demonstrated that this reduction offers an absolute reduction in the risk of fatal 
and non-fatal cardiovascular risk at 6 months of follow-up of 2%. [80] It’s because 
of this that it is recommended to add this drug to the combined therapy with statins 
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with the maximum tolerated dose of statins or who are in the maximum 
recommended dose. What isn’t justified is the use of medicines different to statins 
as monotherapy in the handling of dyslipidemias, including ezetimibe; this 
reasoning is because its potency to reduce C-LDL is low, being the exception to the 
rule those patients who are intolerant to statins. [4] Furthermore, it is known that 
the treatment with addition of ezetimibe to a moderate-intensity statin has an 
additional cardiovascular benefit in comparison with monotherapy in patients with 
diabetes and recent acute coronary syndrome or for those patients who can’t 
tolerate therapy with high-intensity statins. [81] 
 
The sequestrants of biliary acids are another pharmacologic group that may be 
used in patients with dyslipidemia; such is the case of cholestyramine which at 
doses of 24 grams it is associated to a reduction in serum levels of C-LDL of 23.5 
mg/dl, although a significant decrease in the risk of coronary cardiac disease, 
acute infarction of the heart or cardiovascular mortality has not been seen. [82] 
Their use as second-line, non-statin agents has been recommended only in 
patients who don’t tolerate ezetimibe and with levels of triglycerides lower than 
300mg/dl in blood; [74] lacking this drugs the recommendation of use as routine 
treatment for the non-reduction of cardiovascular risk. [4] 
 
 Fibrates have their action on the receptor of peroxysomal proliferators (PPAR), 
expressed in their majority in the liver and in a lesser proportion in the heart, 
kidney, skeletal muscle and intestine. In these tissues the PPAR is implied in the 
control of the expression of proteins and catabolic enzymes for fatty acids; this 
leads to the reduction of the synthesis of triglycerides and a lower production of 
lipoproteins of very low density (VLDL) in the liver. This effect is done through the 
increase of the hepatic lipoproteinlipase enzyme and the reduction in the 
expression of the apolipoprotein C. As an added beneficial effect, the time of 
permanence of the VLDLs in the circulation is reduced and the acceleration of 
their transformation into C -LDL, favoring the formation of C-HDL. [83] A reduction 
in TG has been observed following the use of these agents in 20 to 50% with a 
slight increase of C-HDL from 5 to 15%; by contrast it is known that the decrease 
of C-LDL isn’t significant and it may even increase. In a review of 18 clinical assays, 
it was demonstrated that fibrates reduce in 10% the cardiovascular morbidity but 
they lack effect on the decrease of mortality associated with cardiovascular events. 
[84] The use of an agent of this family called Gemfibrosil in combination with any 
statin is contraindicated, since it has been seen that this produces an alteration in 
its metabolism and increases the risk of myopathy. [72] 

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 Niacin or vitamin B3 is a water-soluble vitamin that acts in reactions that generate 
energy thanks to the biochemical oxidation of carbohydrates, fats and proteins. In 
lipids it acts on the metabolic route of endogenous production, diminishing the 
synthesis of VLDL through two mechanisms: 1) anti-lipolytic effect with decrease 
in the release of free fatty acids from adipose tissue, through the receptor 
GPR109A coupled to protein G and 2) inhibition of the hepatic diaglyceryl 
acylytransferase-2 (DGAT-2) that participates in the synthesis of triglycerides. [85] 
The use of these agents is recommended as monotherapy for secondary 
prevention and management of hypercholesterolemia. [4] 
 
With respect to the inhibitors of PCSK9 it is known that they inhibit the degradation 
of the receptors of LDL in the hepatocyte; they have been studied in patients with 
heterozygote familial hypercholesterolemia, intolerance to treatment with statins 
and in patients with very high cardiovascular risk, proving that they are safe and 
effective in the reduction of C-LDL and lipoprotein a. [86] 
 
Carnitine was discovered in 1905 as a component of muscular tissue, from which 
it derives its name (from Latin carnis), its chemical structure was established in 
1927 by Tomita and Sendju. For its synthesis, it requires essential amino acids 
like lysine and methionine, apart from the cycle of ascorbic acid, niacin, pyridoxine 
and iron; its active form is levocarnitine. [87] L-carnitine (levocarnitine) plays an 
essential role   in the metabolism of energy production. It acts as fatty acid 
transporter from cytosol to the mitochondrial matrix, being the Beta-oxidation of 
intramitochondrial fatty acids the largest and most efficient energy source when 
producing Acetyl- CoA and ATP through the Krebs cycle. [88] It is indicated in the 
treatment of primary deficiencies of carnitine, problems in the biosynthesis starting 
from substrates of the diet or for the secondary treatment by alterations in its 
metabolism. [89, 90] It is approved by the FDA for the primary treatment of carnitine 
deficiency and for the acute and chronic treatment of patients with errors in the 
metabolism that is secondary to the deficiency of carnitine, amongst which 
Diabetes Mellitus type 2, methylmalonic aciduria, propionic academia, glutaric 
aciduria and deficiency in the middle chain of the enzyme Acetyl-CoA 
dehydrogenase, among others, and in patients with dialysis and chronic renal 
failure in terminal stage due to the deficiency of carnitine with which they course. 
[90] In nephropathy patients with hemodialysis it assists in the management of fatty 
acids that accumulate secondary to the blocking of the potassium channels, 
diminishing the resistance to insulin, arrhythmias and the patient’s own weakness. 
Besides, it is used in the prevention and treatment by secondary deficiency due 
to the administration of valproic acid. [89] 

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The efficacy of L-carnitine has been proven in the decrease of C-LDL and TC,[91, 
92] besides, there are also reports in which the consumption of this product offers 
a decrease in the serum levels of TG and an increase in the levels of C-HDL. [7, 
92, 93] This generates a significant impact to execute the therapeutic management 
using L-carnitine in patients with dyslipidemias, decreasing the cardiovascular risk 
associated to these diseases of the lipids, favored by studies that have shown the 
clinical efficacy in patients that were medicated with L-carnitine after presenting a 
cardiovascular disease.[7, 90, 94, 95] 
 
In the follow-up of patients with dyslipidemia, it is advisable to measure the lipids 
profile at 4 to 12 weeks from start-up of treatment or when the dose is adjusted to 
determine the adherence of the subject to the therapy employed; following this 
measurement it is recommended to measure the serum levels of TC, C-LDL. C-
HDL and TG every 6 to 12 months. In turn, it is recommended to lower the dose of 
statins when two consecutive values of C-LDL less than 40mg/dl are obtained. [6] 
 
In patients who don’t reach the therapeutic objective in the reduction of C- LDL, 
the management with statins must be started with a greater intensity dosage. If 
the patient reaches the therapeutic objective then the statin must be continued 
with the currently used dose. [74] 
 
It is recommended to refer to the second level of attention those patients who 
course with familial hypercholesterolemia and who don’t reach the therapeutic 
goals of C-LDL despite being treated with the maximum doses and verifying the 
additional compliance by the patient in adherence to treatment and to the 
established non-pharmacologic measures. It is also recommended to send to the 
second level of attention to the users of statins with reactions such as myopathy 
or elevation of ALT in 3 times its normal value in international units. [2] 
 
Patients with dyslipidemia must be counter-referred once they reach the 
therapeutic goals according to the cardiovascular risk stratified by the Globorisk 
scale for the Mexican population and/or to the resolution of the complications or 
secondary events that maintain relation with the pharmacotherapy employed in 
the patient; when counter-referring, the patient shall be made aware about the 
importance of the treatment and the first-level physician will be advised to keep a 
strict control on the associated cardiovascular risks and the non-pharmacologic 
measures employed in the therapeutic approach of the disease. [2] 

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Since statins are the primary management in dyslipidemias, it is adequate to study 
the formulation of products that add to them a greater therapeutic efficacy than 
what is reported and a better safety profile. 
 
 
 
 
5. 
BACKGROUND 
 
 
 
Dyslipidemias, especially the one related to the elevation of C-LDL, are a factor 
for cardiovascular disease. [2, 6, 54, L1] 
 
Statins are the first-line drug; its effect on the decrease of fatty acids is due to the 
reduction of their synthesis through the inhibition of the HMG-CoA reductase. 
Several studies have proven the significant reduction of cardiovascular diseases in 
morbidity and mortality following the use of statins, thus having a favorable 
benefit/risk relation for the use of these pharmacologic agents. [2, 6, 54, L1] Despite 
these benefits, the risks of managing a therapy with statins are known. 
 
The most common adverse events following treatment with statins are 
gastrointestinal ones, with a greater prevalence of mild diarrhea, although other 
manifestations such as mild abdominal pain and flatulence may exist; the 
occurrence in clinical studies is from 2 to 5%. Other gastrointestinal symptoms 
like nausea, vomit, constipation, dyspepsia, and heartburn occur in 1 to 4% of the 
patients who receive statins in clinical studies. Anorexia has also been reported 
as a gastrointestinal event associated to the use of statins. [96] 
 
The Factors related with the hepatic abnormalities secondary to statins consist in 
the elevation of hepatic enzymes such as AST and ALT 3 times above their normal 
value and depend on pharmacokinetic and physiochemical factors accompanied 
by the selective transport mediated at hepatic level. [97] Besides, they show a 
predisposition to present adverse reactions in those patients who course with 
chronic infections by the hepatitis virus. [98] This effect keeps an occurrence of 0.1 
to 3% with at least 2 times of presentation per individual (which aren’t necessarily 
consecutive) in a period of treatment with statins of at least 11 months. It is very 
rare when this serum elevation is accompanied by jaundice or cholestasis; 
although in several clinical studies at least 1 patient has developed jaundice. 
Another important fact is that the serum elevation reported in the values of ALT 
and AST is usually transitory, decreasing when the treatment with statins is 
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In the dermatologic area, the most common adverse reaction by the use of statins 
is the cutaneous rash, reported in 1 to 4% of the patients included in the clinical 
studies who received this pharmacologic group. Other less common effects may 
be the presence of alopecia, pruritus and changes in the skin (nodules, 
hypochromia, dry skin, changes in the parts attached to the skin). [99] 
 
Within the adverse events of the nervous system, headache is the most commonly 
reported in clinical studies that used treatment with statins. The incidence is 3 to 
17% of the patients. Other events such as asthenia, fatigue and dizziness have 
an occurrence of 1 to 4%. [99] 
 
The cardiovascular effects reported in patients included in clinical studies 
following the administration of statins are very rare; these include precordial pain, 
hypertension, chest angina, palpitation, vasodilation, syncope, postural 
hypotension, peripheral edema and mild arrhythmias. [100] 
 
In the genitourinary system, events have been reported as attributable to the use 
of inhibitors of the HMG-CoA reductase, and these are: loss of libido, erectile 
dysfunction, impotence, epididymitis, abnormal ejaculation, vaginal hemorrhages, 
uterine hemorrhages, metrorrhagia, fibrocystic mastopathy, cystitis, hematuria, 
dysuria, kidney stones, nocturia, albuminuria, nephritis, urinary incontinence, urinary 
retention and urinary urgency. [100] Other extremely rare events include 
gynecomastia, hyperglycemia, hypoglycemia, gout, weight gain, ecchymosis, 
anemia, lymphadenopathy, petechial exanthema, tinnitus, parosmia, agnosia and 
alterations in the sense of taste. [100] 
 
The event of greatest relevance with clinical significance related to the use of 
statins is myopathy. All the statins have been associated with this condition and 
the secondary rhabdomyolysis it may entail, although these are generally 
reversible and mild and very rarely cause rhabdomyolysis. [101, 102] Although it was 
commented about the possibility of the mechanism associated to the myotoxicity 
of statins, this isn’t clear, but is attributed to the mitochondrial dysfunction and to 
the defects in the regeneration of myocytes. [102] This adverse event shows 
predisposition for diverse factors with special demographic characteristics; for 
example, in persons over 75 they are related with the sarcopenia, proper of the 
age, women, polymorphisms of the gene SLCO1B1 (common in Asian 
populations), abnormalities in the polypeptide transporter, isoenzymes of the 
Cytochrome, depletion of ubiquinone, alcoholism, drug-addiction and hereditary 
myopathies. [101] The incidence of myopathy in subjects who take statins without 
any other concomitant drug that may by itself put the patient at risk of presenting 
myopathy is less than 0.1%. On the other hand, alcoholism in patients that use 
statins also increases the risk of myopathy due to 
 
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the synergic effect due to the alcoholic myopathy proper. [103] 
 
Myalgia secondary to myopathy by statins is characterized by an intense muscular 
pain which starts in the arms, thighs and then extends to the whole body in a 
manner similar to that presented in the flu-like syndrome; the symptoms progress 
according to the continuation of use of the medicine or causal medicines. The 
levels of CPK reported as abnormal must be found 10 times above the normal 
superior limit and a urinalysis must be performed in search of myoglobin to rule 
out rhabdomyolysis. Among the motives to discontinue treatment with statins are: 
those patients who course with rhabdomyolysis and patients with high CPK levels 
attributed to the use of statins. Besides, it must also be considered to withdraw 
treatment with statins from those who aren’t able to obtain serum levels of CPK and 
continue with the presence of myalgias; this once other causals are ruled out as 
responsible for the symptomatology. It is known that the use of statins at a dose 
not greater than 25% of the maximum dose of the drug, reduces the risk of 
presenting myopathy. [104] 
 
Once it’s been referenced about the adverse events found by statins, one in 
particular will be discussed for being part of the drug under study and for having 
a good profile of therapeutic efficacy and safety; atorvastatin. 
 
Atorvastatin is a lipophilic statin that was authorized for sale for the first time in 
1997. [105] In a few years it became stellar in the group of statins; this is postulated 
due to 2 important factors; the first one is that it has been proven that Atorvastatin 
and Rosuvastatin are the drugs that have the greatest potency in the diminishing 
of C-LDL and the second one is that Atorvastatin presents a better safety profile 
in patients with renal conditions. [105, 106] More than 500 randomized clinical studies 
that deal about the safety and efficacy of the use of Atorvastatin have been 
conducted. [107] 
 
In terms of clinical benefits, it has been seen that atorvastatin provides an 
important reduction in the morbidity-mortality by cardiovascular diseases, 
including patients with Systemic Arterial Hypertension classified as high risk 
without established coronary disease, [108] patients with an associated comorbidity 
as is Diabetes Mellitus 2 and who don’t course with an established coronary 
disease, [109] patients who suffer some type of acute coronary syndrome [110, 111 ] 
and those who course with a coronary disease in stable conditions [112] Besides, 
there are precedents that atorvastatin at doses of 80 mg/day compared with the 
use of placebo diminishes the incidence of cerebrovascular event in patients with 
previous cerebrovascular event but without 
 
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established coronary disease. [51] 
 
Thus, Atorvastatin counting with more than 500 randomized clinical studies is the 
drug that counts with the greatest evaluated presence than any other drug that’s 
effective in the treatment of dyslipidemia and prevention cardiovascular diseases. 
It is used extensively in a variety of circumstances, including primary and 
secondary prevention of cardiovascular events; for some years, it has also been 
used in patients with chronic renal disease and in diabetics; this is why it has 
been a bastion of safety and tolerability of the drug. [113] 
 
A study in patients with chronic renal disease stage 5 showed the efficacy of 
administrating atorvastatin on the lipid levels in blood, reaching therapeutic goals 
in TC in 65% of the patients, of C-LDL in 50% of C-No-HDL in 40% and of TG in 
45%. The dose used was on average 60.4 mg per day and its administration didn’t 
cause significant adverse events. [114] 
 
With respect to adverse events attributable to the use of atorvastatin, there are 
those that are pre-clinic and others that are clinic. Pre-clinic ones conclude that 
the use of atorvastatin has a lesser incidence of adverse events than those of 
other types of statins. While the inhibitors of HMG-CoA reductase such as 
fluvastatin, lovastatin, pravastatin and simvastatin don’t show evidences of 
mutagenicity (bacterial assay of genetic mutation, clastogenicity assay and assay 
of genetic mutation in bacterial cells as well as in mammals), at long-term the 
studies of carcinogenicity in rodents resulted in a greater incidence in the 
development of tumors when high doses are used. [115] In oral doses of Atorvastatin 
in rats with concentrations of 10, 30 and 100 mg/kg per day for 2 years, there 
was an increase in the incidence of rhabdomyosarcoma and fibrosarcoma in 2 
females treated with high doses. This represents an area under the curve of 
concentration-time (AUC) of an approximate value of 16 times the average of 
plasma concentrations of the AUC in humans at doses of atorvastatin of 80 mg. 
In mice that received oral doses of atorvastatin of 100, 200 or 400 mg/kg per day 
during 2 years there was an increase in the incidence of hepatic adenomas in 
males and hepatic carcinomas in females treated with high doses. This represents 
a value of plasma AUC of approximately 6 times the average of plasmatic 
concentrations of AUC in humans at a dose of atorvastatin of 80 mg. [116] In the 
rats that received oral doses of atorvastatin of 20, 100 or 225 mg/kg per day starting 
on day 7 of gestation until day 21 of lactation (weaning), there was a decrease of 
survival of the progeny when born. Corporal weight decreased on days 4 and 21 
in the progeny of mothers that received 100 mg/kg on the day of birth. 
 
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The weight was reduced on days 4, 21 and 91 with 225 mg/kg daily. The 
development of the progeny was delayed, which was evaluated by performance 
(mothers that received 100 mg/kg daily). It was also observed that there was a 
delay in development, basically at the moment of detachment of the ear and 
ocular aperture (mothers that received doses of 225 mg/kg). These doses 
correspond to an exposition equivalent to 6 times (100 mg/kg) and 22 times (225 
mg/kg) the AUC in humans at 80 mg per day. [116] 
 
The most extensive clinical studied in which there’s experience in the use of 
atorvastatin is “The Treating of New Targets”. In this study were included 10,001 
patients with coronary disease and they were randomized to receive doses of 10 
or 80 mg per day of atorvastatin during 5 years. [112]  No significant clinical 
differences were found associated with the use of atorvastatin among the subjects 
who reached levels of C-LDL from 66 to 106mg/dl; which coursed with myalgia in 
5% and didn’t present persistent elevated levels of CPK (superior to 10 times the 
normal upper limit through international units or that presented rhabdomyolysis). 
No persistent elevation level was found neither in the hepatic transaminase 
levels(less than 3 times above the normal upper level according to international 
units) with an incidence of 0.2% for the group that received atorvastatin in doses 
of 10 mg and 1.2% in the group of 80 mg. Serious adverse events such as 
suicides, cancer and cerebrovascular events of the hemorrhagic type, didn’t 
present statistically significant differences among percentiles. [112] 
 
An analysis that includes clinical studies in patients with coronary alteration, stable 
cardiovascular disease and cerebrovascular event without cardiovascular 
disease, comprising between 25,000 and 69,000 patient-years with the use of 
atorvastatin of 10 mg and 80 mg atorvastatin respectively, found an increase of 
ALT and AST greater than 3 times the normal international units from 1 to 3.3%, 
a persistent increase of 0.1 to 0.4% in CPK levels (greater than 10 times the 
normal upper limit in classified international units), and no case of rhabdomyolysis 
associated to atorvastatin. [117] 
 
In a meta-analysis of 44 studies performed in 1,495 dyslipidemic patients treated 
with atorvastatin (9416 patients), other statins (5290 patients) and placebo (1789 
patients), the safety of atorvastatin was evaluated in doses of 10-80 mg per day; 
it was found that the evidence of adverse events was only 3% for the subjects 
who used atorvastatin, 1% for those who used placebo and 4% for those who 
used other statins. [118] Reporting gastrointestinal events as the most frequent 
adverse event. The largest elevation to 3 times in normal values according to 
international units for hepatic enzymes ALT/AST had an incidence of 0.5% in 
those treated with atorvastatin. With respect to the CPK values, only 

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1 patient treated with atorvastatin showed a persistent elevation in values of CPK 
(elevation greater than 10 times the range established as normal in international 
units) and in this one, no association with myopathy was proven, for lacking 
muscle pain. The incidence associated to myalgia without elevations of CPK was 
low (1.9%) in those who received atorvastatin and no relation was shown with the 
used dose; the placebo group had 0.8% and the group treated with other statins 
had 2%. No case of rhabdomyolysis was reported in any group (myalgia with CPK 
greater than 10,000 international units that conditions acute renal damage). [118] In 
another meta-analysis it was reported equally the non-dependence of 
presentation of adverse events related to the dose used of atorvastatin. This 
analysis included 48 studies with more than 14,000 patients in treatment groups 
that received atorvastatin (doses of 10 to 80 mg per day) or placebo. [119] Besides, 
it was observed that the incidence of related events was 2.4% in the group of 10 
mg of atorvastatin, 1.8% for the group of 80 mg of atorvastatin and 1.2% in the 
control group that received placebo. The serious adverse events related to the 
product were very rare and didn’t present relation with the dose of atorvastatin 
used. Besides, no cases of rhabdomyolysis were observed and there was little 
impact of cases reported with myalgia; this was of 1.4% in patients who received 
atorvastatin 10 mg, 1.5% in the group of 80 mg and 0.7% for the placebo group. 
The persistent elevations of ALT/AST (in ranges greater than 3 times the normal 
upper limit according to international units) were of 0.1, 0.6 and 0.2% for the 
groups of patients with treatment of 10 mg of atorvastatin per day, 80 mg per day 
and the placebo group, respectively. [119] These studies support a positive safety 
profile for the use of atorvastatin, inclusively at doses considered as of high 
intensity. 
 
In patients with treatment for DM2 and cardiovascular disease (through the use 
of atorvastatin at doses of 24 mg per day in comparison with the usual treatment) 
or without established cardiovascular disease (using atorvastatin 10 mg/day vs. 
placebo), a profile of tolerability similar with respect to the usual treatment or 
placebo was found. [109, 120] 
 
For patients with chronic renal failure, atorvastatin doesn’t require dose 
adjustment. [107, 121] Likewise, the good tolerability of atorvastatin was found in the 
groups of patients with diabetic nephropathy. [120] Atorvastatin reduced the levels 
of C-LDL in 42% compared with the basal values during the first month of treatment, 
without presenting any significant event such as death by cardiac causes, non-fatal 
acute cardiac infarction and cerebrovascular event. Besides, the reported safety 
was similar to that obtained with the use of placebo. [122] 

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Interactions have been proven with certain pharmacologic groups and 
atorvastatin. Within these it is known that atorvastatin shows interaction with 
gemfibrozil, clofibrate, phenofibrate and niacin, agents which are related among 
themselves for causing myopathies as secondary reactions; this is probably due 
to the inhibition of the synthesis of esters in the skeletal muscle. There is another 
type of drugs that increase the incidence of adverse events secondary to statins 
by affecting the metabolism of inhibitors of HMG- CoA reductase; causing the 
subsequent increase in its plasmatic levels and active metabolisms. Such is the 
case of macrolides (Erythromycin, Telitromycin and Clarithromycin), Azole anti-
fungi: Ketoconazole, Itraconazole, Fluconazole, Cyclosporine, antidepressants of 
Phenylpiperacine, Nefazodone and protease inhibitors. [104] 
 
In patients who use cholestyramine or colestipol along with inhibitor of HMG-CoA 
reductase, it is advisable that this latter drug be administered 2 to 4 hours 
previously to the use of the mentioned ones, due to the fact that these may reduce 
their viability. Besides, it is recommended that if the patient uses antacids, not to 
administer these along the statins, since it has been documented that antacids 
reduce the plasmatic concentration of atorvastatin in approximately 35%. [123] 
 
One treatment group of the study will receive additionally to atorvastatin, L-
carnitine. L-carnitine is a compound derived from essential amino acids that play 
an important physiological role in the transport of fatty acids of long chain towards 
the interior of mitochondrias for their β-oxidation and the production of ATP by 
oxidative phosphorylation. It may also translocate acetyl - CoA of the 
mitochondria to the cytoplasm of the cell. [124] In adipocytes it produces and antilipid 
activity and increases β-oxidation. [125] Besides, plasmatic levels of insulin above 
90 µU/ml favor, in the presence of adequate amounts of L-carnitine, the 
accumulation of it in the striated muscle in healthy, non-obese volunteers. [126] 
Levocarnitine is used in states that course with deficiency of its basal 
concentration, caused by diverse pathologies whose primary characteristic is 
excessive corporal abrasion and hyper catabolism (sepsis, ischemia, 
myocardiopathy, etc.), or in diseased persons with frequent hemodialysis. Also, 
a decrease of its concentration has been reported in patients with type 2 
diabetes mellitus and above all in women with diabetic complications. [127] It’s 
not clear whether the deficiency of carnitine in diabetic patients is the result of the 
diabetic state or a factor that may contribute to the development of diabetes; [128] 
its administration is cataloged as dietary supplement and as medicinal therapeutic 
principle, which seeks to increase the energetic contribution. It favors the -oxidation 
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performance of the fatty acids as well as the accumulation of triglycerides in 
tissues; there is evidence that upholds the hypothesis that se supplementation of 
carnitine improves the muscular lipid content, reduces oxidative stress and 
increases sensibility to insulin. [129] Instead, its deficiency leads to a progressive 
intracellular toxic state with accumulation of free fatty acids and triglycerides in 
tissues [130] 
 
The evidence of the favorable effect following the use of L-carnitine on fatty acids 
in pre-clinical studies has been proven. It is known that it inhibits the increments 
of triglycerides by atherogenic diets, reduces circulating leptins and with that 
abdominal fat and, modulates the balance of insulin-like growth factors (ILGFs). 
This has been shown by the increase secondary to its administration of protein 
3 of union to the growth factor similar to insulin (IGFBP-3) in diabetic rats, in 
which it is usually reduced. [125] There are reports of normalization in the 
concentrations of carnitine, plasmatic cholesterol and triglycerides in animal 
models with the use of Levocarnitine. 
[131] In more recent studies in 
hypercholesterolemic rabbits, it was demonstrated that Levocarnitine could prevent 
the progression of atherosclerotic lesions, thanks to its antioxidant and 
hypolipidemic effects. [132] 
 
A multi-centric study, double-blind, controlled with placebo demonstrated, upon 
administering L-carnitine in patients who had suffered a first acute myocardial 
infarction, which they benefitted with a secondary reduction of cardiac failure and 
a decrease in mortality figures. [94] In another clinical study where a sample of 574 
subjects was included, the effects were compared of administering L-carnitine in 
comparison with a placebo in patients with cardiac failure, where a significant 
difference was found in the results of resistance time in maximum duration during 
the exercise for the group of L-carnitine compared with the placebo group. [90] 
Combined to these results, a multi-centric study with 472 patients that received 
levocarnitine following an acute myocardial infarction, demonstrated an 
improvement in the parameters of ventricular remodeling and a lesser dilation of 
the left ventricle. [95] 
 
Many experimental studies have observed that levocarnitine reduces myocardial 
damage after it was subject to ischemia and reperfusion, effect attributed to the 
action of L-carnitine to counter toxic effects of the free fatty acids secondary to 
ischemia. Additionally, it was found that the supplementation with L-carnitine 
increases the content of carnitine in the myocardium, functioning as prevention in 
the loss of storage deposits of phosphates, ischemic damage and the 
recuperation of cardiac reperfusion. Clinically, it has been proven that L-carnitine 
has anti-ischemic properties which favor the non-appearance of cardiovascular 
events. [95] 
 
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From January of 2013 to February of 2014 a randomized single blind study was 
performed, controlled with L-carnitine vs. Placebo, in patients diagnosed with 
arterial coronary disease (by catheters with stenosis of at least 50% in one of 
major coronaries or angioplasty with percutaneous transamination), some of which 
presented dyslipidemia and treatment with moderate density statins. It was 
concluded that with one dose of 1g a day of L-carnitine there was a significant 
increase in C-HDL and Apo-A1 lipoproteins, with a slight diminishing in TG. [7] 
 
In patients with hemodialysis, a significant effect on the decrease of lipids has 
been demonstrated following the administration of L-carnitine. [94, 133] 
 
Naini and collaborators found that after treating patients with a dose of 750 mg 
per day of L-carnitine, there were significant decreases in the serum levels of TC, 
TG and C-LDL; also that if the dose used is of 1g of L-carnitine, a significant 
increase in the level of C-HDL is added. [94] This effect is suggested since L-
carnitine increases the mitochondrial transport of fatty acids and reduces the 
viability of fatty acids for the synthesis of lipids. [134] 
 
In a meta-analysis about the impact of L-carnitine in the treatment of plasmatic 
lipoproteins, it was concluded that L-carnitine produces a significant reduction of 
TC and a reduction on the limit, after all significant, of C-LDL, without effects on 
the C-HDL and triglycerides. [91] 
 
In turn, the supplementation with L-carnitine has been suggested in some forms 
of hepatic damage. This is due to the fact that in the final stages of hepatopathy, 
the deficiency in the synthesis of L-carnitine causes low levels of metabolically 
active carnitine in the myocardium and in skeletal muscle. [135] 
 
In patients with resistance to insulin (entity with an important role in the 
development of Diabetes Mellitus type 2), its known that there exists a defect in 
the oxidation of muscular fatty acids; investigations suggest that the 
supplementation with L-carnitine may aid in the sensitivity to insulin in diabetics 
through the decrease of fatty acids in muscle and may diminish the levels of blood 
glucose through cellular oxidation. [94] 
 
There are preceding studies, for the therapeutic intervention and the findings in 
the use of L-carnitine + atorvastatin or other statins, in pre-clinical as well as  
 
 
 
 
 
 
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in clinical phases. 
 
The hepatoprotector effect of these drugs in rat livers was evaluated in a pre-
clinical study, arguing that with a previous induction of hepatic toxicity by infusion 
of statins, there were going to be alterations of cellular markers and inclusively, 
on the cells proper. It was proven that the treatment with the addition of L-carnitine 
decreased cellular death, the instability of the mitochondrial membrane and the 
expression of free radicals and molecules that suggested damage to hepatocytes 
by the statins.  [136] 
 
A review made by experts with the premise of verifying that L-carnitine aids in the 
management of the symptoms of myalgia secondary to statins, mentions that 
owing to the fact that patients who course with myalgias secondary to atorvastatin 
present abnormalities in carnitine levels, it is recommended that studies be 
performed in which L-carnitine is proposed as an option to reduce the presentation 
of this adverse effect secondary to the administration of inhibitors of HMG-CoA 
reductase. [137] 
 
In a study done on patients who suffered Diabetes Mellitus 2, the therapeutic 
efficacy on lipoproteins and apoproteins was compared in treatment groups 
composed by those who used statins + L-carnitine in comparison with only statins. 
It was identified that the group that used the combination of inhibitor of HMG-CoA 
reductase and L-carnitine in comparison with the group that was medicated only 
with statins, presented significant differences for the decrease of glucose, TC, C-
LDL, TG, ApoB, Apo A and a significant increase in C-HDL. [138] 
 
In 2009, Malguarnera and collaborators performed a study on the effects in the 
size of low-density lipoproteins when adding L-carnitine to patients with diabetes 
mellitus 2 on treatment with simvastatin. For this they included 80 randomized 
diabetic patients in a group with oral route simvastatin at doses of 20mg per day 
and another with simvastatin at 20mg/day + levocarnitine 2g per day. The duration 
of treatment was 3 months. The variables to study were total cholesterol, C-LDL, 
C-LDL subclasses, size of LDL, C-HDL, plasmatic glucose, glycosylated 
hemoglobin, index of corporal mass, triglycerides, apolipoprotein A-1 and 
apolipoprotein B-100. Upon completion of treatment a significant reduction was 
found in the group that received L-carnitine + simvastatin in the proportion of small 
size molecules of LDL, C-LDL, triglycerides, total cholesterol, glucose on fasting 
and Apo B-100 in comparison with the group of monotherapy with simvastatin. 
Besides, the group that received carnitine + simvastatin had a significant increase 
in comparison with the monotherapy group of simvastatin for C-HDL and large 
particles of LDL. [139] 
 
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To verify the efficacy and tolerability of a treatment of L-carnitine and simvastatin, 
a study was developed in which the intention was to verify the serum decrease of 
lipoproteins in patients with diabetes mellitus 2. The study was open, randomized 
with 52 patients that had diabetes mellitus 2, triglycerides levels below 400mg/dl 
and Lp (a) greater than 20mg/dl. They were randomized in 2 groups; the 
participants of the first group received simvastatin in monotherapy at doses of 20 
mg per day and those of the other group received simvastatin + levocarnitine at 
doses of 20 mg/2 g once a day. Both treatments were through oral route. There 
was no treatment abandonment or adverse events. No significant differences were 
observed between the groups for the reduction of C-LDL, C-No-HDL and apoB; 
but significant differences were found in therapeutic benefit for those who received 
L-carnitine + simvastatin in the diminishment of the Lp(a). [140] 
 
In a controlled randomized study with placebo on patients who were receiving 
hemodialysis, 52 patients were included, 27 men and 25 women who were being 
treated with atorvastatin or lovastatin to measure the therapeutic efficacy of a 
supplementary therapy. They were divided into 4 groups that received 1 g of 
intravenous carnitine 3 times a week, coenzyme Q10 in oral doses of 100 mg per 
day, both or placebo. After 3 months of treatment levels of lipoprotein (a), 
triglycerides, total cholesterol, C-LDL and C-HDL were measured. Significant 
differences were found in the reduction of lipoprotein (a), in the groups that 
received carnitine, coenzyme Q10 or both compared with the placebo groups. 
There were no changes that were significant in other lipoproteins. [141] 
 
 
 
 
6. 
JUSTIFICATION 
 
 
 
Cardiovascular diseases, including coronary arterial disease, cerebrovascular 
event and peripheral arterial disease, are causative at global level of a mortality 
rate that places them in the first place. It is estimated that in the year 2012 they 
were responsible for 17.5 million deaths; 7.4 million were secondary to acute 
myocardial infarction and 6.7 million were attributed to cerebrovascular disease. 
Apart from the mentioned figures, it is known that cardiovascular diseases or 
causal of almost half of the deaths by non-transmissible secondary diseases 
(46%) and of 37}5 of premature deaths in persons under 70. [1] The fact that the 
majority of these deaths are preventable is of a greater significance. It’s projected 
that for the year 2030 mortality secondary to cardiovascular disease 
 
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has a figure of 22.2 million persons. [1] 
 
These figures aren’t apart from the reality that prevails in Mexico. According to the 
Organization 
for 
Cooperation 
and 
Economic 
Development 
(OCDE), 
cardiovascular diseases in Mexico 2015 were causative in the death of 292 
persons for every 100,000 habitants, thus being considered a high-risk country 
for death associated to a cardiovascular disease. This death not only occurs 
prematurely, but causes the survivors to have a deficient quality of life, require 
long-term health care and have a reduced capacity in their work life. Besides, the 
years of life potentially lost by cardiovascular disease in the Mexican population, 
were 728 for every 100,000 habitant, 25% above the average of OCED countries. 
[44] 
 
Confronting this problem shall maintain relation with the strategic design of the 
National Plan for development for the cycle 2013-2018, where it is posed by 
presidential decree as one of its 3 transversal strategies “Democratize 
Productivity”; its mentioned in this plan that democratizing productivity “means 
generating the correct stimuli to integrate all Mexicans in the formal economy …” 
[L4], elements to consider on knowing the secondary effects of dyslipidemias and 
the subsequent cardiovascular diseases in the reduction of the work life capacity 
and the potentially lost life years, combined to a premature death; leading to 
impingement in its management consistent with the aforementioned argument. 
 
On the other hand, for the year 2006, costs generated by cardiovascular disease, 
diabetes and obesity were 40 billion pesos; figure that corresponds to 7% of the 
total expenditure for the health sector, were 55% is destined to that which is 
related with cardiovascular disease. It is estimated that for the year 2030, costs 
around 557 million dollars will be generated for cardiovascular and 
cerebrovascular disease, and for the year 2050, 797 million dollars generated for 
these conditions. 
[142] Once again, it’s convenient to reference the National 
Development Plan 2013- 2018; for, since one of the 5 national goals is the 
proposal to be an Inclusive Mexico, which promotes the access to health to all 
Mexicans and avoids the unexpected health problems or economic movements, 
be a determining factor in its development. [L4] In this context, the expenses 
generated by cardiovascular diseases may be mitigated by a correct approach to 
prevent them and thus promote health in the Mexican Population. 

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There exist data on the global decrease of mortality secondary to cardiovascular 
diseases that may justify that these are secondary to a problem of social 
inequality. This argument rises from what was reported in the Global Burden 
Disease, where it was discovered that cardiovascular disease has diminished in 
21% globally in the last 20 years, these being figures that have been observed 
only in developed countries and that remain with an increase in mortality rates for 
developing countries. [58] 
 
This success in developed countries has been attributed to preventive strategies 
with inclusion in the last 60 years on two determinant items. The first one consists 
on implementing public health policies with the objective of decreasing the 
morbidity-mortality of cardiovascular diseases. The second one considers the 
strategy of focusing on decreasing the probability of presentation in individuals of 
future cardiovascular events, through the knowledge and appropriate 
management of the modifiable risk factors. [58] The definition of cardiovascular risk 
is defined as the risk of suffering death secondary to cardiovascular disease in a 
period of 10 years. [2, 143] 
 
Having these considerations offers certain advantages such as: having an 
objective evaluation of cardiovascular risk favoring a common language among 
the different health professionals, acknowledging that cardiovascular disease has 
a multifactorial nature and, approaching the problem of young patients with low 
absolute risk but multiple risk factors through their stratification. [4] 
 
An effective implementation of these considerations is recommended to detect 
these patients in a clinical scenario through the use of an adequate and validated 
tool for each geographic region through the recalibration of an already elaborated 
scale. [4] 
 
Mexico participated in a validated multi-centric prospective cohort known as 
Globorisk with the inclusion of patients of 40 to 84 years with follow-up for 15 
years. A high-risk prevalence was found for 16% of men and 11% of women. A 
recalibrated cardiovascular risk equation was developed starting from these data, 
with other models such as Framingham and SCORE that allowed the 
establishment of a risk correlation at 10 years for the Mexican population, 
identifying as high probability risk to present a cardiovascular event those where 
a risk over 10% was present. [53] 

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Starting from this, having an adequate control in the prevention of disease will 
lead to decreasing the incidence of new cases of these nosologic entities. The 
risk factors that are determinant for the presentation of cardiovascular disease 
have been identified. These are called cardiovascular risk factors, which estimate 
the probability of a subject being in risk of suffering a death associated to 
cardiovascular events within 10 years. The control of risk factors to present a 
cardiovascular disease is the main strategy to diminish morbidity-mortality caused 
by this disease. There are modifiable factors such as smoking, hypertension, 
diabetes mellitus, dyslipidemia and obesity and non-modifiable such as age (men 
over 45 and women over 55) sex, race, first-degree premature ischemic 
cardiopathy (men under 55 or women under 65). [2] Dyslipidemias are the most 
frequent modifiable cardiovascular risk factor. [2, L1] 
 
That is why the control of dyslipidemia, especially the elevation of cholesterol-
LDL, takes such relevance for diminishing the presentation of cardiovascular 
diseases. [4] 
 
The argument quoted maintains a relation with the evidence that upon decreasing 
C- LDL 39mg/dl a diminishing 20% is achieved in the incidence of cardiovascular 
events without difference in gender; men and women are benefitted. [51] 
 
The figures of C-LDL have shown elevation attributable to the development of the 
country. In the existing Mexican population the figure of serum levels of C-LDL 
between 100 and 160 mg/dl is considered normal, but when compared to healthy 
primate adults, who have C-LDL levels of 40 to 80 mg/dl, the slow increase in the 
last decades is reflected. [15] The Framingham study proved that men and women 
with C-LDL over 160 mg/dl develop 1.5 times more cardiovascular disease 
compared with a population with C-LDL below 130 mg/dl. In the same manner, 
in the study of communities in risk of atherosclerosis (ARIC) for every increase of 
39 mg/dl, the risk of a cardiovascular event increases 40%. [15] 
 
In the National Survey of Chronic Disease from 1993 to 1994, it was known that 
the prevalence of elevation of TC was of 27.1%, hypertriglyceridemia had a 
presentation in 42.3% of Mexicans and hypoalphalipoproteinemia prevailed in 
61%. [17] Data from the ENSANUT survey 2006 reported a prevalence of 
cholesterol greater than 200mg/dl of 43.6% in people over 20.[20] On the other 
hand, in a recent, a prevalence of 50.5% with a greater predisposition for men 
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55 to 64 years, where it was greater in women. [18] These data suggest that the 
problem of dyslipidemia in the Mexican adult has increased. 
The most frequent dyslipidemias in Mexicans are the diminishing of C-HDL and 
hypertriglyceridemia; [19] being the former the most frequent with a reported 
prevalence of 58.9%. [20] 
 
It’s important to highlight that the association of dyslipidemia with other 
cardiovascular risk factors like diabetes, hypertension, obesity and smoking 
increase the risk of ischemic cardiopathy. [2] 
 
With respect to the pharmacologic therapy for hypercholesterolemia, statins, 
available since 1987m widely prescribed, well tolerated and with a proven 
reduction of cardiovascular events in primary as well as in secondary prevention. 
The levels of C-LDL decrease depending on the dose in 20 to 60%. [3] 
 
Atorvastatin is a type of statin drug that began its commercialization in 1997 and 
since then it plays a stellar role in the group of statins, being atorvastatin the most 
studied drug of the group of those used for the management of dyslipidemias. [147] 
This is considered so since it is 1 of the 2 drugs that provide a greater diminishment 
in the levels of C-LDL. [106, 147] This association is sustained based on the levels of 
concentrations of the drug in blood with a half-life of 20 to 30 hours [104] and 
because it has a very good safety profile in comparison with other statins and its 
uses are documented in special populations [76, 106, 109, 114] and in patients who suffer 
some type of acute coronary syndrome. [107, 109, 110, 111, 112, 113, 117, 118, 119, 120, 121, 122] 
 
Nevertheless, around half of the patients discontinue the therapy with statins 
during the first year, because of the cost or related adverse effects and up to 25% 
of patients in primary prevention abandon it after 2 years for not being convinced 
of requiring treatment. [14] It is also important to know that despite high dose of 
statins, up to 13%of the patients don’t reach concentrations of C-LDL lower than 
100 mg/dl and more that 40% don’t reach levels below 70 mg/dl. [144] 
 
The importance of initiating an adequate control of lipids entails the maintenance 
of optimum levels of fatty acids in blood which are implicit in the increase of the 
risk of acquiring some cardiovascular disease. For this reason, with the 
formulation of a medicine that is effective and has an adequate safety profile, the 
indexes of abandonment of treatment may be decreased. 

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It is with this objective that the necessity of creating a pharmaceutical composition 
that integrates 2 elements to potentiate the efficacy in the reduction of C-LDL and 
at the same time offer a lesser incidence of adverse events is proposed. These 
effects would be achieved with the use of L-carnitine and atorvastatin in a unique 
pharmaceutical form. The L-carnitine counts with studies that corroborate its 
efficacy in the reduction of blood fatty acids and it is known that it has a very good 
safety profile. [7, 90, 91, 92, 95, 124, 125, 129, 130, 133, 134, 135] So it is thought that this could 
attribute a benefic therapeutic factor in the combined administration of L-carnitine 
and atorvastatin for the percentage of reduction of C-LDL and C-No-HDL in blood. 
In the improvement of the safety profile of the treatment in the dyslipidemic 
patient, is assumed that the therapy with L-carnitine + atorvastatin may assist in 
the decrease of the incidence of adverse events attributable to the administration 
of statins, including those of greater clinical significance like hepatic alterations and 
at skeletal muscle level. 
 
Another point in favor is that the use of L-carnitine with statins has been studied. 
[7, 91, 133, 136, 137, 138, 139, 140, 141]  But there are still questions that may be proven or 
ruled out in the following study. 
 
In the end one may have a novel, effective and adequate safety profile in this 
combination for the pharmacologic management in the primary and secondary 
prevention of dyslipidemias; once again highlighting the fact that dyslipidemias 
are the most frequently modifiable cardiovascular risk factor. With this, an ulterior 
benefit is postulated for the adult population that suffers from dyslipidemias, 
estimated in Mexico as half of its habitants. 
 
The problem of some studies that have been performed for dyslipidemias is the 
process of the results of randomization, for they are assigned in groups of patients 
that differ one from the other with respect to the risk because of the clinical profile, 
the non-existence in the balance between the known risk factors and the unknown 
risk factors, and additionally the use of placebo minimizes the adverse events 
among the treatments of the study in the randomized groups, so the differences 
may be due to the differences of conformation of the groups once they are 
randomized. [146] For this reason in this study there is special care in the selection 
of subjects to be included so they present similitude in the associated factors. 
Finally, the idea is to control the assigned treatment and administer in both active 
groups, with the difference of the addition of L-carnitine in one of them and 
performing as a method of statistical analysis a test of superiority. So there is no 
predilection on assigning or pre-judging the experimental or the alternate 
treatment, one blind to the observer will be done. 

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7. 
HYPOTHESIS 
 
 
     Main hypothesis: 
 
 
H0: The combination of L-carnitine + atorvastatin doesn’t show therapeutic 
superiority with respect to the use of atorvastatin as treatment to 
decrease the percentage of C-LDL in patients with dyslipidemia. 
 
H: The combined use of L-carnitine + atorvastatin offers a therapeutic 
superiority with respect to the use of atorvastatin as treatment to 
decrease the percentage of C-LDL in patients with dyslipidemia. 
 
     Secondary hypothesis: 
 
 
H0: The combination of L-carnitine + atorvastatin doesn’t show a lower 
incidence in the presence of adverse events attributable to the 
medicine in comparison with the use of atorvastatin as monotherapy, 
in the treatment of dyslipidemic patients. 
 
H: The combination of L-carnitine + atorvastatin shows a lower incidence 
in the presence of adverse events attributable to the medicine in 
comparison with the use of atorvastatin as monotherapy, in the 
treatment of dyslipidemic patients. 
 
 
 
 
8. 
OBJECTIVES 
 
 
     General Objectives: 
 
 
8.1.1. Evaluate the therapeutic efficacy in Mexican adults with dyslipidemia 
through the oral route use of L-carnitine + atorvastatin in comparison 
with the use of Atorvastatin, after six months of treatment. 
 
8.1.2. Evaluate the safety of the medicines in the study. 

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     Specific Objectives: 
 
 
8.2.1. Evaluate the diminishing of Cholesterol LDL in Mexican adults with 
dyslipidemia through the use of oral route L-carnitine + atorvastatin 
in comparison with the use of Atorvastatin, after six months of 
treatment. 
 
8.2.2. Evaluate the diminishing of Cholesterol no-HDL in Mexican adults 
with dyslipidemia through the use of oral route L-carnitine + 
atorvastatin in comparison with the use of Atorvastatin, after six 
months of treatment. 
 
8.2.3. Evaluate the variability of serum levels of Total Cholesterol in 
Mexican adults with dyslipidemia through the use of oral route L-
carnitine + atorvastatin in comparison with the use of Atorvastatin, 
after six months of treatment. 
 
8.2.4. Evaluate the variability of serum levels of Triglycerides in Mexican 
adults with dyslipidemia through the use of oral route L-carnitine + 
atorvastatin in comparison with the use of Atorvastatin, after six 
months of treatment. 
 
8.2.5. Evaluate the variability of serum levels of Cholesterol HDL in Mexican 
adults with dyslipidemia through the use of oral route L-carnitine + 
atorvastatin in comparison with the use of Atorvastatin, after six 
months of treatment. 
 
 
 
8.2.6. Evaluate the incidence, prevalence and progression of serious and 
non-serious adverse events related through the oral route 
administration of L-carnitine + atorvastatin in comparison with the use 
of Atorvastatin, after six months of treatment in the subjects 
participating in the study. 
 
 
 
     Premises of the study: 
 
 
 
1. Evaluate the effect of the use of L-carnitine + atorvastatin in comparison with 
the use of Atorvastatin, in the basal levels of glycosylated hemoglobin after six 
month of treatment. 

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2. Evaluate the effect of the use of L-carnitine + atorvastatin in comparison with the 
use of Atorvastatin, in the figures of arterial tension of the subjects in the study, 
during their participation in the study. 
 
 
3. Evaluate the effect of the use of L-carnitine + atorvastatin in comparison with 
the use of Atorvastatin, in the levels of corporal mass index after six months of 
treatment. 
 
The cited premises will be demonstrated for effects of procurement, temporality 
and at the convenience of Valeant Pharmaceuticals International and may be 
included or not in their analysis in the report of the study. From these, significant 
findings may rise in benefit of the population and may allow for the generation of 
new investigations focused on new knowledge about the dynamics of 
cardiovascular risk factors associated in an overall manner and at first to the 
Mexican population. 
 
 
 
 
9.    DESIGN OF THE STUDY 
 
 
 
The following study is a Phase III clinical assay, experimental, randomized with 
two treatment groups, multi-centric, longitudinal, to evaluate the therapeutic 
efficacy in the dyslipidemias in Mexican adults. 
 
It is known that the main characteristic of experimental studies is the random 
assignation to the exposition of voluntary human beings that is used to evaluate 
the safety and efficacy of a treatment against diseases or health problems, 
including the adverse reactions. [146] For this case, it shall have the possibility of 
being included in one of the 2 treatment groups (group in which the investigational 
drug is administered or group with control of active). With respect to temporality, 
these are of a prospective character and is cataloged as longitudinal for having 
successive observations. This type of study will include homogeneous populations 
that may be comparable by their disease condition, biological and socio-
demographic characteristics. Under controlled conditions of study, with a group that 
shall receive the investigational product and the other as control. The size of the 
sample used will be fixed; since it will be carried out in more than 1 location the 
study is multi-centric. Although the actives are separately commercialized and 
there’s even existence of studies where they are used in combination, for Mexico 
there is no formulation that is commercialized in combination, for which it doesn’t 
fit as being a Phase III study due to the pretension of generating additional 
information about the safety and effectiveness                                                     

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of using L-carnitine + atorvastatin in the same presentation for the management 
of dyslipidemias. 
 
This assay is a study of superiority, where the intention is to demonstrate that the 
intervention with L-carnitine + atorvastatin is better or equal to the control 
intervention, added to having a better safety profile. 
 
 
 
 
     Selection of the study population 
 
 
The participants to be included in the study must comply with all the inclusion 
criteria that are required and no exclusion criteria previously to the process of 
Informed Consent. In turn, there are criteria that may lead to a patient terminating 
its participation in de study in a premature manner. 
 
Hereunder, the requirements for the study are mentioned: 
 
9.1.1. Inclusion Criteria. 
 Mexicans between 35 and 75 years of age. 
 Gender indistinct. 
 Patient with abnormal lipid profile considered as serum levels 
of C-LDL of 100mg/dl or greater, obtained by laboratory 
parameters. 
 Not being under pharmacologic treatment to manage its 
dyslipidemia or accept to suspend current treatment and be 
evaluated for inclusion in the next 3 weeks starting on the day 
of initial evaluation. 
Women in fertile stage with a safe, hormonal-free family 
planning method. A safe planning method includes surgical 
methods in women, intrauterine device that doesn’t release 
progestines and use of preservative in all their sexual relations. 
Women in fertile stage who don’t wish to become pregnant 
during their participation in the study. 
 Post-menopause women or with hysterectomy history. 
 Have a fixed and/or mobile telephone and accept to receive 
calls from the site for study processes. 
 Grant their duly informed consent. 

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--------- 
9.1.2. Exclusion Criteria. 
 
 Subject lacking the mental capacity to understand the 
processes which imply their participation in the study and thus, 
not capable of granting their participation in a voluntary 
manner 
 History of hypersensitivity to the medicines being studied. 
 Daily intake of at least 240ml of grape juice or sporadic 
ingestion of 1 liter. 
 Potentially fertile women without a safe family planning method, 
who wish to become pregnant during the study, are already 
pregnant or in lactation period. 
 Having on Globorisk scale for Mexicans, or as an associated 
risk factor, a high stratification for cardiovascular risk. 
Basal laboratory values with elevation of ALT 1.5 times larger 
than the upper limit considered normal according to international 
units. 
Basal laboratory values with elevation of CPK not attributable 
to physical activity. 
 Subjects who are under anti-coagulant treatment, suffer from 
coagulation 
disorders, 
or 
any 
circumstance 
which 
contraindicates the taking of a blood. 
 History of acute myocardial infarction, unstable angina, some 
confirmed coronopathy, arrhythmias, congestive cardiac 
failure or cerebrovascular disease. 
 History of muscular conditions of the genetic type or of 
rhabdomyolysis in the patient or first degree relative. 
 History or diagnose of congenital hepatic disorders, chronic 
infection by hepatitis virus, hepatitis with fatty liver, alcoholic 
hepatitis, 
primary 
biliary 
cirrhosis, 
primary 
sclerosis, 
cholangitis  or hepatic failure. 
 History or diagnose of congenital renal disorders, chronic renal 
failure, acute renal damage or nephritic syndrome. 
 History of infection by Human Immunodeficiency Virus. 
 History of Acute or Chronic Pancreatitis. 
History of the following endocrine diseases: non-controlled 
Diabetes Mellitus, lipodystrophy, thyroid disorders, Cushing 
Syndrome and/or Polycystic Ovary Syndrome. 
 Diseases which compromise immunity such as Systemic 
Lupus Erythematous, Rheumatoid Arthritis, Antiphospholipid 
Antibodies Syndrome or Psoriasis. 

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 Diseases by deposit such as Gaucher Disease, disease by 
glycogen deposit, Tay-Sachs juvenile disease or Niemann 
Pick Disease. 
 Diagnose 
of 
Kawasaki 
Disease, 
Werner 
Syndrome, 
intermittent acute Porphyria, Idiopathic Hyperkalemia or 
Klinefelter Syndrome 
Suffer from Idiopathic Hyperkalemia, Klinefelter Syndrome, 
Werner Syndrome, Kawasaki Disease or Porphyria. 
 History of epilepsy. 
 History or diagnose of alcoholism. 
 Intake of more than 20g of alcohol per day. 
 User of marihuana. 
 User of illegal drugs. 
 Intake of medicines with pharmacologic interaction which 
increase or decrease the efficacy of L-Carnitine and/or 
atorvastatin or alter the lipids in blood such as:  
Macrolide antibiotics: Erythromycin, Telithromycin and 
Clarithromycin. Azole anti-fungi: Ketoconazole, Itraconazole, 
Fluconazole and Nefazodone. Quercetin, Amiodarone, 
Aprepitant, Cimetidine, Ciprofloxacin, Cyclosporine, 
Diltiazem, Imatinib, Echinacea, Enoxacin, Ergotamine, 
Metronidazole, Mifepristone, Tofisopam, Gestodene, 
Verapamil, Mibefradil, Fluoxetine, Phenobarbital, 
Carbamazepine, Phenytoin, Rifampin, Modafinil, 
Glucocorticoids, Felbamate, Rosiglitazone, Griseofulvin, 
Pioglitazone, Gemfibrozil, Clofibrate, Fenofibrate, Niacin, 
Nefazodone, Cholestyramine, Colchicine, Colestipol, 
Primidone, Topiramate, Troglitazone, Rifabutin, Digoxin, 
Thiazides, anabolic Steroids, Progestogens, Estrogens, 
Danazol, Amiodarone, fibric Acid, docosahexaenoic acid, 
Isotretinoine, Immunosuppressives, protease inhibitors of HIV 
or of the Hepatitis C Virus, Inhibitors of the co-transport of 
sodium-glucose, Tamoxifen, Raloxifene, non-selective Beta 
blockers, biliary acid sequestrants, asparginase, Sirolimus 
and Interferon. 
 Patients who have been diagnosed with terminal conditions. 
 Patients with recent Cancer diagnose or undergoing any type 
of therapy for same. Patients who have suffered skin cancer 
not of the melanoma type and have been cured and haven’t 
been on treatment for at least 1 year before the start of their 
participation in the study may enter. 

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Patients under lipid lowering treatment and who, because of 
their clinical condition aren’t candidates to the period of lavage 
or detoxification; or well reject it. 
 Being participating in another clinical trial or having concluded 
their participation in the 30 days previous to beginning their 
participation in this study. 
 Any other which, at the Investigator’s criteria, puts at risk the 
safety of the participant and/or interferes with the results of the 
study. 
 
 
 
9.1.3. Criteria for early termination. 
 Subject’s decision not to continue participating in study. 
 Non-serious adverse event related to the medicine of the 
study. 
 Serious adverse event related or not with the investigational 
drug. 
 Lack of adherence to treatment evidenced by medicine count 
during the study. The lack of adherence is defined as the non-
administration of the medicine, or incomplete or overdosed 
administration in 2 consecutive days or 3 alternate days in a 
period of 30 days. 
 In fertile women, positive immunologic test for pregnancy in 
urine. 
 Not attend to programmed visit after 2 times of being re-
scheduled. For these criteria to be valid, the patient will not 
have shown-up for the third rescheduling of the appointment. 
 Use of therapy or treatments not allowed in the study (See 
section 10.1.3 Banned medicines). 
 Elevation of ALT 3 times above the superior limit considered 
as normal according to international units. 
 Elevation of CPK above 10 times the normal superior limit 
according to international units. 
 Diagnose during the treatment of some disease mentioned as 
part of the non-inclusion criteria. 
 Any other circumstance not resolved in this protocol and that 
requires special evaluation by the department of clinical 
research of the sponsor. 
 
 
 
 
 

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     Calculation of the sample size. 
 
 
In clinical studies there is a challenge of determining the adequate sample size; 
on some occasions this is formulated based on studies performed previously with 
similar characteristics that give an idea of the sample based on the intervention’s 
efficacy, persons that have the condition, etc. In randomization studies, the 
estimation of the adequate sample size is of vital importance, being these types 
of clinical studies the best method to compare the effects of the treatments. [148] 
 
Based on the treatments posed in the present study, the type of design 
corresponds to a study of superiority, where the intention is to demonstrate the 
superiority of a new therapy (L-carnitine + atorvastatin) in comparison with the 
established therapy (atorvastatin). This under the premise that the new 
experimental therapy has a superior therapeutic efficacy and a lesser 
presence of incidence of adverse events related to the medicine. The 
declaration CONSORT (Consolidated Standards of Reporting Trials), that 
includes a list of flow diagram, is a guide developed to help authors to improve the 
divulgation of the results of the random controlled assays, in which it is suggested 
that, to estimate an initial sample size in superiority studies it is necessary to know 
by how much must the new therapy be better than the reference and influence of 
random effects. [149] The magnitude of the variation would be determined by the 
variance S2 which is obtained from pilot studies or similar studies previously 
published. 
 
It is known that the therapy with Atorvastatin at doses of 20 mg per day 
(considered as medium intensity) reduces the C-LDL in 30 to 50%, [6] for which it 
will be taken as reference; to estimate the variance, the maximum therapeutic 
efficacy over C-LDL will be taken at this dose (50%), being this value of p1. To 
obtain p2 the estimated percentage of superiority will be placed, being of 51% that 
expected for the treatment group of L-carnitine + atorvastatin (1g/20mg) per day. 
Since the secondary hypothesis held has to demonstrate the non-superiority of 
adverse events in the experimental therapy, the statistical analysis will be 
performed with the sample size estimated for the primary hypothesis. 

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In these type of studies, the true difference between the effect of the treatments 
has to be demonstrated; but due to the random variation the final result may 
deviate from the real difference with incorrect results. If the null hypothesis (H0) of 
no difference were true, it could give some difference in the analysis. This type of 
error is called type 1 error (false positive) and would have as consequence the 
introduction of an ineffective therapy. If, on the contrary the alternative hypothesis 
(Hwere true, the analysis could not show a significant difference in some cases; 
this is called error type 2 (false negative), resulting in the rejection of the effective 
therapy. [149] Thus, the confidence of the test and its potency must be analyzed. 
Representing as the risk of committing the type 1 error; for being a test in which 
the investigational product is compared against another active treatment, a two-
tailed hypothesis test is generated with the possibility of having different 
magnitude. For this study, a confidence interval (CI) of 95%. Thus, the risk of type 
2 error in 2is of 5%. 
 
The type 2 error is the risk, and in clinical studies it gyrates between 10 and 
20%. Since a given value of will always be above or below 0, the type 2 error 
will always be on one side only. In this study, a superiority of the therapeutic 
efficacy is expected in the experimental treatment group compared with the active 
control group, combined with a lesser incidence of adverse events by the 
combination of L-carnitine + atorvastatin; thus, the estimated potency of the test is 
of 75%. 
 
The formula to be applied to estimate the size of the sample in the randomized 
clinical assay, based in the Hypothesis to prove the superiority of the new 
treatment is: 
𝑁= (𝑍2𝛼+ 𝑍𝛽)(𝑆2
∆2) 
 
N = Sample size by treatment group. 
 
Z2= Confidence interval at 95% with two-tailed hypothesis. 
 
Z= Potency of the test at 75% 
 
S = variance of the difference which is equal to a p1 (1 - p1) + p2 (1 – p2) 
 
= Relative difference or clinical meaning 

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With these values, the adequate sample size by treatment group is of: 54 
subjects. 
 
Due to the nature of this clinical study, the possibility exists of losing participants 
during its course and this would compromise the number of data of the subjects 
necessary so that, if there are differences, these would result significant. To 
prevent this success, it was decided to increase the size of the sample as a way 
of compensating the losses with the implementation of a loss proportion, where R 
is the percentage of losses for the adjusted sample size. [150] Based on the 
experience of clinical studies, it is known that it is convenient to estimate a 
proportion of losses of 10% of participants, R being this value. 
 
The formula for the estimation of the adjusted sample size will be the following: 
 
 
𝑛𝑎𝑗𝑢𝑠𝑡𝑎𝑑𝑜= 𝑛(
1
1 −𝑅) 
n = Calculated sample size previous to adjustment which is of 108 participants 
(54 participants per treatment group) 
 
R = 10% 
 
With these data the adjusted sample size will be of 120 participants, 60 
subjects per treatment group. 
 
 
 
 
     Assignation of treatment and treatment groups 
 
 
To ensure a randomization a mechanism governed by chance is required with 
which treatments will be assigned to the subjects of the investigation in such a 
way that it may be proven that the randomization was kept free from sieve.[143] 
Since there are only two probabilities of treatment, the experimental treatment 
with be assigned in a random manner to each participant with the investigational 
drug or the control treatment with active. 
 
To execute the randomization a simple random assignation technique will be 
used, using the program Research Randomizer. The previously randomized 
medicine will be provided to the site; the personnel delegated for the medicine 
provision will be in charge of dispensing treatment to the site in the order that the 
sponsor provides. To corroborate this, a treatment dispensation sheet with the 
treatment number code will be employed. The code of the treatment number is 
composed by the letter L or the letter C, followed by a 3-digit number for 

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assignation of a consecutive order. For example: L-001 or C-001. 
 
The site will be provided with a 10% extra of treatments for the group that receives 
L-carnitine + atorvastatin and a 10% extra for the group of atorvastatin as 
monotherapy. These will be reassigned to the participants in case they lose the 
originally assigned treatment. Caution must be observed so the anterior doesn’t 
happen; but in case the situation arises, the personnel of the site that reassigns 
treatment must notify to the sponsor the motives for which the treatment was 
reassigned and this notification shall be registered in a medical note and be added 
in the corresponding report format. 
 
 
 
 
9.3.1. Experimental Group: 
 
 
 
The population that comprises this treatment group will receive a dose of L-
Carnitine + Atorvastatin in concentrations of 1g/20mg through oral route every 24 
hours. 
 
 
 
 
9.3.2. Control Group with Active: 
 
 
 
The population that comprises this treatment group will receive a dose of 
atorvastatin in concentrations of 20 mg through oral route every 24 hours. 
 
 
Assignation of treatment groups 
CONTROL 
ACTIVE 
NUMBER OF 
SUBJECTS 
EXPERIMENTAL 
GROUP 
 
L-Carnitine +
atorvastatin              60     
CONTROL 
GROUP WITH 
ACTIVE 
Atorvastatin              60 
*The number of subjects in each treatment group may vary according to the randomization. 

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     Processes to perform during study 
 
 
 
9.4.1. Recruitment of patients 
 
 
 
From the moment the site is notified that it may begin recruitment of patients it will 
count with 45 natural days to carry out the search and recruiting of prospect 
participants to be included in the study. The strategies of recruitment and diffusion 
given to the study, as well as the material provided to the probable participant, 
must be subjected and approved by the Ethics Institutional Review Board. 
 
Once the investigator and the personnel designated to carry out the recruiting 
identify the potential participants, these shall obtain the informed consent on part 
of the probable participants so they may commence with the processes of the 
study. 
 
 
 
 
9.4.2. Process of Informed Consent 
 
 
 
The Process of Informed Consent is a dynamic process, in which the main 
investigator shall inform through understandable words to the legally autonomous 
patient or a relative or legal representative, in presence of two witnesses, the 
possibility of being an investigation subject and that an experimental maneuver 
be applied; for which the subject shall receive from the Main Investigator or the 
delegate Sub-investigator sufficient, opportune, clear and truthful information 
about the risks and benefits expected by participating in the clinical trial. 
 
The investigator must formulate said letter and shall submit the document for its 
approval before the Ethics Institutional Review Board; the approved document 
must contain the seal of the Ethics Institutional Review Board, autograph 
signature and date in which said document was authorized. In the event of having 
amendments on the document, the Informed Consent will be submitted again to 
the Ethics Institutional Review Board for its approval and, the Principal 
Investigator shall make sure that this is obtained once again by the participants in 
the study. 
 
The letter of Informed Consent shall have numbering on each one of its pages, 
and must contain a precise and clear language addressed to the probable 
participant, in which the following are made known: 

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name of the sponsor who is implementing the study, name of the main investigator 
and contact info, name of the ethics committee and contact info, justification and 
object of the study, type of intervention done with the project, criteria for forming 
part of the research, clearly establish that the participation is plainly voluntary, 
procedures and protocols that will be carried out, possible risks and benefits 
associated to the participation, the guarantee of receiving answers to any question 
and explanation of any doubt about the procedures, confidentiality guidelines and 
divulgation of results, the commitment of providing updated information obtained 
during the study though it could affect the will to continue participating, treatments 
that may be administered during its participation such as investigational products, 
alternatives of treatment, its possibility of withdrawing its consent to participate in 
the study at any moment, who shall be responsible if the participant results hurt 
by the procedures of the study and who will be in charge of providing medical 
attention, urgency attention and compensations in case of disability; who to 
contact on part of the site in case of doubts and/or presentation of a suspicion of 
adverse event and who to contact on part of the Ethics Institutional Review Board 
in case of doubts. [151, 152, 153, L5, L6, L7] These documents shall be read in the time 
necessary to ensure that the subject understands what entails participating in the 
clinical trial and all doubts must be solved in the clearest manner. If the probable 
participant so desires, he/she may take the document to analyze it  and is in full 
right of asking for the opinion of some medical professional in respect thereof. All 
the procedure must be done before two impartial witnesses who shall bear 
witness to the participation on a voluntary basis by the subject. 
 
If the potential participant decides to participate, he shall place to bear witness of 
the fact with blue ink and print; according to the data contained in its official 
identification, complete name without abbreviations, autograph signature and 
date in which he/she agrees to participate in the clinical trial. In the event that the 
probable participant is illiterate, or presents some physical disability that prevents 
the fulfilling of this act, a person designated by the participant shall place the name 
of the participant and the date, attesting that the participant by its own will decides 
to participate; the participant shall place the fingerprint of the right thumb, with 
blue ink in the section designated for the signature of the participant. Afterwards, 
the two impartial witnesses who were present during the process of Informed 
Consent shall place in the designated section complete name, kinship with the 
participant, address and date. The kinship only considers blood relations; in case 
of not having kinship with the participant, the witness shall place in the section 
designated for kinship the legend “none”. Finally, the personnel that executes the 
process of Informed Consent shall place their full  

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name, signature and date according to the good practices of documentation. Once 
this section is duly filled, a faithful copy of the original shall be granted to the 
participant; the person who conducted the process shall place in the inferior part of 
the final sheet of the document “this document is a faithful copy of the original 
document”; through good practices of documentation and in blue ink. Said 
document shall be provided to the participant. If at the moment of signing the 
Informed Consent there is an error in the data, the person responsible of 
conducting the Informed Consent shall procure that these are corrected according 
to good practices of documentation and, shall clarify it in the note where the 
process of obtainment of Informed Consent is documented. 
 
 
 
 
9.4.3. Assignation of the code of identification of the subject 
 
With the objective of safekeeping of the confidentiality of the participants of the 
study and lead and adequate control of the procedures performed with each 
subject, a code shall be assigned to each one. The method to generate said code 
shall be in the following: 
 
- 
Subject’s initials: These will be constituted by the first letter of the first name, 
first letter of the first surname and first letter of the second surname. No matter 
if they have more than one name or more that 2 surnames; in the event that 
the participant has only one surname, then only the first letter of the first name 
and the first letter of the surname will be placed. All the letters shall be in upper 
case. 
- 
Number of subject: The number shall be assigned in consecutive to those 
who are included in the study once its proven that they fulfill all the inclusion 
criteria and none of the exclusion criteria. The number shall consist of 3 digits 
beginning with zeroes on the left. For example, the first number will be 001. 
- 
Number of the investigation site: This number shall be obtained starting 
from the number that the sponsor assigns to each site. 
 
Between each data an intermediate hyphen shall be placed in the registries where 
it isn’t pre-assigned. 

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With these requirements, the subject code will be conformed in the following 
manner: 
    FFV-001-01 
 
 
        Subject’s initials 
 
 
 
 
     Site number 
Subject consecutive number 
 
 
 
 
9.4.4. Basal visit, day 0. Review of inclusion and exclusion criteria, 
formulation of clinical history, physical exploration, take of 
laboratory sampling and participant inclusion 
 
 
 
Due to the temporality nature of the processes this basal visit will consist at least 
of 2 visits to the investigation site by the subject under investigation. 
 
Prior to reviewing that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria, the information of the subject shall be identified only by the 
initials, exactly as it is indicated in point 9.4.3 section “Subject’s initials.” 
 
Review of inclusion and exclusion criteria 
 
Once the process of informed consent is completed and with the participant’s 
authorization, the physician in charge will review that the patient complies with all 
the inclusion criteria and none of the exclusion criteria. The laboratory values that 
will be necessary for the patient inclusion are not be considered at this moment. 
 
The participants that comply with the analyzed criteria up to this moment to be 
part of the study shall proceed with the process of the basal visit. 
 
The subjects that don’t comply with the analyzed criteria up to this moment to be 
part of the study shall be notified about this and they will be thanked for their time. 
 
Formulation of the clinical history 
 
A complete clinical history of the participants that comply with the criteria to be 
included in the study (excepting until now the laboratory parameters) will have to 
be obtained. This clinical history shall be elaborated in accordance with the 
existing legislation in Mexico. [L8]  It shall contain at least: 

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- 
Identification sheet. 
 
 
- 
Hereditary-familial medical history, emphasizing those that could lead the 
participant to a cardiovascular risk according to the information contained in 
this protocol or that have bearing in the election for participation in the study. 
 
 
- 
Non-pathologic personal background, emphasizing those that could lead the 
participant to a cardiovascular risk according to the information contained in 
this protocol or that have bearing in the election for participation in the study. 
 
 
- 
Pathologic personal background, emphasizing those that could lead the 
participant to a cardiovascular risk according to the information contained in 
this protocol or that have bearing in the election for participation in the study. 
 
 
- 
Current condition. 
 
 
- 
Interrogation by organs and systems, emphasizing those that could lead the 
participant to a cardiovascular risk according to the information contained in 
this protocol or that have bearing in the election for participation in the study. 
 
 
- 
Complete physical examination with exterior habitus, vital signs, weight in 
kilograms, height in centimeters, estimation of corporal mass index, data of 
head, neck, thorax, abdomen, extremities and genitals. Emphasis will be 
placed on those that could lead the participant to a cardiovascular risk 
according to the information contained in this protocol or that have bearing in 
the election for participation in the study. 
 
- 
The taking of vital signs will always be performed with the patient in seating 
position and with the following particular considerations: 
 
- 
Pulse: This shall be evaluated in the radial artery of the right or left arm, as 
convenient to the treating physician and disposition of the subject in the distal 
third of the chosen forearm and in the place clinically known as the anatomical 
snuff-box. The registries shall be expressed in number of pulsations per 
minute. 
 
- 
Arterial tension: It shall be evaluated with a sphygmomanometer or 
manometer for which the standard process mentioned in NOM-030-SSA2-
2009 will be used as reference. The registries shall be in millimeters of 
mercury. 
 
 
 

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- 
Temperature: Shall be evaluated in the axillar region through the use of a 
mercury or digital thermometer and will be expressed in degrees Celsius. 
 
- 
Respiratory frequency: It shall be evaluated with the assessment of the 
number of times that a patient inspires per minute, expressing in this manner 
the results obtained. 
 
 
- 
Previous results of laboratory and cabinet studies, with special emphasis of 
those that could lead the participant to a cardiovascular risk according to the 
information contained in this protocol or that impinge in the election for 
participation in the study. 
 
 
- 
Therapeutic used and results obtained, placing emphasis in those that could 
lead the participant to a cardiovascular risk, interaction with the medicines of 
the study, that impinge with the election for participation in the study or that 
have current management for the problem to be studied. 
 
- 
Diagnoses or clinical problems, performing an initial evaluation with the 
Globorisk scale for Mexicans contained in this protocol to estimate the 
cardiovascular risk, one that could compromise the subject’s participation in 
the study or that could alter the results of same. 
 
- 
Management plan, in which the consideration pertinent to the study shall be 
annotated. 
 
In patient that have current management for dyslipidemias and that accept a 
period of lavage of 3 weeks, the risk of withdrawing this treatment shall be 
evaluated to find if it’s not significant for the patient according to the results 
obtained in the scale of cardiovascular risk and the levels that have been achieved 
in the reduction of lipids with the current treatment. A patient with very high 
cardiovascular risk shall not abandon the therapy used and therefore must not be 
included in the study. If a favorable benefit that outweighs these risks is expected 
from participation in the study, the patient shall proceed to the taking of blood 
samples and electrocardiogram, described hereinafter. Besides, a visit will be 
scheduled to continue with the processes of sample taking for the laboratory and 
cabinet studies in at least 3 subsequent weeks. 
 
If the participant, by clinical evaluation doesn’t comply with the criteria to 
participate in the study, the motive will be indicated and he/she will be thanked for 
participating. 

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For those that do comply with the clinical parameters to join the study, they will be 
invited to proceed with the personnel in the place indicated for the obtaining of 
laboratory and cabinet studies. 
 
Since for their inclusion the laboratory parameters are needed, the personnel 
designated for the gathering of samples shall be indicated to perform, in the 
following order: 
 
1. Taking urine sample in case the subject is a woman in fertile period to perform 
an immunologic pregnancy test in urine. For the taking of the urine sample, 
the delegated personnel of the site will give the participants a sterile container 
for them to go to the bathroom and place the urine in it, after which the 
delegated personnel shall place enough urine in the dispensed device or 
reactive strip for this analysis and will wait and corroborate the result. The 
women who result with a positive result will no longer continue in the processes 
for their inclusion and they will be notified of the reason given counseling about 
their condition. 
 
 
2. Taking of Electrocardiogram (EKG) of 12 derivations. If some abnormality is 
detected which compromises the participation of the subject upon 
consideration of the established criteria in this protocol or of the investigator or 
its designated personnel, the subject will be notified and will be given counseling 
about the condition if it applies; in turn, the participant will not continue with the 
processes of the study. In the process of taking of EKG the participant shall be 
provided with a new disposable gown so that the superior region may be 
uncovered; if there is an excess of corporal hair in the precordial region or in the 
distal extremes of the thoracic and/or pelvic limbs, it shall be procured that this 
doesn’t interfere with the placing of the electrodes. The surface where these 
shall be placed must be clean and free of additives that interfere with the 
registry. In turn, a conductor gel shall be used at the site of placement of the 
electrodes. The patient must not have on him/her metallic objects that interfere 
with the study or any other that causes pressure such as sustainers, tight 
shoelaces, belts, etc. 
 
 
3. Taking of blood sample: the patient shall have fasted for 9 to 12 hours for 
this; if this period is not observed, then the visit shall have to be rescheduled 
for the participant to comply with it. The process for the gathering of samples 
is contained in section 10.2 of this protocol. In subjects who have at least 12 
hours of fasting, 2 tubes of 10 ml each will be obtained from each participant; 
in this sample, the following will be evaluated: 

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3.1. 
Blood Biometry without differential and Glycosylated 
Hemoglobin. 
 
3.2. 
Blood Chemistry to evaluate: TC, C-LDL, C-HDL, TG, 
C-no HDL, Glucose, Urea, Creatinine, Uric Acid, ALT, 
AST and CPK. 
 
Once these laboratory and cabinet studies have been obtained, the participant 
will be indicated the following date to continue with its inclusion with the previous 
analysis of the results or, its inclusion in the study will be ruled-out and the 
participant will be notified of the reason for not being able to participate. 
 
 
 
 
9.4.5. Basal visit day 0, treatment assignment 
 
 
 
Only the participants who comply with all the inclusion criteria and none of the 
exclusion criteria may be assigned to treatment. 
 
At this point they will be assigned an identification code with the necessary 
requirements quoted before. 
 
The personnel delegated with the responsibilities to assign treatment on part of 
the main investigator’s team shall do it in accordance to what is described in point 
“9.3 Assignation of treatment and treatment groups”- The treatment number will 
be registered, lot number, expiration date and number of tablets dispensed. All 
this will be contained in the report format of corresponding cases. 
 
Moreover, the delegated personnel shall corroborate in combination with the 
participant that he/she was given treatment for 33 days, for the matter of window 
period for the next visit. The designated personnel of the investigation site will 
indicate the patient the method of administration according to the reference point 
in this protocol, “Administration of the investigational product”. Emphasis shall be 
placed in that the designated treatment is unique and non-transferable, so the only 
person who shall undergo this treatment is the participant. Besides, a card 
contained in Annex 2 will be provided, which has the title: “Treatment Control Card 
of the Participant Basal Visit”; explaining how to fill it and referring that the 
participant must bring it in the next visit. 
 
In the event of adverse events, the patient shall be informed of any new clinical 
or laboratory condition, it shall be reported to the investigation site, reminding 

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contact numbers of the site and work hours to do it and the telephone number of 
the designated personnel to receive notifications in working hours. 
 
Finally, the date of the next visit shall be assigned and be reminded that he/she 
will be contacted by telephone by site personnel 7 days after the basal visit. 
 
 
 
 
9.4.6. Telephone call posterior to basal visit, day 7 +/- 2 days 
 
 
 
A telephone call will be made to the participant at 7 days +/- 2 days posterior to 
the initiation of the treatment (complete basal visit). The finality of this call is to 
corroborate that the investigational product is being adequately administered and 
find out about the incidence of adverse events related to the product and/or new 
concomitant medicines. In turn, the participant will be asked about the filling of the 
treatment control card and if there are any doubts these will be solved. This 
information must be registered. Besides, the next appointment day will be 
corroborated and the participant will be reminded to attend with a 9 to 12 hour 
period of fasting, and to bring the package of the investigation drug and all the 
elements it included, even if the pharmaceutical forms had been concluded. In the 
telephone call it will also be verified that the subject has the necessary medicines 
to be administered at least until the following visit. 
 
If there is any relevant finding that deviates what’s accented in this protocol, it 
shall be notified in the corresponding instances. 
 
 
 
 
9.4.7. Visit 1, day 30 +/- 3 days with respect to complete basal visit 
 
 
 
The patient will be asked and referred that he/she attended with 9 to 12 hours of 
fasting. 
 
A clinical evaluation will be performed with the aim of updating the clinical history 
in accordance to what is contained in the Mexican Official Norm of the Clinical 
Expedient. [L8] Besides, the CMI will be evaluated. 
 
The patient will be asked about the incidence of adverse events and/or about new 
concomitant medicines that have been administered. 
 
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It will be verified that the patient has administered the medicine with the adequate 
posology; if there is any non-compliance a note shall be made and the 
continuation of the subject will be evaluated. The site staff shall collect the 
package of the anterior medicine, even if it has remnants of the investigational 
product. The treatment number shall be registered, along with lot number, 
expiration date, number of tablets used and number of remaining tablets. Also, 
the basal treatment card will be received, clarifying the pertinent discrepancies in 
the filling of the form. Everything will be contained in the format of corresponding 
case report. 
 
It will be corroborated that the participant doesn’t fulfill criteria for early termination 
of the study. 
 
In the case of fertile women, they will be questioned and registration will be made 
about the family planning method used, seeing that these are permitted in the 
study; besides, a urine sample will be obtained to perform an immunologic 
pregnancy analysis according to the characteristics referred in the basal visit. 
 
In this visit a blood sample will be taken to evaluate through blood chemistry the 
following laboratory parameters: Glucose, urea creatinine, ALT, AST, TC, C -LDL, 
C-HDL, C-No-HDL, TG and CPK. Upon reception of the results, it will be seen if 
there was any change in comparison with the previous results; all new parameters 
must be registered; if the laboratory analysis doesn’t include the measurement of 
C-No-HDL, the investigator or delegated staff shall calculate it through the use of 
the equation contained in this protocol. Besides, if there is any suspicion of 
adverse event by the laboratory parameters, this shall be reported according to 
the classification and notified to the investigation subject and to the pertinent 
authorities in the temporality contained in the section of adverse events of this 
protocol. 
 
The designated staff will ask the sponsor to grant the treatment code and will give 
the investigation subject enough medicine to complete 66 days of treatment. The 
patient will be reminded about the administration method of the medicine. The 
number of treatment, lot number, expiration date and number of tablets 
dispensed. Everything will be contained in the corresponding case report formats. 
Besides, the patient will be provided with the card contained in Annex 3 that has 
the title “Control Card of Treatment of Participant Visit 1”, explaining its filling and 
referring that it must be brought on the next visit. 

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A date for the next visit will be assigned and the contact numbers of the site will 
be reminded, in work-hours and non-work-hours. Also, the participant will be 
reminded that at 37 and 60 days posterior to basal visit he/she shall be contacted 
on the telephone by staff from the site. 
 
 
 
 
9.4.8. Telephone calls posterior to visit 1, days 37 (+/- 3) and 60 (+/- 
3) 
 
 
 
A telephone call will be made to the participant after 37 days of completing the 
basal visit with a window period of +/- 3 days and at 60 days with a window period 
of +/- 3 days, both concerning the completion of the basal visit. 
 
The finality of these calls is to corroborate that the investigational product of 
investigation is being administered adequately and to find about the incidence of 
adverse events related with the product and/or new concomitant medicines. In the 
telephone calls it will also be verified that the subject has the necessary medicine 
to be administered at least until the next visit. In turn, the subject will be asked 
about the filling of the treatment control card and if there are any doubts these 
will be clarified. This information must be registered. 
 
If there is any relevant finding that deviates what’s accented in this protocol, it 
shall be notified in the corresponding instances. 
 
In the call of day 60 the date of the next appointment will be corroborated and the 
subject reminded to bring the package of the drug in investigation with all the 
elements it included, even if its pharmaceutical forms have been concluded. 
 
All the information gathered in these calls must be registered. 
 
 
 
 
9.4.9. Visit 2, day 90 +/- 5 days to compete basal visit 
 
 
 
It must be verified that the patient attended with 9 to 12 hours of fasting. 
 
It will be verified that the patient has administered the medicine with the adequate 
posology; if there is any non-compliance a note shall be made and the 
continuation of the subject will be evaluated. The site staff shall collect the 
package of the anterior medicine, even if it has remnants of the drug in 
investigation. The treatment number shall be registered, along with lot number, 
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the basal treatment card will be received, clarifying the pertinent discrepancies in 
the filling of the form. Everything will be contained in the format of corresponding 
case report. 
 
A clinical evaluation will be performed with the aim of updating the clinical history 
in accordance to what is contained in the Mexican Official Norm of the Clinical 
Expedient. [L8] Besides, the CMI will be evaluated. 
 
The patient will be asked about the incidence of adverse events and/or about new 
concomitant medicines that have been administered. 
 
It will be corroborated that the participant doesn’t fulfill criteria for early termination 
of the study. 
 
In the case of fertile women, they will be questioned and registration will be made 
about the family planning method used, seeing that these are permitted in the 
study; besides, a urine sample will be obtained to perform an immunologic 
pregnancy analysis according to the characteristics referred in the basal visit. 
 
In this visit a blood sample will be taken to evaluate through blood chemistry the 
following laboratory parameters: Glucose, urea creatinine, ALT, AST, TC, C -LDL, 
C-HDL, C-No-HDL, TG and CPK. Upon reception of the results, it will be seen if 
there was any change in comparison with the previous results; all new parameters 
must be registered; if the laboratory analysis doesn’t include the measurement of 
C-No-HDL, the investigator or delegated staff shall calculate it through the use of 
the equation contained in this protocol. Besides, if there is any suspicion of 
adverse event by the laboratory parameters, this shall be reported according to 
the classification and notified to the investigation subject and to the pertinent 
authorities in the temporality contained in the section of adverse events of this 
protocol. 
 
The designated staff will ask the sponsor to grant the treatment code and will give 
the investigation subject enough medicine to complete 99 days of treatment. The 
patient will be reminded about the administration method of the medicine. The 
number of treatment, lot number, expiration date and number of tablets 
dispensed. Everything will be contained in the corresponding case report formats. 
Besides, the patient will be provided with the card contained in Annex 4 that has 
the title “Control Card of Treatment of Participant Visit 2”, explaining its filling and 
referring that it must be brought on the next visit. 
 
A date for the next visit will be assigned and the contact numbers of the site will 
be reminded, in work-hours and non-work-hours. Also, the participant will be 
reminded that at 97 120 and 150 days posterior to basal visit he/she shall be 
contacted on the telephone by staff from the site. 
 

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9.4.10. Telephone calls posterior to Visit 2, days 97 (+/- 3), 120 (+/- 
5) and 150 (+/- 5) 
 
 
 
A telephone call will be made to the participant after 97 days of completing the 
basal visit with a window period of +/- 3 days, at 120 days with a window period 
of +/- 3 days and at 150 days with a window period of +/- 3 days. All dates and 
periods of estimated windows shall be used as reference the complete basal visit 
of each subject. The finality of these calls is to corroborate that the medication is 
being administered adequately and to find about the incidence of adverse events 
related with the product and/or new concomitant medicines. In the telephone calls 
it will also be verified that the subject has the necessary medicine to be 
administered at least until the next visit. In turn, the subject will be asked about 
the filling of the treatment control card and if there are any doubts these will be 
clarified. This information must be registered. 
 
If there is any relevant finding that deviates what’s accented in this protocol, it 
shall be notified in the corresponding instances. 
 
In the call of day 150 the date of the next appointment will be corroborated and 
the subject reminded to bring the package of the investigational drug with all the 
elements it included, even if its pharmaceutical forms have been concluded. 
 
All the information gathered in these calls must be registered. 
 
 
 
 
9.4.11. Visit 3, day 180 +/- 7 days with respect to complete basal visit 
(Final Visit) 
 
 
 
It must be verified that the patient attended with 9 to 12 hours of fasting. 
 
It will be verified that the patient has administered the medicine with the adequate 
posology; if there is any non-compliance a note shall be made and the 
continuation of the subject will be evaluated. The site staff shall collect the 
package of the anterior medicine, even if it has remnants of the treatment. The 
treatment number shall be registered, along with lot number, expiration date, 
number of tablets used and number of remaining tablets. Also, the basal treatment 
card will be received, clarifying the pertinent discrepancies in the filling of the form. 
Everything will be contained in the format of corresponding case report. 
 
A clinical evaluation will be performed with the aim of updating the clinical history 

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in accordance to what is contained in the Mexican Official Norm of the Clinical 
Expedient. [L8] Besides, the CMI will be evaluated. 
 
The patient will be asked about the incidence of adverse events and/or about new 
concomitant medicines that have been administered. 
 
It will be corroborated that the participant doesn’t fulfill criteria for early termination 
of the study. 
 
In the case of fertile women, they will be questioned and registration will be made 
about the family planning method used, seeing that these are permitted in the 
study; besides, a urine sample will be obtained to perform an immunologic 
pregnancy analysis according to the characteristics referred in the basal visit. 
 
In this visit a blood sample will be taken to evaluate through the following 
laboratory parameters: 
 
1.1. 
Blood Biometry without differential and Glycosylated 
Hemoglobin. 
 
1.2. 
Blood Chemistry to evaluate: TC, C-LDL, C-HDL, TG, 
C-no HDL, Glucose, Urea, Creatinine, Uric Acid, ALT, 
AST and CPK. 
 
Upon reception of the results, it will be seen if there was any change in comparison with 
the previous results; all new parameters must be registered; if the laboratory analysis 
doesn’t include the measurement of C-No-HDL, the investigator or delegated staff shall 
calculate it through the use of the equation contained in this protocol. Besides, if there 
is any suspicion of adverse event by the laboratory parameters, this shall be reported 
according to the classification and notified to the investigation subject and to the 
pertinent authorities in the temporality contained in the section of adverse events of this 
protocol. 
 
9.4.12.Summary of the processes to be performed by the subjects 
during their participation in the study. 
 
 
 
Process to perform during the visits 
VISIT 
PROCEDURES 

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PATIENT 
SELECTION 
- 
Acquiring letter of Informed Consent. 
BASAL VISIT, DAY 0 
(FIRST PART) 
- 
Review of inclusion and exclusion criteria that don’t 
require laboratory parameters. 
- 
Lavage period of 3 week for those who apply. 
- 
Formulation of clinical history that counts with:  
identification sheet, hereditary-familial background, 
non-pathologic 
personal 
background, 
pathologic 
personal background, current condition, interrogatory 
by organs and systems, physical exploration with 
exterior habitus, taking of vital signs, weight, height, 
estimation of CMI, data of head, neck, thorax, 
abdomen, limbs and genitals; previous laboratory and 
cabinet results, therapeutic used, diagnose and plan. 
- 
Taking of urine sample in case of women in fertile 
period to perform immunologic pregnancy test. 
- 
Taking of Electrocardiogram of 12 derivations. 
- 
Taking of blood sample with 9 to 12 hours of fasting; 
two 10 ml tubes will be obtained to perform the 
following studies: Blood Biometry without differential 
and Glycosylated Hemoglobin. Blood Chemistry to 

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evaluate: TC, C-LDL, C-HDL, TG, C- no HDL, 
Glucose, Urea, Creatinine, Uric Acid, ALT, AST and 
CPK. 
 
 
 
 
 
 
 
BASAL VISIT, DAY 0 
(SECOND PART) 
- 
It will be verified that the participant counts with all the 
inclusion criteria and none of the exclusion criteria, 
including those of laboratory. 
 
 
- 
Assignation of identification code of the subject. 
 
 
- 
Assignation of treatment. 
 
 
- 
Assignation of next date of appointment for visit 1. 
 
 
 
 
 
 
TELEPHONE CALL 
POSTERIOR TO 
BASAL VISIT, DAY 7 
+/- 2 DAYS 
- 
Corroborate 
adequate 
administration 
of 
investigational product and filling of treatment control 
card. 
 
 
- 
Obtain information about the occurrence of adverse 
events. 
 
 
- 
Corroborate date of next appointment for visit 2, 
reminding that participant must attend with a fasting 
period of 9 to 12 hours and with the packages and 
remnants of the investigational drug. 
 
- 
Verify fasting of participant of 9 to 12 hours. 
 
 
- 
Make medical note and update of clinical history. 
 
 
 
 
VISIT 1, DAY 30 +/- 3 
DAYS 
- 
Ask about and record the occurrence or non-
occurrence of adverse events. 
 
 
- 
Review the administration of the medicine of study 
and collecting of packages and packages if there are 
any. 
 
 
- 
In women in fertile phase, urine sample to perform 
immunologic pregnancy test. 
 
 
- 
Verify criteria of early termination. 

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- 
Taking of 10 ml of blood sample to evaluate: Glucose, 
urea, creatinine, ALT, AST, CT, C-LDL, C- HDL, C-
No-HDL, TG and CPK. 
 
 
- 
Assignation of treatment. 
 
 
- 
Assignation of next appointment date for visit 2. 
 
 
 
TELEPHONE CALL 
POSTERIOR TO VISIT 
1, DAY 37 +/- 3 DAYS 
- 
Corroborate 
adequate 
administration 
of 
the 
investigational drug and filling of treatment control 
card. 
 
 
- 
Obtain information about the occurrence of adverse 
events. 
 
 
 
 
 
 
 
TELEPHONE CALL 
POSTERIOR TO VISIT 
1, DAY 60 +/- 3 DAYS 
- 
Corroborate 
adequate 
administration 
of 
the 
investigational drug and filling of treatment control 
card. 
 
 
- 
Obtain information about the occurrence of adverse 
events. 
 
 
- 
Corroborate date of next appointment for visit 2, 
reminding that participant must attend with a fasting 
period of 9 to 12 hours and with the packages and 
remnants of the investigational drug. 
 
- 
Verify fasting of the participant of 9 to 12 hours. 
 
- 
Make medical note and update of clinical history. 
 
 
VISIT 2, DAY 90 +/- 5 
DAYS 
- 
Ask about and record occurrence on not of adverse 
events. 
 
 
- 
Review of administration of medicine of study and 
gathering of packages and, it there are any, the 
remaining pharmacologic forms. 
 
- 
In women in fertile phase, urine sample to perform 
immunologic pregnancy test. 

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- 
Verify criteria of early termination. 
 
- 
Taking of 10 ml of blood sample to evaluate: Glucose, 
urea, creatinine, ALT, AST, CT, C-LDL, C- HDL, C-
No-HDL, TG and CPK. 
 
- 
Assignation of treatment. 
 
- 
Assignment of date for nest appointment for visit 3. 
 
 
 
TELEPHONE CALL 
POSTERIOR TO 
VISIS 2, DAY 97 +/- 3 
DAYS 
- 
Corroborate 
adequate 
administration 
of 
the 
investigational drug and filling of treatment control 
card. 
 
 
- 
Obtain information about the occurrence of adverse 
events. 
 
 
 
TELEPHONE CALL 
POSTERIOR TO VISIT 
2, DAY 120 +/- 5 
DAYS 
- 
Corroborate adequate administration of the product of 
the investigational drug and filling of treatment control 
card. 
 
 
- 
Obtain information about the occurrence of adverse 
events. 
 
 
 
 
 
 
 
TELEPHONE CALL 
POSTERIOR TO VISIT 
2, DAY 150 +/- 5 
DAYS 
- 
Corroborate 
adequate 
administration 
of 
the 
investigational drug and filling of treatment control 
card. 
 
 
- 
Obtain information about the occurrence of adverse 
events. 
 
- 
Corroborate date of next appointment for visit 2, 
reminding that participant must attend with a fasting 
period of 9 to 12 hours and with the packages and 
remnants of the investigational drug. 
 
 
  VISIT 3, DAY 180 +/- 7   
  DAYS (FINAL VISIT) 
- 
Verify fasting of the participant from 9 to 12 hours. 
 
 
- 
Make medical note and update of clinical history. 

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- 
Ask about and register the occurrence or not of 
adverse events. 
 
- 
Review of administration of medicine of study and 
gathering of packages and, it there are any, the 
remaining pharmacologic forms. 
 
- 
In women in fertile phase, urine sample to perform 
immunologic pregnancy test. 
 
- 
Verify criteria of early termination 
 
- 
Taking of blood sample with 9 to 12 hours of fasting; 
two 10 ml tubes will be obtained to perform the 
following studies: Blood Biometry without differential 
and Glycosylated Hemoglobin. Blood Chemistry to 
evaluate: TC, C-LDL, C-HDL, TG, C- no HDL, 
Glucose, Urea, Creatinine, Uric Acid, ALT, AST and 
CPK. 
 
*Window periods: Will be taken starting on the date of complete basal visit. Being the visit date 
considered as 0 and the window periods in less or more days with respect to this day. For example, 
a patient who has visit 2 in December 31 of 2017, December 31 will be considered as day 0 and 
having a window of +/- 5 days, it will be counted starting from this day in more or less, the visit 
being had form December 26 of 2017 to January 5 of 2018. 

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9.4.13.Patients to Sieve to comply with the Sample Size 
 
 
 
 It is estimated that around 400 subjects will have to be sieved to comply with the 
desired sample size, this based on the calculation of excluded patients. For this, 
it is calculated that of the total of evaluated subjects for selection 75% will accept 
to participate in the study; of the 350 remaining subjects it is estimated that 75% 
will comply with clinical, electrocardiographic, and/or non-pregnancy criteria for 
their inclusion; finally, it is estimated that an aggregate of 46% will comply with the 
laboratory parameters to be included (for example, it is known that the prevalence 
of hypercholesterolemia in Mexican adults is 50.5% [18]). Truncating the result to 
whole numbers 120 investigation subjects remain. 
 
Evaluated for selection: 400. 
 
Subjects who wish to participate: 75% of the 400 = 
350. 
 
Of the subjects who wish to participate, subjects who comply with clinical, 
electrocardiographic and non-pregnancy criteria for their inclusion: 
 
75% of 350 = 262.5 
 
Of the remainder, the estimate of subjects who’ll comply with laboratory criteria in 
blood for their inclusion is of: 
 
46% of 262.5 = 120.75, 120 subjects. 
 
The 120 patients will be randomized with the “Research Randomizer” program to 
receive treatment with the investigational product (atorvastatin + l- carnitine) or 
with the active control (atorvastatin); being able to have 60 patients per group. 
 
This number of patients was the one calculated in the size of sample per group 
based on an estimate of losses which are expected: 
 
Patients per group = 60, of which a 10% loss is estimated = 6 losses per group; 
completing analysis of efficacy 54 patients per group. 
 
As is mentioned in the protocol, the intention is to analyze the efficacy data in 
those that finish the intervention, but for the safety analysis of the medicines of 
the study, the data of all the participants who receive treatment will be included, 
whether they concluded or not all the processes of the study. 

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Analysis 
Follow-up 
Asignation 
Recruitment 
 
 
 
Evaluated for selection 
N= 400 
 
 
 
Excluded N = 280 
Don’t comply with selection 
criteria = 240 
Don’t wish to participate = 40 
 
 
 
 
Randomized 
N= 120 
 
 
 
 
 
 
 
Assigned to 
investigational Product 
N = 60 
 
 
 
 
Losses = 6 
 
1.-  Losses to follow-up = 3 
Unidentifiable 
change 
of 
address. 
 
2.- Interrupt intervention = 3 
Criteria of early termination. 
 
 
 
 
 
Analyzed N = 54 
 
All patients who receive 
treatment will be included in 
the safety analysis (60). 
Assigned to Active 
Control 
N = 60 
 
 
 
 
Losses = 6 
 
    1.-  Losses to follow-up = 3 
Unidentifiable change of 
address. 
 
2.- Interrupt intervention = 3 
Criteria of early termination 
 
 
 
 
 
Analyzed N = 54 
 
All patients who receive 
treatment will be included in 
the safety analysis (60). 

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9.4.14.Procedures based on the study groups 
 
 
 
 
 
N=120 subjects 
 
 
Random assignation 
 
60 participant* receive: 
2 tablets of 
Atorvastatin10mg + L- 
carnitine 500mg 
 
60 participants* receive: 
2 tablets of 
Atorvastatin10mg 
 
 
 
 
Recruitment and patient 
selection 
 
 
 
 
 
 
Visits 
Telephone Calls 
 
 
 
Basal visit, 
first part 
(Day 0) 
 
Basal visit, 
second part 
(Day 0) 
 
 
 
Telephone call 
day 7 
 
Visit 1 (Day 30)  
 
Telephone call 
day 37
 
Telephone 
call day 60
 
Visit 2 (Day 90)  
 
Telephone call 
day 97 
 
Telephone 
call day 120 
 
 
 
                                                                      Visit 3 (Day 
                                                                          180, Final Visit) 
 
Telephone 
call day 150 
 

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*The sample size per group of treatment may change according to the result of simple 
randomization. 

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VISIT 
Patient 
Selectio
n 
Basal 
Visit, 
Day 0 
(First 
Part 
Basal 
Visit, 
Day 0 
(Secon
d Part) 
Teleph
one 
Call 
Day 7 + 
2 
Visit 
 1 
Day 
30 
± 3 
days 
Telepho
ne Call 
Day 37 
± 3 
days 
Teleph
one 
Call  
Day 60 
± 3 
days 
Visit 
2 
Day 
90 
±5 
days 
Teleph
one 
Call 
Day 97 
± 3 
Teleph
one 
Call 
Day  
120 ± 
5 
Teleph
one 
Call 
Day  
150 ± 
5 
Visit 
3 
Day 
 180 
± 7 
days 
(final 
visit) 
 
 
 
PROCEDURE 
Obtention of 
Informed 
Consent Form 
X 
Review of Inclusion 
/Exclusion Criteria 
X 
X 
Period of lavage of 3 
weeks (for those who 
have previous 
treatment for 
dyslipidemias) 
X 
Revision of Early 
Termination Criteria 
X 
X 
X 
Clinical history 
X 
X 
X 
X 
X 
Verify 9 to 12 hour 
fasting 
X 
X 
X 
X 
Taking of urine 
sample for IPT* 
X 
X 
X 
X 
Taking of EKG 
X 
Taking of samples for 
laboratory exams 
 (BH, HbA1c, 
Glucose, Urea, Cr, 
uric acid, TC, C-LDL, 
C-HDL, TG, C-no 
HDL, ALT, AST and 
CPK) 
X 
X 
Taking of samples 
for laboratory 
exams ( Glucose, 
Urea, Cr, uric acid, 
TC, C-LDL, C-HDL, 
TG, C-no HDL, ALT, 
AST and CPK) 
X 
X 
Assignation of 
identification code 
of subject 
X 
Assignation of 
treatment 
X 
X 
X 
Delivery of 33 days of 
treatment 
X 
Delivery of 66 days of 
treatment 
X 
Delivery of 99 days of 
treatment 
X 
Corroborate 
administration of the 
medicine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Information about 
adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Date of next visit 
X 
X 
X 
X 
X 
X 
X 
End of the study 
X 
*IPT: Immunologic pregnancy test for female patients in fertile stage 

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9.4.15. Visits not stipulated by protocol 
 
 
 
Visits not stipulated by protocol may be secondary to events detected through the 
telephone on part of the investigation site, from the participant and even upon 
request from the investigator during visits established in the protocol. Also, the 
participant may go to the investigation site for medical evaluations. 
 
These, shall be registered in a medical note and be referred in the corresponding 
CRF for visits not stipulated in protocol. 
 
 
 
 
9.4.16.Capture and processing of data 
 
 
 
The data obtained during the study will be registered in the case report formats 
(CRF) that the sponsor indicates, filled by hand, with blue ink and in script. No 
registry of any data shall be omitted in these. The personnel delegated for CRF 
registry shall do it with the use of good documentation practices. This doesn’t omit 
the fact that the source documents are found at the investigation site with the 
information of who originally gathered the data and the follow-up of good practices 
of documentation. Once this information is obtained the personnel of the 
investigation site shall capture them in an electronic database created by the 
sponsor and provided by the main investigator. The sponsor will have faculties of 
edition of the registries captured by the site personnel, generate questions about 
unclear data in the registries and modify the format and the operation of the 
database if deemed pertinent; for their part, the personnel delegated on the site 
will only have faculties for inclusion and reading of new data. Once the data are 
saved, it may only be modified with the authorization of the sponsor based on 
doubts generated for their clarification. 
 
The data obtained will be used for their processing by the competent person to 
do this on the sponsor’s behalf. 

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9.4.17.Statistical analysis and interpretation of the information 
 
 
 
A first analysis which is performed in the controlled clinical assays is to compare 
the groups of treatment in their basal conditions and that generally are 
demographic characteristics (for example: age, gender), anthropometric 
measures (for example, corporal mass), inherent conditions to its clinical state (for 
example, severity of the disease, metabolic control) and other prognosticate 
variables related with the primary result variable. Usually presented as summary 
measures (means, medians) and dispersion (standard deviations and ranges) in 
continuous variables and in percentages for the categorical variables. This 
comparison is also useful to describe the sample of subjects who entered the 
study. Significance tests are used (t or Ji squared) with values of p. When a 
difference occurs between groups, they aren’t necessarily due to a failure in 
randomization, but by accident. Altman recommends that the descriptors are 
basally compared using a combination of clinical knowledge and common sense. 
If the groups aren’t balanced a non-adjusted analysis must be made and another 
one adjusted by the variable that unbalanced both groups. [146, 154] The statistical 
method used to compare 2 averages in different groups of treatment is the t test 
of student, compares the media of 2 groups of continuous variables and 
expresses the probability that any difference is due to the role of chance (rejects 
the null hypothesis). The assumptions that follow the t of student is that the data 
in both groups follow a normal distribution and that for non-paired samples the 
variance for each group is equal. [146] 
 
Base on the above, for the descriptive statistic the media and median will be used 
as measures of central tendency. As measures of dispersion, variance, standard 
and minimum and maximum values will be used. 
 
For the inferential statistic the analysis of variance (one-way ANOVA) will be used 
to compare the variations in the levels of TC, C-LDL, C-No-HDL, C-HDL and TG, 
from the basal values to the end of the study. In turn, the laboratory values that 
give correlation with incidence of adverse effects may be analyzed by laboratory 
parameters and, if convenient, the ones required to obtain the premises of the 
study. This test will also be used to search for significant association within the 
two groups of treatment. 
 
The non-paired, two-tailed test of Student will be used to evaluate these 
comparisons between the two groups of treatment and its reduction in the 

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percentage of C-LDL and C-No-HDL. 
 
The intergroup stratification will be done based on the concentration of plasmatic 
C-LDL, taking as the cutting point the upper limit for the cardiovascular risk of the 
patients and the 2 test for comparison of proportions between the groups of the 
study. 
Values of P < 0.05 (2 tails) will be considered statistically significant. 
  
For the statistical treatment of the data thrown by the study one of the professional 
programs of statistics may be used (SPSS, SigmaPlot, Origins, 
GraphPad Prism, etc.). 
 
 
 
 
10. OBSERVATIONS OF THE STUDY. 
 
 
  Medicine 
 
 
 
10.1.1. Doses 
 
 
 
The patient will self-administer the medicine through oral route, at least 30 
minutes before the intake of food in a nocturnal intake schedule between 20:00 to 
21:00 hours and with a temporality of 1 time per day. 
 
The patient must not administer the medicine of the study in combination with any 
other medicine. 
 
So much the experimental group as the active control will have to administer 2 
caplets or tablets. 
 
The aforementioned process is the same for the subjects who participate in any 
group, the difference is in the active of each group. 
 
The differences between the medicines of the study consist in that the 
experimental medicine is in caplets in which L-carnitine is added to the 
atorvastatin; in the active control group the medicine only contains atorvastatin (in 
the same concentrations as the experimental group). The formulations are 
exemplified hereunder: 

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Active content according to treatment group 
TREATMENT 
GROUPS 
 
Active by 
pharmaceutical 
form 
Product to be 
administered 
per day and 
content of final 
active 
EXPERIMENTAL 
GROUP 
L-Carnitine 500mg + 
atorvastatin 10mg 
2 caplets that 
contain in total 
 L- Carnitine 1g + 
atorvastatin 20mg 
ACTIVE CONTROL 
GROUP 
Atorvastatin 10mg 
2 tablets that in 
total contain 
atorvastatin 20mg 
 
 
 
 
10.1.2.Labeling of the medicine. 
 
 
 
The label will indicate the following: the patient’s code, the study code, the month 
of treatment, the bottle corresponding to the month of treatment, the consecutive 
code of treatment, the number of the treatment, the lot number, the expiration 
date, the administration instructions and the legend “Exclusive use for 
investigation; its sale is forbidden”. 
 
The treatment code shall be formed by 1 upper-case letter and 3 consecutive 
digits. In the case of the experimental treatment the letter will be “L” and for the 
active control the letter will be “C”. For example: L-001. 
 
In the extra treatment the month of treatment will not be placed and its code will 
be formed by the upper-case letters “EXT”, followed by an L or C as is the case 
previously explained and 3 consecutive digits. The rest of the label will be the 
same. 

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EXAMPLE: 
 
Patient: 
. 
Code of study GMX-001-2017 
Month 1: Bottle 1 
Treatment code: L-001. 
 
Exclusive use for investigation, its sale is forbidden. 
 
Bottle with 66 caplets. 
Lot No. 14DY4837. Expiration date: JAN/2018 
 
Dosage: Take 2 tablet at night through oral route 30 min before dinner. 
 
 
 
Patient: 
. 
Code of the study GMX-001-2017 
Month 1: Bottle 1 
Treatment code: C-001. 
 
Exclusive use for investigation, its sale is forbidden. 
 
Bottle with 66 tablets. 
Lot No. 14DY4837. Expiration date: JAN/2018 
 
                                   Dosage: Take 2 tablets at night through oral route 30 min before dinner. 
 
 
 
 
 
10.1.3.Banned medicines. 
 
 
 
The following are the medicines that may cause some interaction with the 
experimental or active control treatment; besides the ones that may modify the 
serum levels of lipids relevant for this study; for which this shall be considered as 
not-authorized use during the present study; if its administration is necessary, it 
shall be a criteria for early termination of the participant: 
 
 
Macrolide antibiotics: Erythromycin, Telithromycin and Clarithromycin. 
 
 Azole anti-fungi: Ketoconazole, Itraconazole, Fluconazole and 
Nefazodone 
 
Protease inhibitors: Saquinavir, Indinavir y Ritonavir 

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 
Quercetin  
 
Amiodarone  
 
Aprepitant  
 
Cimetidine  
 
Ciprofloxacin  
 
Cyclosporine  
 
Diltiazem  
 
Imatinib  
 
Echinacea  
 
Enoxacin  
 
Ergotamine  
 
Metronidazole  
 
Mifepristone  
 
Tofisopam  
 
Gestodene  
 
Verapamil  
 
Mibefradil  
 
Fluoxetine  
 
Phenobarbital  
 
Carbamazepine  
 
Phenytoin  
 
Rifampin  
 
Modafinil  
 
Glucocorticoids  
 
Felbamate  
 
Rosiglitazone  
 
Griseofulvin  

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 
Pioglitazone  
 
Gemfibrozil  
 
Clofibrate  
 
Fenofibrate  
 
Niacin 
 
Cholestyramine  
 
Colchicine  
 
Colestipol  
 
Primidone  
 
Topiramate  
 
Troglitazone  
 
Rifabutin  
 
Digoxin  
 
Thiazides  
 
anabolic Steroids  
 
Progestogens  
 
Estrogens  
 
Danazol  
 
Amiodarone  
 
fibric Acid  
 
Docosahexaenoic acid  
 
Isotretinoine  
 
Immunosuppressives  
 
protease inhibitors of HIV or of the Hepatitis C Virus  
 
Inhibitors of the co-transport of sodium-glucose  
 
Tamoxifen  
 
Raloxifene  
 
non-selective Beta blockers  

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 
biliary acid sequestrants  
 
asparginase  
 
Sirolimus  
 
Interferon 
 
Antacids, alone or in combined use with the administration of the 
investigational product. 
 
 
 
 
 
10.1.4. Inventory of the medicine 
 
 
 
The medicines of the study will be received in the investigation center by the 
principal investigator or the delegate personnel. Once identified the medicines, 
they will remain under safeguard by the investigation site until its dispensation to 
the patients; the corresponding sponsor format will be filled for assignation of 
medicines and its capture in electronic will be done subsequently. 
 
The patient must return all the bottles and/or boxes, either empty or containing 
medicines from the study. The amount of medicine dispensed will be quantified 
for its registry and control. 
 
The medicine of the study that is returned by the patients shall be quantified, 
stored and safeguarded in wait of instructions by the sponsor. 
 
The main investigator or delegate personnel shall keep and store all the original 
containers returned by the patients, until this containers are inventoried by the 
sponsor, unless the sponsor indicates otherwise. 

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At the end of the study, the main investigator or the delegate personnel will return 
all the original containers, either empty or with the surplus medicine of the study, 
as instructed through the monitor. 
 
The main investigator or the delegate personnel shall not store or manage the 
medicine in study in any other place other than the ones agreed on previously 
with the sponsor. 
 
The sponsor will guarantee an adequate disposition of the original containers, 
either empty or full of returned or unused medicine. The adequate documentation 
will be kept. 
 
 
 
 
10.1.5. Storage of the medicine 
 
 
 
The main investigator or the person designated by her/him will ensure that the 
medicine of study will be stored in a safe manner, in a dry place, in a cabinet 
under lock and key, at a temperature not greater than 30°C, with restricted 
access. 
 
All the supplying of the medicines will be registered in the accountability inventory 
forms of the medicines, according to the procedure indicated by the sponsor. 
 
The medicine in the study may not be re-labeled or reassigned for use in other 
patients 
except 
under 
special 
circumstances 
approved 
by 
Valeant 
Pharmaceuticals International. 
 
The main investigator must make sure that the medicines supplied for the study 
be kept under lock and key in a place of access limited to those assigned by 
her/him. 
 
The main investigator shall keep a record of the medicine stored in accordance 
with the format generated by Valeant Pharmaceuticals International. This format 
will include spaces for registering the reception date, amount of treatment, 
treatment code, lot number, expiration date and amount received. When the 
medicine is received at the site, a reception note must be filled by the main 
investigator or the delegate personnel. 

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The administration registry must be kept updated indicating the amount of 
medicine provided to each patient, which patient received the medicine and the 
amount that was left over after the treatment period. All the surplus medicine and 
the one that hasn’t been used must be returned to Valeant Pharmaceuticals 
International at the end of the study. The processes for medicine return will be 
specified by the sponsor, with the proper filling of the format provided by the 
sponsor. 
 
 
 
  Taking and processing of laboratory samples 
 
 
To avoid biases in the quality of the information, the taking of laboratory samples 
and its processing is important, for the efficacy and safety profile of the study will 
depend on the laboratory results. 
 
The taking of blood samples and its processing will be identical for each occasion 
these are obtained in the different visits, differing in the parameters to analyze, it 
will be performed by trained personnel that proves to have the capacity to obtain 
it. The main investigator will delegate to the ideal personnel. New material shall 
be used, which will be labeled with the identification code of the subject. Once the 
sample is contained, it will be transported to the laboratory of the site, where its 
processing may begin according to the required particulars. 
 
For the taking of the blood sample, the personnel shall use sterile gloves, new 
and sterile equipment, and label the tubes with the data previously to extraction 
with the data of the code of the subject of investigation. Afterward, the personnel 
shall locate the vein to puncture and perform antisepsis of the region; the puncture 
may be done with a needle of 21 to 23 G, mounted on a hub or by means of a 
device with “butterfly” needle. Once the site is punctured, the blood must be 
extracted in the adequate type of tube (see in the next section). If 2 different tubes 
are required, the effort shall be made not to puncture more than once the vein of the 
patient and extract the blood through 1 sole puncture. The ideal site is that where 
the trained and delegate personnel may obtain with the least number of tries 
venous blood. It is suggested, but isn’t exclusive, that the puncture be done in the 
“venous M” of the ante-cubital fold; formed by the basilic cephalic, median basilic 
and median cephalic veins. If it isn’t possible to obtain a blood sample in this region, 
or another is preferred to procure causing the least harm to the patient, it can be 
done. 

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The preservation and processing of each blood sample will depend on the studies 
to be performed. Hereunder are mentioned the peculiarities to consider for the 
laboratory analysis according to protocol. 
 
- 
Blood biometry and glycosylated hemoglobin: Non-coagulated blood is 
required, that is, total or complete blood. The anticoagulant of choice in 
hematology must meet the following basic characteristics: not alter the size of 
erythrocytes, not produce hemolysis, and avoid platelet aggregation and not to 
alter the morphology of the leukocytes. The most indicated in these type of 
studies is potassium salt of ethylendiaminotetraacetic acid (EDTA), dipotassium 
salt (EDTA-K2) at a concentration of 3.7 to 5.4 µM, or tripotassium salt (EDTA- 
K3) at a concentration of 3.3 to 4.0 µM. The use of heparin is totally 
contraindicated. 
The sample must be delicately homogenized, moving the tube with smooth 
oscillatory movements, to avoid hemolysis and impregnate well the blood with 
the anti-coagulant to avoid the appearance of small clots. Once the blood is 
homogenized, it shall be refrigerated with continuous monitoring of temperature 
at 4°C, with a possibility of deviation of +/- 2°C. The maximum admitted period 
of refrigeration shall be 24 hours.  The sample must never be frozen or located 
in direct contact with the thermal accumulators uses for the delivery in 
refrigeration. 
 
 
- 
Biochemical studies: 
For these, blood serum will be used. The processing 
of samples in the laboratory of the investigation site will require that the sample 
be laid to rest at ambient temperature during 15 to 20 minutes for the adequate 
formation of the clot. The serum shall never be processed until the clot has 
completely formed. The tubes to be used for an adequate separation of the clot 
shall be of treated polystyrene or glass. Once the clot is formed it shall be 
centrifuged at a speed of 1500 G for 15 minutes. 
Once the serum is obtained it shall be deposited in another tube with the previous 
labeling with the patient’s data and caution that it isn’t confused with another 
sample. 
The sample of final serum will be refrigerated with continuous monitoring of 
temperature of 2 to 6 °C. The maximum period of refrigeration will be 24 hours. 
 
Once the samples are processed in the laboratory of the site, they will be prepared 
for their shipping to the laboratory that the sponsor designates. The delivery shall 
be made with monitoring of temperature at departure from the laboratory of the 
site and the arrival for processing of sample. No more than 24 hours must pass 
for their processing. The reminder of blood and/or serum of the samples will be 
disposed of by the designated and the laboratory analysis  

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contained in this protocol will only be performed in the samples of the 
participants of the study. 
 
All the processes of the taking and processing of samples must be recorded in 
the report format of corresponding case. 
 
 
 
 
  Records of the study, case report forms and source document 
 
 
The information gathered in the study shall be registered under the following 
principles: 
 
Attributable: to person that obtains it. 
 
Legible: for which caution has to be observed when recording 
information. 
 
Contemporary: the hour must be indicated in the format of 24 hours and 60 
minutes; also the date in format of 2 digits for the day, the first 3 letters of the 
month and the 4 digits of the year. This with the aim of preserving the moment of 
obtention. 
 
Original: the obtained information shall not be modified for the compliance with 
this precept and it must be truthful. In the event that errors exist in the registry, 
the corrections must be made according to the good clinical practices of 
documentation. 
 
Accuracy: it must contain pertinent information and of the subject of investigation 
to whom its executed. 
 
Use of blue ink: it will be used for all registries of the study. 
 
The site where the information was recorded originally is denominated the source 
document. Every place where the initial information is recorded or from where it 
is obtained must be annexed, even when the information were registered in the 
place where it originally should be placed; not omitting annexing the source 
document the registry in the corresponding place. This shall be clarified in the 
section of notes of the case report format. If nothing is annotated in this section it 
shall be cancelled according to good practices of documentation. 
 
Also, the information reported in the case report formats will be recorded by the 
delegate personnel of the investigation site on an electronic database created 

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by the sponsor and provided to the main investigator. The sponsor will have 
faculties for the editing of the records already captured by the personnel of the 
site, generate questions about unclear data in the registries and modify the format 
and the operation of the database if pertinent; for their part, the delegate 
personnel of the site will only have faculties for inclusion of new data and reading 
of same. Once the data are saved, they may only be modified with the 
authorization of the sponsor based on the doubts generated for their clarification. 
 
 
 
 
  Efficacy criteria 
 
 
 
10.4.1. Success 
 
 
 
The efficacy of the treatment will be evaluated by the measurements of the 
biochemical parameters. 
 
Final Comparator vs. basal: The lipid-lowering effect on the following variables: 
TC, C-LDL, C-No-HDL, and TG, will be identified. 
 
Therapeutic efficacy: The percentage of decrease of C-LDL of both treatment 
groups will be compared after 6 months of treatment. 
 
 
 
 
   Safety criteria. 
 
 
The safety shall be evaluated through the report of adverse events, physical exams 
and laboratory results between the 2 treatment groups. 
 
The subjects shall report to the medical personnel responsible for the conduction 
of the study any symptom they present. In the same way, the investigator or 
delegate personnel will ask the subjects, at every period of the study, about the 
symptoms presented during the study period, and in case of manifestation will 
provide attention to the subject and annotations will be made in the corresponding 
Case Report Forms. 

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11. SAFETY 
 
 
 
The opportune and adequate report of the adverse events, suspect of being 
associated to the medicine under study, helps the sponsor to identify reactions 
that are potentially related with the medicine. This permits a) to evaluate the safety 
of the medicine, b) possess a greater comprehension of the toxicity potential of 
the medicine, c) perform indispensable modifications in the study protocol, and d) 
adhere to the regulatory requirements designed for the protection of the patient, 
of the prescribing physician, of the sponsor and of the participating 
pharmaceutical companies. 
 
During the study, the safety of the treatments will be monitored through laboratory 
tests, by collecting information from the patient, as well as by the search for signs 
and symptoms that may identify adverse events that lead to the causal suspicion 
of the administration of the medicines of the study. The subjects shall report to the 
medical personnel responsible for the conduction of the study any symptoms they 
present. In the same manner, the investigator or delegate personnel will ask the 
subjects about the symptoms presented during the period of the study, and in 
case of a manifestation, annotations will be made in the corresponding Case 
Report Formats, as well as in the internal format of adverse events 
 
 
 
  Adverse events 
 
 
The adverse events in a clinical trial are diseases, signs and/or symptoms, or 
abnormal laboratory values that appear or worsen since the inclusion of a 
participant in the clinical trial, related or not with their participation in the study. [L9] 
The adverse event, whether thought to be related or not, must be recorded. 
 
All the adverse events that occur in subjects who are participating in this study 
must be reported to Valeant Pharmaceuticals International regardless of the 
severity or causal relation. The format and the time of the report are determined 
by the classification of the event. The following definitions will be used to make 
the determination: 
 
1. Adverse Event  (AE):  any alteration and/or physiological occurrence that 
may present during the treatment with a pharmaceutical product, but than 

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doesn’t necessarily present a causal relation with the treatment. [L9] 
 
 
2. Adverse Drug Reaction (ADR) or Secondary Effect: Response to a 
pharmaceutical product that is harmful, unintentional and that occurs at normal 
doses used in humans for prophylaxis, diagnose, therapy for a disease, or for 
the modification of a physiological function. [L9] 
 
 
3. Expected adverse event: Harmful, unintentional and undesirable response 
to a pharmaceutical product which has been observed and recorded in the 
monograph for the investigator or in the information for prescription. The 
possibility that these reactions appear must be included in the informed 
consent. [L9] 
 
 
 
 
11.1.1. Classification of adverse events, suspicion of adverse reaction 
and the adverse reactions of the medicines: 
 
I. 
Intensity 
 
The severity of the adverse event, suspicion of adverse reaction and the adverse 
reaction, regardless of the cause, must be graded by the investigator using the 
following terms: 
 
A. Mild. These present easily tolerated signs and symptoms, don’t 
require treatment or prolong hospitalization and don’t necessarily 
require the suspension of the medicine. The patient is aware of the 
sign or symptom but easily tolerates it. [L9] 
 
 
B. Moderate: Interferes with habitual activities (perhaps causing work 
or academic leave), without directly threatening the patient’s life. 
Requires pharmacological treatment and doesn’t necessarily 
require the suspension of the medicine that caused the event, 
reaction or suspicion of adverse reaction. Consider it as a discomfort 
sufficient to cause interference with normal activity. [L9] 
 
 
C. Severe: Interferes with habitual activities (able to cause work or 
academic leaves). Requires pharmacological treatment and the 
suspension of the medicine causing the event, reaction or suspicion 
of reaction. These events are Disabling with impossibility   
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of working or performing normal activities. [L9] 
 
II. 
Severity or seriousness 
 
Based on the outcome, adverse events, the suspicions of adverse reaction and 
adverse reactions are classified according to the seriousness of the clinical 
manifestation in: 
 
A. Serious Adverse Events (Severe). Any clinically significant 
manifestation that presents with the administration of any dose of a 
medicine, and that                         : 
a. Cause the death of the patient. [L9] 
b. Put the life of the patient at risk at the same moment they appear. 
[L9] 
c. Makes hospitalization necessary or prolongs hospital stay. [L9] 
d. Causes disability, or persistent or significant inability. [L9] 
e. Causes alterations or malformations in the newborn. [L9] 
f. For this study, Serious Adverse Event will be considered the 
elevation of 3 times the normal upper value of ALT with clinical 
correlation and confirmation of occurrence due to the 
investigational product. 
g. For this study, Serious Adverse Event will be considered the 
elevation of CPK in 10 times its upper limit reported as normal in 
ranges of international units and its causality proven with the 
investigational product. 
 
The investigation site shall have 24 hours starting from the moment the serious 
adverse event is known to inform the sponsor and fill the corresponding report 
format; this report may be completed afterwards with documents. In turn, the site 
of must report this occurrence to the Ethics Institutional Review Board. 
 
The sponsor will be in charge of reporting the serious adverse events to the health 
ministry. 
 
B. Non-serious adverse events 
(Not 
Severe). 
The events, 
suspicions and adverse reactions that don’t comply with the criteria 
of severity specified in the anterior numerals of the section of 
Serious Adverse Events. [L9] 

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The investigation site must report them in the corresponding format to the sponsor 
and generate the subsequent report to the ethics committee. The occurrence may 
be informed to the sponsor, who’ll ask for the information to be completed before 
the next programmed monitoring visit. 
 
The sponsor will be in charge of reporting the non-serious adverse events to the 
health ministry. 
 
 
 
 
11.1.2. Quality of the obtained information 
 
 
 
The notification of adverse events, suspicions of adverse reaction and adverse 
reactions, according to the quality of the information, understanding by it the 
exhaustive quality and integrity of the data contained, are classified in: 
 
Grade 0. When the notification only includes one identifiably patient, one 
suspicion of adverse reaction, adverse event or adverse reaction to a suspect 
medicine and the notifier’s details. [L9] 
 
Grade 1. When in addition to data from Grade 0, the dates of the start of the 
suspicion of adverse reaction, adverse event or adverse reaction and of start and 
end of treatment (day, month and year) are included. [L9] 
 
Grade 2. When in addition to data from Grade 1, the generic and distinctive 
denomination, posology, route of administration, motive of prescription, 
consequence of the event and important data of the clinical history are included. 
[L9] 
 
Grade 3. When in addition to the data from Grade 2, the reappearance of the 
clinical manifestation consequent to the re-administration of the medicine (positive 
re-administration) is included. [L9] 
 
 
 
 
11.1.3. Causality 
 
 
 
The adverse reactions are classified according to the evaluation of causality under 
the following probabilistic categories: 
 
Certain. Consists in an event (clinical manifestation or abnormal result of a 
laboratory test) that occurs with plausible time relationship to drug intake and can’t 
be explained by the natural evolution of the condition, a concomitant pathology or 

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to the administration of other medicines. The response to the suspension of the 
medicine must be clinically evident. [L9] 
 
Probable. Consists in an event (clinical manifestation or abnormal result of a 
laboratory test) that follows a plausible time sequence posterior to the 
administration of the medicine and can hardly be attributed to the natural evolution 
of the condition, concomitant pathologies or to the administration of other 
medicines. On suspension of the administration of the suspect medicine(s), a 
reasonable clinical response is obtained. [L9] 
 
Possible. Consists in an event (clinical manifestation or abnormal result of a 
laboratory test) that follows a plausible time sequence posterior to the 
administration of the medicine, which may also be attributed to the natural 
evolution of the condition, concomitant pathologies or the administration 
of other medicines. The information related with the suspension of the 
administration of the suspect medicine isn’t available or isn’t clear. [L9] 
 
Doubtful. Consists in an event (clinical manifestation or abnormal result of a 
laboratory test) that follows a plausible time sequence posterior to the 
administration of the medicine that makes the causality relation improbable (but 
not impossible), which could be explained in an acceptable manner for being part 
of the natural evolution of the condition, or due to the presence of concomitant 
pathologies or to the administration of other medicines. [L9] 
 
Conditional-Unclassified. Consists in an event (clinical manifestation or 
abnormal result of a laboratory test) that can’t be adequately evaluated due to the 
fact that additional data is required or these are being analyzed. [L9] 
 
Unassessable-Unclassifiable. Consists in a report suggesting an adverse 
reaction that can’t be assessed because the gathered information is insufficient or 
contradictory. The report can’t be completed or verified. [L9] 
 
The causality of the adverse events shall be reported by the main investigator 
and/or the delegate personnel based on clinical findings, which may or may not 
be related to the investigational drug; this shall be recorded in the corresponding 
format. Nevertheless, the personnel in the Pharmacovigilance area of the sponsor 
will evaluate among other things the causality of the adverse event using the 
algorithm of Naranjo and collaborators (See ANNEX 5). [155] 

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11.1.4. Special conditions 
 
 
 
There are special conditions that must be reported; their report is specified 
hereunder: 
 
Pregnancy. [L9] If a woman resulted pregnant during the study, this event shall be 
reported to the sponsor and to the ethics committee. The participant may not 
continue in the study and a follow-up will be made until the pregnancy period ends, 
reporting the conditions that arise during the pregnancy and its resolution, in the 
mother as well as in the product. 
 
Lactation. [L9] This condition doesn’t apply for this protocol because of the non-
inclusion of lactating women. 
 
Event related to the quality of the product. [L9] This will be considered an 
adverse event and will be reported to the sponsor, until the sponsor confirms the 
causality or not with the quality of the product. 
 
Overdose. [L9] Overdose shall be reported as an adverse event and be notified to 
the sponsor and the ethics committee. 
 
Error in medication. [L9] This condition doesn’t apply to the investigational drug, 
in case of taking a different product this must be reported and the criteria of early 
termination be evaluated to see the relation of the non-administration of the 
investigational drug. 
 
Misuse. [L9] This shall be reported to the sponsor detailing on what consists the 
misuse. 
 
The others such as lack of efficiency, degenerative chronic disease, transmission 
of infectious agent and abuse don’t apply because of the methodology or detailed 
compilation of same in this protocol. [L9] 
 
 
 
 
  Report of the adverse events 
 
 
 
It shall be performed in temporality according to its aforementioned severity 
classification; the filling of the report shall be in electronic format. Also, it must be 
registered in the CRF corresponding to the adverse event. 

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  Follow-up of the adverse events 
 
 
Any abnormal finding either clinic or in the laboratory values shall be kept under 
narrow watch until it is resolved. 
 
According to the characteristics of the adverse event, the sponsor may require 
copies of the medical record of the patient, as well as the results of the laboratory 
tests performed. If the patient was hospitalized, an effort will be made to gather a 
copy of the summary of the hospital stay to be sent with all the source documents 
recovered to Valeant Pharmaceuticals International, indicating that they are 
faithful copies of the original with good practices of documentation and with blue 
ink as soon as they are available. In some cases a letter may be required from 
the investigator where the adverse events related with the case will be 
summarized. In all cases, the main Investigator must perform follow-up to the 
patients until the final result of the event is known. 
 
If a patient is eliminated or excluded from the study due to the occurrence of 
abnormal laboratory values, these must be repeated at adequate intervals 
(determined by the investigator) until they return to normal or during the time the 
investigator considers convenient. If it is clinically indicated, the patient must be 
referred to his/her treating physician or to an external physician for a posterior 
evaluation. If the patient is withdrawn before termination of the study, the decision 
of this action shall have to be plainly justified and recorded in the case report 
forms and included in the analysis of this study. 
 
 
 
 
  Data for notification of serious adverse events 
 
 
The serious adverse events shall be reported and investigated on part of the 
investigation site and its personnel, in turn; the sponsor of the study shall be 
notified within the first 24 hours following its presentation and/or detected. 
 
The contact data are the following: 
 
Clinical Research Coordinator: Dr. Francisco Javier Figueroa Vallejo. 
Responsible of Pharmacovigilance: Dr. Paola Andrea Martínez Serrano. 
Office telephones: 01-55-50624190 and 01-55-50624175 

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24-hour Emergency mobile telephones for SAE:  5523009656  and 5543731344. 
 
Report of SAE by electronic mail: farmacovigilancia.mexico@valeant.com and 
francisco.figueroa@valeant.com 
 
 
 
  Expected adverse events for the medicine in study 
 
 
 
11.5.1. Atorvastatin 
 
 
 
There are individuals who find themselves with a predisposed risk to present 
adverse events related with the use of statins; conformed (not in a limited manner) 
by those who course with multiple or serious comorbidities, including renal 
damage and hepatic failure, history of previous intolerance to statins in muscular 
comorbidities, elevation of ALT in blood 3 times the upper limit considered as 
normal in an unexplainable manner (reported in international units), age above 
75, have Asian descent, history of having suffered a cerebrovascular event of the 
hemorrhagic type and, characteristics proper to the patient or of the concomitant 
treatment that affect the metabolism of statins. [6] 
 
Nevertheless, atorvastatin is usually well-tolerated; the adverse reactions are 
usually mild and transitory. In clinical studies less than 2% of the patients were 
discontinued due to adverse effects attributed to atorvastatin. 
 
In a meta-analysis of 44 studies in which were included data of 16,495 patients 
with dyslipidemia treated with atorvastatin (9416 patients), other statins (5290 
patients) and placebo (1789 patients), the safety of atorvastatin was evaluated in 
doses of 10 to 80 mg per day; it was found that the incidence of adverse events 
was of only 3% for the individuals who used atorvastatin, 1% for those that used 
placebo and 4% for those who used other statins. [118] 
 
The most frequent adverse reactions that were found associated to the use of 
atorvastatin had an incidence a little over 1% and these are: constipation, 
flatulence, dyspepsia, abdominal pain, headache, nausea, myalgia, asthenia, 
diarrhea and insomnia. 
 
Likewise, there are reported effects that haven’t necessarily been associated to  
 
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the use of atorvastatin such as: muscular cramps, myositis, myopathy, 
paresthesias, peripheral neuropathy, pancreatitis, hepatitis, cholestatic jaundice, 
anorexia, vomit, pruritus, impotence, hyperglycemia and hypoglycemia. 
 
 
 
 
Gastrointestinal disorders, not including hepato-biliary: 
 
This type of effects are the most common related with the use atorvastatin 
reported in clinical studies, being the most frequent mild diarrhea. Other effects 
are intestinal constipation, flatulence, dyspepsia, abdominal pain, nausea and 
with a lesser frequency, vomit [113, 118]. Adverse effects that have been documented 
in patients that use atorvastatin but causality hasn’t been proven in clinical studies 
are: cholestatic jaundice, hepatitis and pancreatitis. 
 
Common: constipation, flatulence, dyspepsia, nausea, mild diarrhea. 
 
Uncommon: vomit, superior and inferior abdominal pain, eructation, pancreatitis. 
 
 
 
 
Disorders of the nervous system: 
 
In a meta-analysis of 44 clinical studies an incidence of adverse events related to 
the nervous system was found in 3% of the patients who used statins compared 
with 2% for the placebo group. Among these, the most frequent is headache; 
although paresthesias and peripheral neuropathy have also been documented. 
[118] 
 
Common: headache. 
 
Uncommon: dizziness, paresthesia, hypoesthesia, dysgeusia, amnesia. 
Rare: peripheral neuropathy. 
 
Disorders of the skin and of subcutaneous tissue: 
 
The incidence of adverse events by atorvastatin is of 2% compared with the 
placebo which is 1% in disorders of the skin and subcutaneous tissue. It has been 
found without verifying if the causal effect is the medicine; the most common 
effects found are pruritus and urticaria. [118] 
 
 
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Uncommon: urticarial, cutaneous eruption, pruritus, 
alopecia. 
 
Rare: angio-neurotic edema, epidermolysis bullosa, including multiform 
erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis. 
 
 
Hepato-biliary disorders: 
 
Initial post-commercialization studies were performed of the statins and data of 
elevation in ALT 3 times superior to the normal limit were found in 1%, finding 
relation dependent on the dose used. Law and collaborators in 2003 conducted a 
study with statins (among them Atorvastatin at 10 and 40mg) and placebo. Their 
reported results were from 1 to 3% in elevation of ALT in comparison to the 1.1% 
of the placebo group. There were no cases of hepatic damage. Due to the fact 
that hepatic damage secondary to the use of statins shows an extremely low 
annual incidence, less than 2 cases per million patients, the increase of hepatic 
enzymes associated to the use of statins is an occasional finding in most cased, 
potentially reversible, for which the routine measurement of hepatic enzymes isn’t 
recommended in the patient who uses statins. [69] In spite of this, in those who 
present symptoms suggestive of hepatotoxicity such as unusual fatigue or 
weakness, loss of appetite, abdominal pain, choluria and jaundice, it is 
recommended to perform biochemical tests that evaluate the hepatic function. In 
turn, it is recommended not to include in clinical studies subjects that present 
basal levels of ALT above 1.5 to 2 times the normal superior limit reported in 
international units. [4] It is also recommended that they don’t be used in patients 
who suffer from hepatic failure or established cirrhosis. [69] In the meta-analysis 
performed by Newman and collaborators, an incidence without dependency on the 
dose was found in 0.5% if elevation of ALT/AST 3 times greater than the superior 
limit on at least 2 consecutive takes in comparison with the 0.3% of the placebo 
population. Of these patients less than 1% had persistent elevations of 
transaminases. [118] In another analysis derived from 49 clinical studies with 
14,236 patients who received atorvastatin at doses of 80mg through oral route, 
10 mg or placebo; the findings were of persistent elevations in hepatic 
transaminases (in ranges greater than 3 times the normal upper limit according to 
international units) in 0.1% for atorvastatin 10 mg, 0.6% for atorvastatin 80 mg and 
0.2 for the placebo group. [119] La Rosa and collaborators performed an analysis 
of 10,001 patients with evidence of cardiovascular disease and levels of C-LDL of 
130 mg/dl or less. Once randomized, 5,006 patients were assigned atorvastatin 
in doses of 10 mg/day and 4,995 atorvastatin in doses of 80 mg/day. After a 4.9 
follow-up they found an incidence of sustained elevation of 
 
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aminotransferases in at least more than 3 times the upper limit in 1.2% of those 
who received 80mg/day and in 0.2% of those who received 10mg/day. The report 
system of the FDA mentions that 1 event appears in 1 million study-years of 
persons. Even so, it is justified to measure ALT to keep a control with respect to 
this effect. [113] 
 
Uncommon: Hepatitis  
Rare: cholestasis. 
Very rare: hepatic failure. 
 
 
Musculoskeletal disorders, and disorders of connective tissue: 
 
The muscular effects associated to the use of statins have an important clinical 
relevance; previously, the physiopathologic bases of this condition have been 
commented upon. [76, 77] Their presentation is greater in adults of the female 
gender and in those who course with complex medical problems or have a history 
of using multiple medicines. [6] The greater presentation in elder adults is justified 
by sarcopenia (diminishing of muscular mass), increasing the risk of developing 
myopathy secondary to the use of statins; combined with the fact that enzymes 
that metabolize the statins may be less functional increasing the interaction 
among drugs. [75] 
 
Among the effects secondary to the use of statins, the patient may course with 
myalgia, myopathy, myositis, myonecrosis and myoglobinuria with a possible 
secondary acute renal damage. [6] The measurements of Creatin kinase are 
advised for individuals with an elevated risk of suffering muscular adverse events 
based on familial history of intolerance to statins, muscular disease, clinical 
presentation or concomitant therapy that increases the risk of suffering myopathy. 
It is reasonable to measure the levels of CPK in patients who present muscular 
symptoms, including pain, augmented sensitivity, cramps, tiredness or 
generalized fatigue. [6] In patients who course with muscular symptoms additional 
to the measurement of CPK, it is recommended to measure creatinine and perform 
a urinalysis with intentional search of myoglobin to rule out rhabdomyolysis. Upon 
resolution of the muscular symptoms, in the absence of rhabdomyolysis, the 
patient may return to treatment with statins at low doses. If after 2 months of 
withdrawal of the use of statins the muscular symptoms or the levels of CPK don’t 
improve, these levels must be considered secondary to other muscular causes. 
[6] Studies have sustained that in the presence of myalgias in patients with statins 
treatment without elevation of CPK or intolerance,  
 
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strategies of error assay may be performed, starting with statins of low potency at 
low doses. Also, we may recur to the change of statin used or through the 
administration of different doses between the days of treatment, with a gradual 
increase by tolerance each week. [5] In the study of La Rosa and collaborators 
where 10,001 patient were included who used atorvastatin in doses of 10 mg or 
80 mg, no persistent elevations of CPK were found in none of the groups (defined 
as elevations of 10 times the upper limit in consecutive measurements with 
differences of 4 to 10 days). 2 cases of rhabdomyolysis were reported for the 
group of atorvastatin in doses of 80 mg/day and 3 for the group of 10 mg. Of the 
5 cases of rhabdomyolysis only 3 presented elevations greater than 10 times the 
limit for CPK. The presentation of the clinical condition per patient was posterior 
to: congestive cardiac failure with infarction of the myocardium and 
pneumothorax, accidental fall, pneumonia and sepsis, muscular cramps with 
concomitant 
ingestion 
of 
alcohol 
and 
cetirizine 
and 
post-operatory 
thromboembolic disease. [112] Newman and collaborators in a meta-analysis of 44 
clinical assays with 9,416 patients found that with the use of atorvastatin and other 
statins 4% of the patients presented  myalgia. In this analysis only 1 patient 
presented persistent elevations of CPK greater than 10 times the upper limit and 
they weren’t accompanied by muscular symptoms. The patient was a man of 16 
years with severe hypercholesterolemia and a history of xanthomas, systemic 
arterial hypertension, headache and who received atorvastatin through oral route 
at doses of 40 mg for 28 days followed by 80 mg per day of atorvastatin through 
oral route during 479 days. [118] In another meta-analysis which evaluated the 
safety of using atorvastatin at 10 mg per day or at 80 mg per day in comparison 
with placebo, found an incidence of myalgia in 1.4% of those who took 10 mg/day 
of atorvastatin, 1.5% in the group of 80 mg/day and 0.7% in the placebo group. 
Not one case of rhabdomyolysis was reported. The elevations in CPK of at least 
10 times the upper limit considered as normal were of 0.21% for the group of 10 
mg/day of atorvastatin and of 0.47% for the group of 80 mg/day of atorvastatin. With 
respect to the severity of the myalgia, it was reported as serious in 0.09% of the 
patients who received placebo, 0.08% of those who received doses of 80 mg and 
there were no serious adverse events related to myalgia in those who received 
atorvastatin in doses of 10 mg. [119] 
 
Between 1987 and 2001 the FDA found 42 deaths by rhabdomyolysis associated 
to the use of statins. This range is maintained in 1 death per 1 million prescriptions. 
 
In clinical studies, rhabdomyolysis occurs in 8 patients compared with 5 in the 
placebo population. Besides, of the patients who have active medication with 

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statins, 0.17% develops levels of CPK 10 times above the normal limit (limit used 
to define rhabdomyolysis secondary to statins), compared with the 0.13% 
presented in those who received placebo. In conclusion, the incidence of 
myopathy is of 0.01%, but the risk of myopathy and rhabdomyolysis increases 
according to a larger proportion of plasmatic concentrations of the statins. [104] 
The concomitant therapy with drugs that diminish the catabolism of the statins is 
found in 50 to 60% of the patients who coursed with myopathy and 
rhabdomyolysis. The most common interaction occurs with fibrates of gemfibrozil 
in the 38%, cyclosporine in 4%, digoxin in 5%, warfarin in 4%, macrolides in 3%, 
Mibefradil in 2% and Azole Antifungal in 1%. [104] Within the clinical presentation, it 
is characterized by intense myalgia similar to that of a cold, it starts in arms and 
thighs and then it disseminates to the whole body, accompanied by fatigue. The 
symptoms are progressive if the use of statins continues. Myoglobinuria, renal 
failure and secondary death have been reported. The serum levels of CPK are 
typically elevated in these patients. As soon as myopathy is suspected in patients 
that are users of statins, a laboratory measurement must be made of these 
parameters. As a common rule, statins that are administered in combination with 
the drugs that predispose these reactions must be administered at no more than 
25% of their maximum dose to decrease the risk of these events, for atorvastatin 
at doses of 20 mg/day. [104] 
 
Common: myalgia, arthralgia, pain in limbs, muscular spasms, swelling of joints, 
dorsal spinal pain. 
 
Uncommon: pain in neck, muscular fatigue. 
 
Rare: myopathy, myositis, rhabdomyolysis, tendinitis, sometimes complicated 
with rupture of the tendon. 
 
 
 
 
Disorders of the blood and lymph system: 
 
Rare: thrombocytopenia. 
 
 
 
 
Disorders of the immunologic system: 
 
Common: allergic reactions. 
Very rare: anaphylaxia. 

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Metabolic and nutritional disorders: 
 
Common: hyperglycemia. 
 
Uncommon: hypoglycemia, increase of weight, anorexia. 
 
 
 
 
Psychiatric disorders: 
 
Uncommon: nightmares, insomnia. 
 
 
 
 
Disorders of the ear and labyrinth: 
 
Uncommon: tinnitus. 
 
Very rare: loss of hearing. 
 
 
 
 
Disorders of the genitals: 
 
Very rare: gynecomasty. 
 
 
 
 
General disorders: 
 
Uncommon: general discomfort, asthenia, peripheral edema, fatigue, pyrexia. 
 
 
 
 
Infections and infestations: 
 
Common: nasopharyngitis. 
 
 
 
 
Ocular disorders: 
Uncommon: blurry vision. 
Rare: visual disturbance. 

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Respiratory, thoracic and mediastinal disorders: 
 
Common: pharyngeal-laryngeal pain. 
 
Uncommon: epistaxis, thoracic pain. 
 
 
 
 
Alterations in laboratory tests: 
 
Common: tests of abnormal hepatic function, increase of blood creatin kinase. 
 
Uncommon: leukocytes in urine positive. 
 
 
 
 
11.5.2.L-Carnitine 
 
 
 
The only documented contraindication is hypersensitivity to the drug. 
 
Since L-carnitine is a product which is habitually found in the organism, it is safe 
even in doses of 15 g/day. 
 
 
 
 
Body odor: 
 
In some individuals, especially in men (less than 1.9% of the population), 
trimethylaminemia has been described with presence of discreet smell of fish, 
which is avoided when dose is lowered. Patients who receive levocarnitine expel 
a fish-like smell which is eliminated decreasing the dose. [156] In a clinical study this 
relation was seen after the oral administration of L-carnitine due to the formation of 
trimethylamine. [157] 
 
 
 
 
Gastrointestinal disorders: 
 
Diarrhea: In adults, using a dose of L-carnitine of at least 3 g/day has been related 
with softening of feces, and in some cases, presence of diarrhea without clinical 
significance. [156, 158, 159, 160, 161, 162] The adverse effect decreases with the 

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slow intravenous administration or with a greater dilution in the oral solution. [156, 
158, 160] Ellaway and collaborators found in patients from 3 to 35 years of age with 
Rett syndrome that when they were administered with L-carnitine at doses of 100 
mg/kg/day they experienced diarrhea. This effect disappeared when reducing the 
dose to 75 mg/kg/day. [159] In a study of mitochondrial myopathy 10% of the 
patients experienced gastrointestinal adverse effects, including diarrhea. [161] 
 
Nausea: In a study of mitochondrial myopathy, 10% of the patients experienced 
gastrointestinal adverse effects, including nausea. [161] This adverse effect is 
reduced with the slow administration through intravenous route and a greater 
dilution of the oral solution with levocarnitine. [156, 158, 160] 
 
Vomit: Vomit has been found with a greater prevalence in high doses of L-
carnitine than in placebo (21% vs. 16%) or low doses (9-16%). This effect is 
reduced with the slow administration or with a greater dilution of the oral 
solution.[156, 158, 160] 
 
Heartburn: Heartburn was reported in 1 patient with chronic stable angina who 
received L-carnitine at doses of 1 gram 2 times a day to increase tolerance to 
exercise. [162] 
 
 
Disorders of the nervous system: 
 
Dizziness: Dizziness was reported in 1 patient who received 6 grams of 
intravenous levocarnitine. [163] 
 
Headache: Levocarnitine has been reported as related to headache. Harper and 
collaborators reported the presence of headache in 1 patient who received a dose 
of levocarnitine through intravenous route. [163] During an intravenous treatment 
subsequent to sessions of dialysis in patients with chronic renal failure, stage 5; 
the headache was more common in those who received levocarnitine (22%) in 
comparison with placebo(16%), with a larger prevalence in the group that received 
20 mg/day (37%). Also, it was reported in one patient that received 6 g 
intravenously of levocarnitine. [164] 
 
Convulsions: With the oral or intravascular route use of levocarnitine, an increase 
in the frequency and/or severities of the convulsions in patients with antecedents 
has been reported. Besides, they have also been reported in patients without pre-
existing activity of convulsions. [164] 
 
Transitory blurry vision: It was reported in 2 patients who received intravenous 
carnitine in 6 grams. 
 

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Disorders of the genitourinary system 
 
Change in the color or urine: the association has been reported in those who 
use levocarnitine. 
 
 
Adverse effects in chronic renal failure in end stage 
 
Care must be observed in the administration of L-carnitine in nephropathy. 
 
Hyperkalemia: During the intravenous treatment of levocarnitine in dialyzed 
patients with end stage of chronic renal failure, hyperkalemia was found in 15% 
of those treated with doses of 10 mg/kg, 6% at doses of 20 mg/kg and 8% at 
doses of 40 mg/kg compared with 3% of the patients who received placebo. [164] 
 
Paresthesias: Levocarnitine in 40 mg/kg intravenously was associated to 
paresthesia in 12% of the patients, in contrast with 3% presented by the placebo 
group or at doses of 10 to 20 mg/kg. [164] 
 
Parathyroid disorders: Disorders of the parathyroid gland were found after an 
administration of levocarnitine of 10 mg/kg intravenously in 4% of patients 
compared with 2% in placebo. [164] 
 
Disorders of the sense of taste: dysgeusia was found in 9% of those who 
received levocarnitine at doses of 40 mg/kg by infusion. An additional 2% of 
patients who received this drug at doses of 20 mg/kg has disorders of the sense 
of taste. This wasn’t found in those who received L-carnitine at doses of 10 mg/kg 
or placebo. [164] 
 
Cardiovascular disorders: Auricular fibrillation was found by electrocardiogram 
with the intravenous use of L-carnitine at doses of 40 mg/kg in 6% compared with 
3% or less in the patients that received lesser doses of levocarnitine. The patients 
who received placebo had no changes. With respect to arterial tension, it was 
common in those who received levocarnitine in doses of 10 mg/kg (18% 
presented the effect) at 40 mg/kg (21% presented the effect) compared with 
placebo (14%). Also tachyarrhythmia was observed with a greater incidence in 
those who received levocarnitine at doses of 40 mg/kg in comparison with those 
that received placebo or levocarnitine at doses of 10-20 mg/kg with percentages of 
9% and 5-6%, respectively. [164] 
 
Anemia: Anemia after administrating L-carnitine at 40 mg/kg was reported in 12% 
administrated posterior to dialysis, in contrast with 3% found in patients with doses 
of 10 to 20 mg/kg or placebo. [164] 
 
There are no restrictions of use during pregnancy and lactation. L-carnitine is a 

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normal component of maternal milk. 
 
 
 
 
12. ADMINISTRATIVE ASPECTS OF THE STUDY 
 
 
  Confidentiality 
 
 
Upon acceptance of this protocol the investigator compromises to maintain 
(confidentiality) of the information provided, and that it shall only be divulged to 
the Ethics Institutional Review Board on the understanding of confidentiality of this 
group. 
 
The names, identities of the subjects and any information of the participant which 
could place at risk the confidentiality of the participant in the study, shall be 
safeguarded in the site, consequently it will not appear in the case report forms or 
any other record granted or withheld by Valeant Pharmaceuticals International. 
 
To safeguard the identity of the subjects, they will be assigned a code in the study; 
the method of obtention of the code may be seen in the section corresponding to 
protocol. 
 
 
 
 
  Retention of the data 
 
 
All records and documents pertinent to the study, including those described in 
records of the study, not being limited to these shall be kept by the investigator 
for a period of: 
 
Five years following the conclusion of the clinical trial. 
 
Two years after the approval of the medicine for the indication in study. 
 
Five years after the rejection of approval or the medicine or 
 
Two years after the cancellation of the authorization under which the study was 
performed. 
 
To avoid any possible error, the investigator will get in contact with Valeant 
Pharmaceuticals International previous to the destruction of any record of the 
study. The investigator shall notify immediately to Valeant Pharmaceuticals 
International in case of accidental loss or destruction of the records of the study. 
 
 

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  Authorization of the protocol by the Institutional Review Board 
 
 
The registry of the protocol and documentation such as: investigator’s manual, 
informed consent and case report formats before the Ethics and Research 
Institutional Review Board, has the purpose of assessing that it complies with the 
necessary requirements according to the law for clinical studies and that in turn 
considerations be kept for an ethical treatment of the participants in the clinical 
trial. Also, it is a documental requisite to present and obtain registry before the 
Federal Commission for Protection against Health Risks (COFEPRIS) of the 
Health Ministry. 
 
Before initiating the recruitment of patients in the study, the protocol and the form 
of informed consent, these shall be reviewed and approved by the Ethics and 
Research Institutional Review Board. On signing the “approval of the investigator”, 
the investigator will guarantee that all the aspects of the review by the Ethics and 
Research Institutional Review Board will be performed in accordance with the 
applicable regulations. 
 
The Ethics and Research Institutional Review Board shall issue a letter 
documenting the approval of the following documents: 
 
1) Informed Consent. 
 
2) Study Protocol. 
 
3) Investigator´s Brochure. 
 
4) Case Report Formats. 
 
The amendments to the protocol and informed consent shall be subjected to the 
same requirements as the original protocol. 

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  Authorization of the protocol by the Federal Commission for 
Protection against Health Risks (COFEPRIS) 
 
 
An enabled unit of COFEPRIS may be used for it to perform a pre-verdict of the 
protocol study. 
 
The following documents must be sent by the investigator to the sponsor for 
registry of the protocol in COFEPRIS: 
 
1) Letter of approval of protocol by the Ethics and Research Institutional 
Review Board. 
2) Letter of informed consent issued by the Ethics and Research 
Institutional Review Board. 
3) Letter of approval of the investigator’s brochure issued by the Ethics 
and Research Institutional Review Board. 
4) Simple copy of the operating permit (Sanitary license or notification 
of operation as the case may be). 
5) Letter of authorization to conduct the clinical trial, signed by the 
titleholder of the unit or institution where the clinical trial will be 
effected. 
6) Document where the description of the available resources of the unit 
or institution where the clinical trial will take place is expressed, 
including areas, equipment, auxiliary services of laboratory and 
cabinets, number of personnel; all the previous solely and specifically 
for the development of the i clinical trial. 
7) For the case of investigation centers that hold agreements for the 
attention of medical emergencies with other institutions, include 
simple copy of the existing agreement. 
8) Simple copy of the Operating Permit of the Institution for attention of 
emergencies. 
9) Letter of the description of available resources for the management of 
emergencies. 
10) Letter of acceptance, confidentiality and commitment of report of 
suspicions of adverse events, dated and signed by the main 
investigator. 
11) Summary of the professional history of the main investigator. 
12)Simple copy of the documentation, legally issued and registered by 
the competent educative authorities in case of license numbers. 
13) Summary of the academic preparation and experience of the medical 
personnel, infirmary and other experts who will participate in the 
activities of the clinical trial. 

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14) Descriptive letter of the delegating of responsibility of the 
investigator´s team. 
 
 
  Start of the study 
 
 
The approval of the Federal Commission for the Protection against Health Risks 
(COFEPRIS) of the Health Ministry will be necessary for the commencement of 
the study. 
 
Once the favorable verdict is issued, an initial visit to the site will be made, 
previous to the inclusion of patients. In this visit, the procedures of the protocol 
and case report forms, areas to be used and documents of the study will be 
reviewed. 
 
 
 
13. DURATION OF THE STUDY 
 
 
 
The time of participation of each patient in the clinical assay will not be greater 
than 6 months. 45 days will be considered for the inclusion of the patients and 6 
months of treatment. Considering times in the processes of the study, the 
estimated duration is from 10 to 11 months until the delivery of the report and 
briefing of the results. The exception to the rule would be the presence of adverse 
events, in which case a follow-up will be made until the event is resolved; for 
example, pregnancies. 
 
 
 
 
14. MONITORING OF THE STUDY 
 
 
 
According to the Mexican normativity and the guidelines of clinical practice of the 
International Conference of Harmonization, [151, L5, L6, L7] Valeant Pharmaceuticals 
International will perform periodic monitoring of the study at the commencement, 
during and at the termination of the study on mutually agreed dates with the site 
of the research. 
 
The monitoring visits will allow Valeant Pharmaceuticals International the 
opportunity to evaluate the progress of the study, verify the veracity and filling of the 
Case Report Forms, guarantee that all the requirements of the protocol are being 
met, including the characteristics of the design of the study; the compliance of the 
regulations and the obligations of the investigators will be reviewed, resolve  

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any inconsistency in the records of the study; this includes the inspection of all 
documents and records, which must be kept by the investigator and includes the 
clinical files of the subjects being studied. 
 
The study shall be executed exactly as described in this approved protocol. The 
monitor designated by the sponsor will be in charge of verifying that all the actions 
described in the protocol are carried out neatly. 
 
The regulations require that the investigator permit access to authorized 
representatives of the Health authorities to review and obtain information from the 
clinical files. The names and identities of the subjects may not be revealed to 
Valeant Pharmaceuticals International; however, all the documents where the 
personal information of the subject in the study is not included may be reviewed. 
The confidentiality of the patient may be kept with the number of identification of 
the study and initials. If these requirements come into conflict with local regulations 
or policies of the institution, the investigator shall report it to 
Valeant 
Pharmaceuticals International before commencing the study. 
 
The 3 grand objectives of the monitoring will be kept: 
 
1. Review and document that the rights and well-being of the human 
beings are protected. 
2. Review and document that the reported data of the study are complete, 
precise and may be verified in the source documents. 
3. Review and document that the conduct of the study is in conformity with 
the protocol and/or amendments if these are approved, with the Good 
Clinical Practices and with the applicable regulatory requirements. 
 
 
  Responsibilities during the monitoring 
 
The sponsor’s personnel that performs the monitoring shall make sure that the 
study is conducted and documented appropriately, carrying out the following 
activities when they are relevant and necessary for the study and the site where 
the study is being done: 
 
1. Act as the main communication line between the sponsor and the investigator. 
[151] 
 
 
2. Verify that the investigator is qualified and counts with the adequate resources  

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and that these are maintained during the study; that the facilities, including the 
laboratory, equipment and personnel are ideal to conduct the study in a safe and 
appropriate manner and remain as such for its duration. [152] 
 
 
3. Verify with respect to the investigational product(s) that: 
a) 
the timing and conditions of storage are 
acceptable and that the supplies are sufficient 
during the study. [151] 
b) 
the investigational products are supplied only to 
the subjects who are eligible to receive it and at 
doses specified in the protocol. [151] 
c) 
the necessary instructions are provided to the 
subjects 
about 
the 
appropriate 
use, 
management, storage and return of the products 
of investigation. [151] 
d) 
the reception and use and return of the 
investigational products in the places where the 
study is carried out is adequately controlled and 
documented. [151] 
e) 
the disposition of the unused investigational 
products, in the sites where the study is 
conducted 
complies 
with 
the 
applicable 
regulatory requirements and is in conformity with 
the sponsor. [151] 
 
 
4. Verify that the investigator follows the approved protocol and all the approved 
amendments, in case there are any. [151] 
 
 
5. Verify that the written informed consent of each subject has been obtained 
before they participate in the study. [151] 
 
 
6. Make sure that the investigator receives the prevailing Brochure of the 
Investigator, all the documents and supplies necessary to appropriately conduct 
the study and to comply with the applicable regulatory requirements. [151] 
 
 
7. Make sure that the investigator and the personnel of the study of the investigator 
are adequately informed about the study. [151] 
 
 
8. Verify that the personnel of the study of the investigator is performing the specific 
functions of the study in conformity with the protocol and any other 

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agreement in writing between the sponsor and the investigator/institution and 
that they haven’t delegated these functions to unauthorized persons. [151] 
 
 
9. Verify that the investigator is only including eligible subjects. [151] 
 
 
10. Report the rate of recruiting of subjects. [151] 
 
 
11. Verify that the source documents and other records of the study are precise, 
complete and are kept updated. [151] 
 
 
12. Verify that the investigator provides all the reports, notifications, requests and 
submissions required and that these documents are precise, complete, 
opportune, legible, dated and identify the study. [151] 
 
 
13. Revise the precision and that the data of the case report formats, source 
documents and other records related with the study are complete, maintaining 
correlation among themselves. [151] 
 
 
14. Determine if all the adverse events are appropriately reported within the time 
periods required by the Good Clinical Practices, the protocol, the Ethics 
Institutional Review Board, the sponsor and the applicable regulatory 
requirements. [151] 
 
 
15. Determine if the investigator preserves the documents essential for the 
conduction of the study. [151] 
 
 
16. Communicate deviations of the protocol, standard operative procedures, good 
clinical practices and applicable regulatory requirements to the investigator and 
take the appropriate measures to prevent a recurrence of the detected 
deviations. [151] 
 
 
17. All the processes shall be done according to the procedures of the sponsor. [151] 
 
 
 
 
  Reports on monitoring 
 
 
 
The monitor shall present a report in writing to the sponsor after each visit to the 

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place where the study is carried out or a communication related with the study. This 
report shall include the date, place, name of the monitor and name of the investigator 
or other individuals who have been contacted. 
 
In the reports will be included studies in summary of what the monitor reviewed 
as well as declarations regarding findings, significant deviations, conclusions, 
actions taken or to be taken and the actions recommended to guarantee 
compliance. 
 
All of the above shall be documented. 
 
 
 
 
15. AUDITS 
 
 
 
The sponsor may perform audits as implementation of the assurance of quality. 
Besides, any regulatory authority may perform them, in which case the sponsor 
must be notified. [151] 
 
For the audits on part of the sponsor, it must be understood that these are 
independent and separate from the routine monitoring and quality control. [151] 
 
In these, the conduction of the study and the compliance with the protocol, 
standard operative procedures, good clinical practices and applicable regulatory 
requirements will be evaluated. [151] 
 
The sponsor shall designate persons to perform audits that are independent of 
the clinical studies or systems. [151] 
 
The sponsor must make sure that the auditors are qualified based on their training 
and experience to conduct audits appropriately. The aptitudes of the auditor must 
be documented. [151] 
 
The following are procedures of auditing: 
 
Conformity of the auditing: shall be with the written procedures of the sponsor 
about what to audit, how to audit, frequency of audits and the form and content of 
the reports of an auditing. [151] 
 
Plan and procedures of auditing:  shall be guided by the importance of the study 
for submitting to the regulatory authorities, the number of subjects in the study, the 
type and complexity of the study, the level of risk for the subjects of the 

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study and any issues identified. [151] 
 
All the observations and findings of the auditing must be documented. [151] 
 
Preservation of the independence of the audit: to comply with this, the 
regulatory authorities must not routinely request reports of same. They may do it 
in specific cases when there is evidence of a serious non-compliance of the Good 
Clinical Practices or in the course of legal procedures. [151] 
 
Certificate of auditing: Shall be provided by the sponsor when required by the 
law or applicable regulation. [151] 
 
In the case of auditing by regulatory authorities, the main investigator shall 
immediately notify Valeant Pharmaceuticals International any inspection 
programmed by the competent authorities and deliver without delay the copies of 
the inspection reports. 
 
 
 
 
16. NON-COMPLIANCE 
 
 
 
Non-compliance with the protocol, standard operative procedures, good clinical 
practices and/or applicable regulatory requirement(s) by an investigator/institution 
or by the member(s) of the sponsor’s personnel, shall conduct an immediate 
action by the sponsor for assurance of compliance. [151] 
 
If the monitoring, and/or auditing identifies a serious and persistent non-
compliance on part of the investigator or institution, the sponsor shall terminate 
the participation of the investigator and/or institution in the study. In this case, the 
sponsor shall notify the regulatory authorities as soon as possible. [151] 
 
 
 
17. SUSPENSION OF THE STUDY 
 
 
 
Valeant Pharmaceuticals International reserves the right of suspending the study 
totally or partially at any moment for administrative or scientific reasons that so 
require. 

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This study may be suspended temporarily or definitively by duly justified decision 
of the Sponsor, Main Investigator, the CIEI or the Health Ministry. 
 
The causes may be diverse, among others the frequency and/or type of adverse 
events, new information of the drug that directly affects the safety of the patients 
or the implementation of the study or by a substantiated decision of the Ethics 
Institutional Review Board and/or COFEPRIS. 
 
In case of temporary suspension the patiens selected for the study shall be 
informed immediately and an appointment will be scheduled to make known the 
definitive decision of the course of the study. In case of definitive suspension, the 
Main Investigator will inform of this decision and will determine the application of 
the procedures of withdrawal of the study. 
 
If the suspension of the study is by decision of the Sponsor and/or the Main 
Investigator, the decision shall be documented between both of them and 
informed in writing, giving a detailed explanation of the temporary or definitive 
suspension to the Ethics Institutional Review Board. 
 
If for any reason the treatment is suspended before the completion of the active 
phase, the reason shall be reported in the case report form, with a detailed 
description of the event. 
 
If the treatment is suspended because of intolerance, the patient must not be 
restored and it must be reported as an adverse event, and also be monitored until 
the outcome. 
 
If the suspension of the treatment was due to an adverse event, the patient shall 
continue with follow-up by the investigator during the time he/she deems 
necessary. 
 
 
 
 
18. DEVIATIONS FROM PROTOCOL 
 
 
 
Every process which isn’t contemplated in this protocol and results during the 
study shall be notified to the Institutional Review Board and to the Sponsor. 
 
When it is necessary to implement a deviation or modification to the protocol to 
eliminate an immediate risk or risks, Valeant Pharmaceuticals International shall 
be notified as soon as possible. 

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It is necessary to count with the approval/favorable opinion of the Medical 
Direction of Valeant Pharmaceuticals International to establish said deviation or 
modification in an operative and sequential manner. 
 
The main Investigator shall not implement any deviation or modification of the 
protocol without the previous review and approval of said amendment, which shall 
be duly documented, excepting those necessary to eliminate an immediate 
potential risk(s) to the subjects of the study. 
 
Any significant deviation from the protocol shall be documented in the clinical 
record and Case Report Form. 
 
 
 
 
19. AMENDMENTS 
 
All the revisions to the protocol shall be discussed with the sponsor. 
Any amendment to the protocol must be approved by the Institutional Review 
Board and by the Federal Commission for Protection from Health Risks 
(COFEPRIS). 
 
Once authorized, the participants in the study must be informed about the 
modifications and apply the due informed consent for those that apply. 
 
 
 
 
20. ETHICAL ASPECTS 
 
 
 
This study shall be implemented in conformity with the ethical principles that 
originate in the Good Clinical Practices (GCP), [151] the ethical guidelines issued 
by the 64th World Medical Assembly, Fortaleza, Brazil, October 2013, of the 
Helsinki Declaration [153], the General Health Law, [L6] the Regulations of the 
General Health Law on Matters of Research for Health [L7 ] and the Mexican 
Official Norm NOM-012-SSA3-2012, which establishes the criteria of research 
projects in human beings. [L5] According to what is established in these laws, this 
research implies a risk above the minimum. All the personnel involved in this study 
and who deals with patients must have verifiable knowledge about ethics in 
research and the processes to implement for the research in humans. Thereby, 
they must have verifiable knowledge about the good clinical practices. 

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The sponsor may request this documentation on part of the main investigator and 
delegate personnel. 
 
In light of every process the ethical principles for the medical reseaeches in 
human beings must be safeguarded. The sponsor shall verify that the personnel 
dealing with the human subject has verifiable knowledge of the general principles 
of ethics in researches in human beings, risks, costs and benefits of the protocol 
of research in human beings, groups and vulnerable persons, shall have 
knowledge about the scientific background of the study, the documents to apply for 
submitting or reporting to the committee of ethics in research, the privacy and 
confidentiality of the subject, that the personnel that applies the informed consent 
be competent and implements it in an adequate manner and has the knowledge 
that the publishing and diffusion of the results requires previous authorization of the 
sponsor. 
 
The personnel that performs functions at the site or who may be under any 
circumstance that positions them as ethically vulnerable, may not be included in 
this study. [153] 
 
 
 
 
21. MATERIAL RESOURCES AND FINANCING 
 
 
 
Valeant Pharmaceuticals International will be responsible of providing the 
financing so the clinical trial is implemented under the postulates of this protocol. 
Every omission to be considered her that is detected on part of the sponsor and 
results in a secondary expense, shall be notified to Valeant Pharmaceuticals 
International and they will evaluate that it isn’t cohesive for the investigator or the 
patient. Also, the economic rectification is determined or not. 
 
The investigational product to use and the material that Valeant Pharmaceuticals 
International provides to the site shall be returned to the sponsor; unless there is 
another indication on part of the sponsor. 

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ANY SEVERE ADVERSE EVENT, INCLUDING DEATH DUE 
TO ANY CAUSE THAT OCCURS DURING THE RESEARCH, 
BE IT RELATED OR NOT WITH THE INVESTIGATIONAL 
MEDICATION, SHALL BE IMMEDIATELY REPORTED TO THE 
MEDICAL 
DIRECTOR, 
MANAGER 
OF 
PHARMACOVIGILANCE 
AND 
CLINICAL 
RESEARCH 
COORDINATOR FOR MEXICO AND LATIN AMERICA OF 
VALEANT PHARMACEUTICALS INTERNATIONAL. 
 
 
 
MEDICAL DIRECTOR, MEXICO AND LATIN AMERICA 
DR. VENTURA AGUIRRE ROJAS 
 
 
MANAGER OF PHARMACOVIGILANCE, LATIN AMERICA 
 
M.C. SAR ALIK PEDRAJO ZENTENO 
 
 
 
RESPONSIBLE OF PHARMACOVIGILANCE, MEXICO  
DR. PAOLA ANDREA MARTÍNEZ SERRANO 
 
 
CLINICAL RESEARCH COORDINATOR, MEXICO AND LATIN AMERICA 
DR. FRANCISCO JAVIER FIGUEROA VALLEJO 
 
ADDRESS: CALZADA TLALPAN 2021 
COL. PARQUE SAN ANDRES 
C.P. 04040 
CIUDAD DE MÉXICO 
MÉXICO 
TEL: (55) 5062 4190 
TEL 24 HORAS: 044(55) 23009656, 044 (55) 43731344 
FAX: (55) 5062 4172  
E-MAIL: 
farmacovigilancia.mexico@valeant.com 
francisco.figueroa@valeant.com 

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148. Armitage P, Berry G. Statistical methods in medical research. 3rd ed. Oxford: Blackwell; 
1994. 
 
149. Rosas M, Santos LE, Magaña J, Valencia JS, Garrido M, Pérez G. Metodología para los 
estudios clínicos de superioridad frente a los de equivalencia y estudios de no inferioridad. 
Una revisión aplicada. Revista Médica del Instituto Mexicano del Seguro Social. 
2016;54(3):344-53. 
 
150. Camacho J. Tamaño de muestra en estudios clínicos. Nota estadística. Ene-mar 
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151. International  Conference  on  Harmonisation,  Guideline  for  Good  Clinical  Practice. 
Federal Register, 9 May 1997; 62 (90): 25691-709. 
 
 
152. Secretaría de Salud/Comisión Nacional de Bioética. Guía nacional para la integración y 
el funcionamiento de los Comités de Bioética. 6 ed. México: 2016. 
 
153. Asociación Médica Mundial, Declaración de Helsinki. Principios éticos para las 
investigaciones médicas en seres humanos. Fortaleza, Brasil. 64ª asamblea de octubre 
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154. Altman DG. Comparability of randomized groups. Journal od the Royal Statistical 
Society. 1985;(34):125-136. 
 
155. Martin JD. Algorithms for assessing the probability of an Adverse Drug Reaction, 
Respiratory Medicine CME. 2009; (2):63-67. ISSN 1755-0017. 
 
156. De Vivo DC, Bohan TP, Coulter DL, Dreifuss FE, Greenwood RS, Nordli DR Jr., et al. L- 
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157. Van Oudheusden LJ, Scholte HR. Efficacy of carnitine in the treatment of children with 
attentiondeficit hyperactivity disorder. Prostaglandins, Leukotrienes and Essential Fatty 
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158. Rizos I. Three-year survival of patients with heart failure caused by dilated 
cardiomyopathy and Lcarnitine administration. American Heart Journal. 2000;(139):S120- 
S123. 
 
159. Ellaway C, Williams K, Leonard H, Higgins G, Wilcken B, Christodoulou J. Rett 
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160. Plioplys AV, Plioplys S. Amantadine and L-carnitine treatment of chronic fatigue 
syndrome. Neuropsychobiology 1997; (35):16-23. 

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161. Campos Y, Huertas R, Lorenzo G, Bautista J, Gutierrez E, Aparicio M. Plasma carnitine 
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162. Cherchi A, Lai C, Angelino F, Trucco G, Caponnetto S, Mereto PE, et al. Effects of L- 
carnitine on exercise tolerance in chronic stable angina: a multicenter, double blind, 
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163. Harper P, Elwin CE, Cederblad G. Pharmacokinetics of intravenous and oral bolus doses 
of Lcarnitine in healthy subjects. European Journal of Clinical Pharmacology. 1988; 
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164. Product Information: CARNITOR ® injection, levocarnitine injection. Sigma-Tau 
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Legislative annex 
 
 
[L1] 
Secretaría de Salud. Norma oficial mexicana NOM- 037-SSA2-2012, para la prevención, 
tratamiento y control de las dislipidemias. Diario Oficial de la Federación del 13 de julio de 2012. 
 
[L2] 
Secretaría de Salud, Norma Oficial Mexicana NOM-030-SSA2-2009, para la prevención, 
detección, diagnóstico, tratamiento y control de la hipertensión arterial sistémica. Diario Oficial 
de la Federación del 24 de noviembre de 2009. 
 
[L3] 
Secretaría de Salud, Norma Oficial Mexicana NOM-015-SSA2-2010, para la prevención, 
tratamiento y control de la diabetes mellitus. Diario Oficial de la Federación del 05 de agosto del 
2010. 
 
[L4] 
Gobierno de la República de los Estados Unidos Mexicanos, Plan Nacional de Desarrollo 2013- 
2018. Diario Oficial de la Federación del 20 de mayo de 2013. 
 
[L5] 
Secretaría de Salud, Norma Oficial Mexicana NOM-012-SSA3-2012, Que establece los criterios 
de proyectos de investigación para la salud en seres humanos. Diario Oficial de la Federación 
del 04 de enero de 2013. 
 
[L6] 
Honorable Congreso de la Unión, Ley General de Salud, Título Quinto. Investigación para la 
Salud, Capítulo único. Diario Oficial de la Federación del 27 de enero de 2017. 
 
[L7] 
Presidencia de la República de los Estados Unidos Mexicanos, Reglamento de la Ley General 
de Salud en Materia de Investigación para la Salud. Diario Ofical de la Federación del 7 de 
febrero de 1984. 
 
[L8] 
Secretaría de Salud, Norma Oficial Mexicana NOM-004-SSA3-2012, Del expediente clínico. 
Diario Oficial de la Federación del 29 de junio de 2012. 
 
[L9] 
Secretaría de Salud, Norma Oficial Mexicana NOM-220-SSA1-2012, Instalación y operación de 
la farmacovigilancia. Diario Oficial de la Federación del 07 de enero de 2013. 

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Annex 1. Globorisk Scale 
 
 
 
 
 
 

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Annex 2.Control Card of Treatment of the Patient, Basal Visit 
 
 
 
 

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Annex 3. Control Card of the Treatment of the Patient Visit 1 
 
 
 
 

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Annex 4. Control Card of Treatment of the Participant, Visit 2 
 
 
 

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Annex 5. Format for the Evaluation of Causality 
 
 
 
Naranjo Algorithm for the evaluation of the 
Causality 
Yes 
No 
N/D
Score 
1) Is there conclusive previous evidence about this 
reaction? 
1 
0 
0 
2) Did the adverse reaction appear after the 
administration of the implied medicine? 
2 
-1 
0 
3) Was there an improvement of the adverse reaction 
when the medicine was suspended or when a specific 
antagonist was administered? 
1 
0 
0 
4) Did the adverse reaction reappear when the 
medicine was re-administered? 
2 
-1 
0 
5) Are there alternative causes that may have 
caused the reaction? 
-1
2 
0 
6) Did this reaction occur after administrating 
placebo? 
-1
1 
0 
7) Was the presence of the medicine proven in the 
corporal fluids in concentrations known as toxic? 
1 
0 
0 
8) Was there a variation in the severity of the 
reaction when the dose of the medicine was varied? 
1 
0 
0 
9) Has the patient experienced a similar reaction in 
previous expositions to the medicine or to similar 
medicines? 
1 
0 
0 
10) Has the adverse reaction been confirmed 
through some objective evidence? 
1 
0 
0 
TOTAL SCORE 
 
 
  TOTAL 
SCORE 
CLASSIFICATION 
Less than 0 
Doubtful 
            From 1 to 4  
Possible 
            From 5 to 8 
Probable 
9 or more 
Certain 
 
References: 
 
Martin J. Doherty, Algorithms for assessing the probability of an Adverse Drug Reaction, Respiratory Medicine CME, 
Volume 2, Issue 2, 2009, Pages 63-67, ISSN 1755-0017.