Clinical trial NCT02548832
Conditions: Mixed Dyslipidemia
Keywords: Berberine Bezafibrate
Sponsor: University of Guadalajara
Start date: 2013-04-01; Completion date: 2020-04-01
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Dyslipidemia, is a cardiovascular risk factor of great importance whose prevalence has increased over the last decade. Part of the components of metabolic syndrome and consensus so far contemplated to increased triglycerides (TG) and reduced high-density lipoprotein cholesterol (HDL-C) as part of the elements for classification, which includes mixed dyslipidemia.

Currently, fibrates, such as bezafibrate, are drugs used in treating hypertriglyceridemia, besides reducing the risk of coronary disease. However, although this treatment is safe, it is not without risks; with increased prevalence of adverse effects as the dose thereof is increased or joins combination with a statin drug for the treatment of mixed dyslipidemia long term.

Among the alternative therapies is berberine, which to reduce cholesterol and triglycerides may be useful in combination with bezafibrate in the treatment of mixed dyslipidemia and as an option with lower cost and lower frequency of adverse events.

Detailed description:
The aim of this study is to evaluate the effect of berberine plus bezafibrate administration on the lipid profile of patients with mixed dyslipidemia.The investigators will conduct a double-blind randomized pilot clinical trial with parallel groups in men and women aged 30-60 years old with diagnosis of mixed dyslipidemia.

Patients will be assigned to 3 groups:

1. 12 patients will receive berberine, 1500 mg / day
2. 12 Patients will receive bezafibrate 400 mg / day
3. 12 patients will receive a combination of berberine (1500 mg / day) plus bezafibrate (400 mg / day).

All participants will be determined before and after the intervention: lipid profile, total cholesterol (TC), triglycerides (TG), HDL-C, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein (VLDL).

Also weight, Body Mass Index (BMI), waist circumference (WC), glucose, systolic blood pressure (SBP), diastolic blood pressure (DBP), creatinine (CR) uric acid (UA) and tolerability.

Statistical analysis was performed upon the sample of subjects.

Previous start the statistical analysis of the groups will proceed to verify the behavior of the distribution of the variables included by Z Kolmogorov-Smirnov goodness of fit.

The distribution of all the variables under this test is cataloged in normal or not normal, which define the type of statistical test would be performed (parametric or non-parametric). However, based on the sample size, non-parametric tests will be those considered most suitable for application.

The data obtained will be expressed and presented using measures of central tendency and dispersion for quantitative (mean and standard deviation) variables and qualitative variables are expressed as frequencies and percentages.

Arms: arm 1: Berberine 500 mg with breakfast, meal, and dinner. arm 2: Bezafibrate 200 mg on breakfast and dinner. arm 3: Berberine 500 mg with breakfast, meal, and dinner, and bezafibrate 200 mg only on breakfast and dinner.
Interventions: intervention 1: Berberine intervention 2: Bezafibrate intervention 3: Berberine plus Bezafibrate
Intervention descriptions: intervention 1: Berberine 1500 mg, each 24 h for 90 days

1 Berberine capsule 500 mg for breakfast.

1 Berberine capsule 500 mg for lunch.

1 Berberine capsule 500 mg for dinner. intervention 2: Bezafibrate capsule 400 mg each 24 h for 90 days.

1 Bezafibrate capsule 200 mg for breakfast.

1 Bezafibrate capsule 200 mg for dinner. intervention 3: Berberine 1500 mg each 24 h for 90 days

1 Berberine capsule 500 mg for breakfast.

1 Berberine capsule 500 mg for lunch.

1 Berberine capsule 500 mg for dinner.

Bezafibrate 400 mg each 24 h for 90 days.

1 Bezafibrate capsule 200 mg for breakfast.

1 Bezafibrate capsule 200 mg for dinner.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Bezafibrate Plus 
Berberine in Mixed 
Dyslipidemia 
NCT 02548832 
04-09-2013 


 
INTRODUCTION 
 
Food and beverages have radically changed in recent decades, with an 
increase in their caloric content, production, distribution and availability at low 
cost. This has modified the lifestyle, which by having these comforts has led the 
world to a sedentary lifestyle. These factors, as well as the genetic ones, have 
influenced the increase in health risks as well as metabolic diseases, where 
cardiovascular diseases, as well as disorders of lipid and glucose metabolism 
wreak havoc on the health of those who have these alterations.1,2 
Among the risk factors that can be modified are dyslipidemias, which constitute 
a group of diseases related to an alteration in the lipid profile. Its classification 
depends on the value that is altered in relation to total cholesterol (TC), 
triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), as well as low- 
density lipoprotein cholesterol (C- LDL). The reference values to consider an 
alteration in lipid metabolism based on its concentration is for TC ≥ 200 mg / dL, 
in a profile in which only this value is altered, it is called isolated 
hypercholesterolemia, when a TG value is presented. ≥ 150 mg / dL is 
considered hypertriglyceridemia and if we have an alteration in both TC ≥ 200 
mg / dL and TG ≥ 150 mg / dL it is considered as mixed dyslipidemia. Mixed 
dyslipidemia is considered to have a higher potential health risk than isolated 
dyslipidemia, 
these 
patients 
may 
develop 
complications 
related 
to 
hypercholesterolemia such as chronic renal failure, loss of sight, atherosclerosis 
or related to hypertriglyceridemia such as pancreatitis and fatty liver , or the 
above at the same time. It is necessary to mention that atherosclerosis is a 
condition that can trigger cardiovascular diseases and is present in mixed 
dyslipidemia.2 
The National Health and Nutrition Survey (ENSANUT) 2006 reported a 
prevalence of hypercholesterolemia of 26.5% of the surveyed population, in turn 
18.2% was diagnosed with mixed dyslipidemia,1 on the other hand, ENSANUT 
2012 reported that 25.8% of the Mexican population suffers from 
hypercholesterolemia. Therefore, the diagnosis and treatment of dyslipidemias 
is considered a priority for health systems.3 


For the treatment of this disease, the guidelines establish changes in diet as 
well as in lifestyle, as a basic action. However, in some patients these 
measures do not work, which makes it necessary to start a pharmacological 
intervention with a lipid-lowering agent, which can be a monotherapy or a 
combination therapy. 
Combined therapies with lipid-lowering drugs for the treatment of mixed 
dyslipidemia are still under investigation, it has been shown that in some 
patients or groups of patients the available therapeutic options are not the best 
option given the monetary cost they represent and the adverse events that can 
complicate the health of patients, which is why it is necessary to find combined 
therapies with a low presence of adverse events that help patients meet the 
therapeutic objectives that are TC values <200 mg / dL and TG <150 mg / dL.4 ,5 
From the group of lipid-lowering drugs, bezafibrate has been used for the 
treatment of mixed dyslipidemia as a therapeutic option due to its main action 
as a TG reducer with a low presence of adverse events; Its mechanism of 
action is as an agonist of the peroxisome proliferator activated receptor (PPAR) 
alpha (α), beta (β) and gamma (γ), it forms a temporary bond with the retinoid X 
receptor (RXR) at the cellular level. The cellular machinery increases the 
catabolism of lipoproteins (LP) in the blood, which is why the concentration of 
TG, as well as LDL-C and very low-density lipoproteins (VLDL) decreases, with 
an increase in levels and the quality of C-HDL.6,7 
The use of natural extracts for the treatment of diseases and the recovery of 
health has accompanied humanity since its origins, today in the cultures of the 
world the use of these extracts in an empirical way prevails and the Mexican 
culture is not the exception. In Asian culture there is an extract of natural origin 
that has been used for the treatment of various diseases where dyslipidemia is 
one of them, this extract is obtained from plants of the genus Berberis bulgaris, 
the extract from the rhizome and stem of the plants of this genus is known as 
berberine (BBR). The combination of BBR plus bezafibrate could offer a 
pharmacological treatment alternative for patients with mixed dyslipidemia. 


 
 
 
 
BACKGROUND 
 
A study by the Ministry of Health on the health of Mexicans determined that 
conditions such as hyperglycemia, overweight and obesity, poor dietary habits, 
HA, alcohol or drug consumption, low glomerular filtration, smoking, elevated 
TC (≥ 200 mg / dl), malnutrition and low physical activity, are the 10 main risk 
factors to the health of Mexicans and these factors can act synergistically in the 
development of cardiovascular disease. Given that TC ≥ 200 mg / dL, it is one 
of the 2 components of mixed dyslipidemia, treating those who suffer from it 
early is of the utmost importance since this can avoid the increased risk of 
cardiovascular disease. Diagnosis is by determining the plasma concentration 
of TC and TG, treatment consists of general nutrition and exercise 
recommendations, as well as lipid-lowering drugs in many cases.8,9,10 
When non-pharmacological measures are insufficient, it is necessary to use 
lipid-lowering drugs.10 Of these, statins are the first-line drug, they are effective 
in reducing TC levels, in high doses they are effective in lowering TG, however 
When TG values ≥ 442.5 mg / dl occur, it is no longer a first-line therapy.11 This 
is why combined therapies are used for the treatment of mixed dyslipidemia. 
Combined therapy for the management of mixed dyslipidemia, the combination 
of statins and fibrates leads the drug treatment guidelines, however this 
combination presents a muscle involvement between 0.3-33% and its 
association increases the probability of presenting myopathy that can increase 
the presence of rhabdomyolysis.12 
Plants and natural extracts have been used to treat diseases since the dawn of 
mankind. In recent times, this trend has increased and today the search for 
natural therapeutic options that are effective for the treatment and recovery of 
health continues, where BBR has shown to be an extract that can be used for 
the treatment of mixed dyslipidemia.13 
A meta-analysis on the use of BBR in which 11 clinical trials were included in 
which a daily dose of 500 to 1500 mg of BBR was administered, results of this 


work showed a significant reduction in CT and TG values, without modifying the 
rest lipid profile.14 
In a clinical trial carried out in patients with hypercholesterolemia, it is shown 
that the administration of BBR at a dose of 500 mg every 12 h orally, allows 
changes in TC in 18% (p <0.001), TG in 28% (p <0.001) and LDL-C by 20% (p 
<0.001), although HDL-C values remained unchanged.15 
 
Pérez Rubio et al., 9 conducted a clinical trial in which BBR 500 mg V.O. every 
8 h for 12 weeks in a population with metabolic syndrome, reported a significant 
decrease based on statistical tests in the values of TC (187.0 ± 33.3 vs 175.6 ± 
27.0 mg / dL) and TG (215.9 ± 64.7 vs 131.1 ± 51.2 mg / dL), however, HDL-C 
and LDL-C did not change. 
From the group of lipid-lowering drugs, bezafibrate has been a drug of choice 
for the treatment of hypertriglyceridemia and in combination with some other 
lipid-lowering drug for the treatment of mixed dyslipidemia.16 
The safety and efficacy of bezafibrate make it a useful drug for the treatment of 
dyslipidemia, it is well tolerated and can be combined to achieve better control 
of mixed dyslipidemia. In turn, a meta-analysis of the use of bezafibrate in 
relation to the lipid profile, showed its effect in reducing the concentration of TC 
and TG and an increase in HDL-C levels, as well as a cardioprotective effect, 
which helped in reducing coronary heart disease by up to 28%.17 
A clinical trial where bezafibrate was compared against placebo with a duration 
of 5 years in which 400 mg of bezafibrate were administered per day, showed a 
reduction in TG of up to 20.6 mg / dL without showing significant changes on 
TC, LDL-C, They also report an increase of up to 17 mg / dL of HDL-C.18 
In the Mexican population, another clinical trial was carried out in patients with 
mixed dyslipidemia, to which bezafibrate was administered at a dose of 400 mg 
V.O. every 24 h for 12 weeks, it was reported that after treatment and when 
comparing with baseline values, TG were significantly reduced by 24.4% in the 
group that was administered bezafibrate (p <0.05), however, the rest of the lipid 
profile such as CT, HDL-C and LDL-C did not show a significant statistical 


difference.16 This is the first study in which BBR was used in combination with 
bezafibrate as a therapeutic option for the treatment of mixed dyslipidemia. 
 
 
HYPOTHESIS 
 
The effect of the administration of the combination of BBR plus bezafibrate 
modifies the lipid profile in patients with mixed dyslipidemia. 


OBJECTIVES 
 
General 
 
To assess the effect of the administration of the combination of BBR plus 
bezafibrate on the lipid profile in patients with mixed dyslipidemia. 
Specific objectives 
 
Determine the concentration of CT, TG, HDL-C, LDL-C, and VLDL-C before and 
after the intervention with BBR, bezafibrate and BBR plus bezafibrate. 
Secondary objectives 
 
To determine the effect of the administration of BBR, bezafibrate and BBR plus 
bezafibrate on body weight, height, body mass index (BMI), 
waist 
circumference, blood pressure, fasting glucose, creatinine, uric acid. 
 
 
Describe the tolerability of the administration of BBR, bezafibrate and BBR plus 
bezafibrate. 


METHODOLOGY 
 
To assess the effect of the administration of the combination of BBR plus 
bezafibrate on the lipid profile in patients with mixed dyslipidemia. 
Specific objectives 
 
Determine the concentration of CT, TG, HDL-C, LDL-C, and VLDL-C before and 
after the intervention with BBR, bezafibrate and BBR plus bezafibrate. 
Study design 
 
Single randomized, parallel group, double-blind clinical trial. 
Resident 
population of the Guadalajara Metropolitan Area between 30 and 60 years of 
age, of any sex, with a diagnosis of mixed dyslipidemia. 
Study site 
 
Institute of Experimental and Clinical Therapeutics (INTEC) located in the 
Department of Physiology, University Center for Health Sciences, University of 
Guadalajara. 
The sample size was calculated according to the formula for clinical trials, 61 in 
which the following values were taken into account for its calculation: The Zα 
corresponds to the value of statistical confidence, which was prefixed to a value 
of Z1-β of 95%, for a type I error of 5% expressed as a value of 0.05 with two 
tails. For this confidence, the value of Z was 1.96. 
Z1-β that expresses the statistical power or power and was prefixed to the value 
of Z-β of 80%, for a type II error of 20%, which is equivalent to a value of 0.20. 
For this statistical power and this type II error, the typified Z score was 0.842. 
The expression δ refers to the standard deviation in the basal TG 
concentrations obtained from the BBR studies, which was 35 mg / dL.62 d is the 
expected TG difference of 44.2 mg / dl.36 
The result was n = 10 for each intervention group, in order to ensure sufficient 
statistical power, the sample size was increased by 20% due to possible losses, 
giving n = 12 patients per group. 
Inclusion criteria 


The study population was selected based on the fulfillment of the following 
criteria: 
Men and women, age completed: 30 to 60 years residents of the Guadalajara 
metropolitan area, ability to communicate and comply with the established 
requirements. 
Diagnosis of mixed dyslipidemia (TG ≥ 150 mg / dL and TC ≥ 200 mg / dL), No 
drug treatment on lipid profile, signing of the consent letter under information. 
People with suspected or confirmed pregnancy, lactating or puerperium, TC ≥ 
400 mg / dL were not included, TG ≥ 500 mg / dL, BMI ≥ 39.9 kg / m2, DM2, 
Kidney and / or liver disease, Intolerance to bezafibrate or BBR, PAS / DBP 
≥140 / 90 mmHg, consumption of drugs with known action on lipid profile, 
glucose metabolism, BP or body weight. 
Elimination criteria. The withdrawal of informed consent, loss of follow-up, 
presence of a serious adverse event, adherence to treatment <80% were 
considered as a reason for exclusion, but not so in the final statistical analysis. 
Presence of any non-inclusion criteria during the intervention. 
Variables 
Independent variable 
Pharmacological intervention: 
 
Administration of 1500 mg of BBR homologated with 400 mg of placebo 
(calcined magnesia) 
Administration of 400 mg of approved bezafibrate with 1500 mg of placebo 
(calcined magnesia) 
Administration of 1500 mg of BBR with 400 mg of bezafibrate 
Dependent variables 
Primary: lipid profile (TC, TG, LDL-C, HDL-C, VDL) 
 
Secondary: weight, height, BMI, WC, BP, glucose, creatinine and uric acid, as 
well as tolerability 


Control variables 
 
Diet: They were given general nutrition recommendations based on the 
provisions of the dietary and physical activity recommendations of the National 
Academy of Medicine of Mexico, as shown in ANNEX document. 
Exercise: They were asked to continue with the daily physical activity they 
already did and not to increase it. 
The patients who came voluntarily for clinical evaluation generally had some 
cardiovascular risk factor such as dyslipidemia, smoking, etc. 
Groups, intervention allocation and blinding 
 
Three groups were formed randomly which were integrated in the following way. 
 
The first group of 12 patients with mixed dyslipidemia received O.V. one 500 mg 
BBR capsule and one 500 mg placebo capsule at breakfast, one 500 mg BBR 
capsule at lunch, and one BBR capsule and one 500 mg placebo capsule at 
night. 
The second group of 12 patients with mixed dyslipidemia received one 200 mg 
bezafibrate capsule in the morning and one 500 mg placebo capsule, one 500 
mg placebo capsule with food, and one 200 mg bezafibrate capsule and one of 
500 mg placebo in the evening. 
The third group of 12 patients with mixed dyslipidemia received 200 mg of 
Bezafibrate in the morning with 500 mg of BBR, a 500 mg capsule of BBR in the 
meal and finally a 200 mg capsule of bezafibrate and a 500 mg of BBR at night. 
During the visit at the beginning of the intervention period, all participants who 
met the inclusion criteria and agreed to participate in the study were asked to 
select a sealed envelope of 36; 12 sachets from group 1, 12 from group 2 and 
12 from group 3, which were mixed. At the time of selection, they were all equal 
with a number corresponding to each intervention group. Once scrambled, they 
were arranged in a box and the patient took one at random. 
The opening of the envelope selected by each participant allowed to know a 
numerical code that identified the intervention that the participant received. 
Blinding was guaranteed in which the participant was unaware of the type of 


treatment received, as well as the investigator. At the end of the study when the 
data were completed, the treatment codes were opened for statistical analysis, 
this without the person in charge of carrying out the statistical analysis knowing 
the treatment that the participants received. Participants who left the study 
without having completed the procedures, but who received at least one dose of 
the intervention, were taken into account for statistical analysis. 
Clinical determinations 
 
All the anthropometric and vital signs determinations as well as the procedures 
for the interrogation of the physical examination and the integration of the 
corresponding clinical history were carried out using accepted universal 
methods and in accordance with the General Health Law in its regulations on 
the presentation of care services medical. 
The physical examination as well as the clinical questioning were performed 
again on all the occasions required within the development of the study or when 
adverse events were suspected, which were also directly recorded in the 
attachment diary of each participant. 
Age: defined as the number of years elapsed since the patient's date of birth 
Gender: considered as the phenotypic sex of the participant at the time of birth 
and registered as female or male 
Weight: taken in kilograms (kg), the participant was placed in an upright position 
with his feet resting on the electrodes of the TANITA bc100 scale, this model 
has the ability to determine the user's body composition thanks to the bioelectric 
impedance system. The participant was placed in a standing position dressed in 
light clothing, without shoes and with bare feet, with the bladder evacuated 
before the measurement. 
Height: it was measured in centimeters (cm) using the stadiometer integrated 
into the TANITA bc100 scale, it was taken standing up, with the knees fully 
extended, upright posture, the gaze at right angles to the vertical and the lower 
edge of the orbit in the same horizontal plane as the external auditory canal. 


BMI: is the relationship between weight in kilograms and that of height in meters 
squared. This reading is provided automatically by the TANITA scale with the 
Quetelet formula (kg/m2). 
BP: was determined by OMRONMR digital sphygmomanometer in mmHg. With 
the participant sitting upright to form a right angle with both feet resting on the 
floor without crossing the legs and after 15 min of rest, a cuff was adjusted 3 cm 
above the elbow crease of the left arm. 3 shots were taken with a time 
difference of 3 minutes between each of them to obtain the average value of 
BP. 
WC: A fiberglass tape was used to obtain the measurement in cm, based on the 
ISSAC method for anthropometric determinations, when visualizing an 
imaginary line that started from the armpit hollow to the iliac crest, based on the 
point middle between the last rib and the top of the iliac crest (hip). At this point 
the 
WC 
was 
taken. 
All clinical determinations were carried out by medical and nutritional personnel 
in charge of this project. 
Laboratory determinations 
 
For the collection of all blood samples in the visits to the research center, all 
participants were summoned at 8 a.m., the essential requirements in each of 
the visits were: 1) fasting state of 12 h, 2) They were recommended to consume 
low-fat foods during the three days prior to the collection, 3) adequate intake of 
fluids, 4) not to attend in a state of wakefulness during the night preceding the 
collection of the samples. 
Collection of blood samples for clinical chemistry analysis was performed by 
simple venipuncture in the anterior ulnar region at the height of the elbow 
crease, the procedure used to collect blood samples, as well as the volume of 
the It was established based on the activities required in each of the work visits. 
The total volume of blood required to collect during the entire field work was 10 
ml per patient. The determinations of lipids, as well as glucose were carried out 
using colorimetric-enzymatic techniques as described below, as well as the 
expected intra- and inter-assay CVs based on the information provided by the 


manufacturer (Biosystems) for each of the reagents and we use mg / dL as the 
unit of measure for all determinations. 
TC: The serum concentrations of TC were determined by the method based on 
the use of three enzymes, TG: The concentrations of TG in blood were 
measured by a method based on the enzymatic hydrolysis of serum TG to 
glycerol and FFA by the action of LPL, HDL-C: Serum HDL-C concentrations 
were measured using a method based on a modification of the classical 
precipitation procedure using optimized amounts of polyvinyl sulfonic acid, LDL- 
C: The Fridewald formula LDL-C = TC - (HDL-C + TG / 5) in mg / dL was used 
to calculate this value, VLDL: The TG / 5 ratio was used to calculate this value. 
Glucose: it was determined using the glucose oxidase technique. The glucose 
in the sample is oxidized to glucuronic acid and hydrogen peroxide (H2O2) in 
the presence of glucose oxidase, CR: it was quantified by the Jaffé method, by 
means of which a reaction with picrate occurs in an alkaline medium, causing a 
complex colored, UA: It was measured by means of a technique that involves 
two reactions. All measurements were made automatically in the ERBA 
Mannheim XI 100 equipment, the reagents used were appropriate for each test 
and specific for each one. 
STATISTIC ANALYSIS PLAN 
 
The data obtained were expressed in measures of central tendency and 
dispersion for quantitative variables (mean and standard deviation) and for 
qualitative variables (frequencies and percentages). Statistical significance (p- 
value) was determined by: 
When performing the normality test (Shapiro-Wilk) of the variables of the 3 
groups, it was found that, among others, the TG did not present a normal 
distribution, therefore, for the interpretation of the results, non-parametric tests 
were used. 
Kruskal-Wallis test to identify differences between the three intervention groups 
in relation to the quantitative variables of the included participants. 


Wilcoxon rank test to identify differences between the baseline and final 
evaluation of each intervention group in relation to the quantitative variables of 
the included participants. 
Mann-Whitney U test to identify differences between two intervention groups in 
relation to the quantitative variables of the included participants. 
X2 test or Fisher's exact test to identify differences between two intervention 
groups in relation to the qualitative variables of the included participants. 
The preset level to consider the probability obtained from any of the statistical 
methods used was p ≤ 0.05. 
All variables were analyzed with the SPSS v22 program for windows. 
Recruitment 
15 detection campaigns were carried out in different points of the metropolitan 
area of Guadalajara, in which 290 people were attended, who were asked if 
they suffered or were referred to suffer from any cardiovascular disease, 
dyslipidemia, diabetes, prediabetes, etc. They were determined if they had 
obesity by calculating the BMI and the WC was determined; A capillary glucose 
test was also taken, for which a One touch ultra-glucometer was used to 
discard, by way of scrutiny, any alteration related to glucose metabolism. 
Of these patients, 60 reported having a dyslipidemia reference of their own or of 
a direct relative and were invited to the INTEC located at the University Center 
for Health Sciences of the University of Guadalajara to carry out a more 
complete scrutiny. 
Scrutiny 
 
Each patient was summoned to INTEC at 08:00 am with a 12-hour fast. The 
visit during the scrutiny period, like the rest of the scheduled visits, took place at 
INTEC from 8 a.m. During the first visit, a complete clinical record was 
integrated, for which a clinical interrogation and comprehensive physical 
examination were carried out, all the clinical characteristics required for the 
evaluation of the selection criteria for admission were corroborated. 5 ml of 


venous blood were taken by venipuncture with an 18 Gy catheter in the brachial 
vein to determine the lipid profile (CT, TG, HDL-C) and glucose. 
The 60 patients who were attended with the intention of knowing whether or not 
they suffered from mixed dyslipidemia, after carrying out the laboratory 
procedures, the results showed that 21 patients did not suffer from mixed 
dyslipidemia, so they did not continue as part of the study, however they were 
offered nutritional care by nutrition staff. Of the 39 who met the criteria for mixed 
dyslipidemia, 3 decided not to participate in the study and 36 agreed to 
participate; They were explained in detail each of the aspects of the project, the 
consent letter was read and explained under detailed information and they were 
asked to come the next day or the third day to begin their inclusion in the study 
and thus have a scheduled visit cycle for each one. 
Intervention period 
 
Through the indicated laboratory tests, each of the biochemical selection criteria 
was identified and documented. The patient who met the inclusion criteria was 
assigned to one of the intervention groups. 
Visit 1. Participants who met the inclusion criteria, signed the consent letter and 
agreed to participate in the study, were invited to extract one of the sealed 
envelopes that contained the assignment code to any of the three interventions. 
A treatment adherence diary was provided to the participant. In the diary, 
adherence to treatment was recorded day by day and the participant recorded 
each taking of the intervention, as well as the discomfort that she might feel 
daily. The indication to take each of the capsules was: “take one capsule from 
bottle 1 and one from bottle 2 and ingest them with liquid in the first bite of 
breakfast, one from bottle 3 with the first bite of food and one from bottle 4 and 
another from jar 5 with the first bite of dinner only Once the first visit was 
concluded, each patient was asked to come within the next 30 ± 3 days and 
was asked to keep the attachment diary, as well as the bottles to count the 
capsules consumed, it is in this visit in which were given the food 
recommendations that appear in the food guidance guide of the Ministry of 
Health.63 


Visits 2 and 3. They were carried out on days 30 and 60 ± 3 days after starting 
treatment. During these visits, the treatment adherence diary was reviewed, the 
capsule consumption record in the adherence diary and the number of capsules 
that were in each of the bottles were counted, and likewise, the patient was 
questioned to identify the possible presence of adverse events and were 
recorded in the file of each participant. The doubts that each patient might have 
were solved, they were reiterated about any doubts that the participant might 
have at the time, the bottles were collected, the capsules contained in each of 
them were quantified, the happy faces marked in the Attachment diary and 
finally the patient was given treatment for one more month. An appointment was 
made in 90 ± 3 days. 
End of the intervention period 90 ± 3 days after the start of the intervention 
period. The clinical and laboratory measurements were taken again as at the 
beginning of the project. Adherence to treatment was evaluated 
ETHICAL ASPECTS 
 
The study is classified according to the Regulation of the General Health Law 
on Research for Health, in its Third Title, Chapter I, Article 64 as a study with 
greater than minimal risk, for which it required signing of consent under 
information of each participant (see ANNEX). 
The procedures adhered to the ethical norms, the Regulations of the General 
Health Law in Research Matters and the principles emanating from the l8th 
Medical Assembly of Helsinki, Finland in 1964 and the modifications made by 
said Assembly in Tokyo Japan in 1975, in Venice, Italy in 1983, in Hong Kong in 
1989 and the 48th General Assembly of Somerset West, Republic of South 
Africa in 1996, 59th General Assembly, Seoul, Korea, October 2008 64th 
General Assembly, Fortaleza, Brazil, October 2013 where the medical research 
(clinical research). The study qualified for research in humans.19 
- In accordance with the guidelines of good clinical practice, all participants in 
the study were identified only by initials and number in the electronic database. 
The data was kept confidential, as were the results of clinical and laboratory 
tests, to ensure privacy. The results of this study are presented in this work, 
without indicating information that could reveal the identity of the participants.65 


The present work was approved by the Bioethics Committee of the Department 
of Physiology of the University Center for Health Sciences, with the record 
number DF / CB059 / 13, as well as by the Clinical Trials where the record 
number NCT 02548832 was obtained. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FINANCING 
 
It was funded in parallel with other studies 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFLICT OF INTEREST 
 
The project does not present conflicts of interest, it is an original research 
generated by the researchers involved in this project and it was not sponsored 
by the pharmaceutical industry. The interest of the present investigation is 
entirely the search for new knowledge in the field of therapeutic options for the 
treatment of mixed dyslipidemia. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIBLIOGRAPHY 
 
1. 
Olaiz-Fernández G, Rivera-Dommarco J, Shamah-Levy T, Rojas R, 
Villalpando-Hernández S, Hernández-Avila M, Sepúlveda-Amor J. Encuesta 
Nacional de Salud y Nutrición 2006. Cuernavaca, México: Instituto Nacional de 
Salud Pública, 2006. 


2. Arellano O, Barquera S, Barriguete J, Lara-Esqueda A, López-Ponce A, 
Rosaset M. Protocolo clínico para el diagnóstico y tratamiento de las 
dislipidemias 2 ed. México, Secretaría de Salud 2011. 
3. Gutiérrez JP, Rivera-Dommarco J, Shamah-Levy T, Villalpando-Hernández 
S, Franco A, Cuevas-Nasu L, Romero-Martínez M, Hernández-Ávila M. 
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Annex I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LETTER OF CONSENT UNDER WRITTEN INFORMATION 
 
NCT 02548832 


 
 
This informed consent form may contain words that you do not 
understand. Please ask the study doctor or research team staff to explain any 
words that you do not understand clearly. Do not sign this form unless you have 
received satisfactory answers to all of your questions. 
 
Purpose and description of the study 
 
Cholesterol and triglycerides are fats that are normally found in the blood, 
however when their concentrations are higher than normal they become a 
health risk, since they increase the possibility of different diseases, including 
heart problems. . When a person has cholesterol or triglyceride levels higher 
than normal, the diagnosis of dyslipidemia is established. For the treatment of 
people with dyslipidemia, it is usually started with measures of diet and 
exercise, however, despite these measures, some patients require adding one 
or two medications to the treatment in order to normalize the values of fats in 
the blood. . 
The drugs that will be studied for the treatment of mixed dyslipidemia are: 1) 
Berberine, which is a natural substance of Asian origin that has been shown to 
improve blood fats. 2) Bezafibrate, which is one of the first choice drugs to lower 
triglycerides and cholesterol. 3) The combination of berberine + bezafibrate. 
This study will last 90 days, from the first visit to the last, with an average 
of 5 visits (appointments to the research center). The study will involve 32 
people diagnosed with dyslipidemia who will be randomly assigned to one of the 
following 3 treatments: 
• Berberine 1500 mg orally 
• Bezafibrate 400 orally 
• Combination of berberine (1500 mg) plus bezafibrate (400 mg) 
You and the rest of the study participants will take the medicine as directed, 
and it will be provided free of charge by the investigator in charge of your 
evaluation in sufficient quantity for you to take in the interval between your 
appointments. Since this study is blind, you will not know which treatment group 
it belongs to, however this information will be accessible if necessary. 


 
Procedures 
 
If you agree to participate, the following will occur: 
 
Procedures that are routine in the care of patients in this service: 
 
You will go to the Research Unit fasting from 12 noon to 8:00 am. 
 
a) Clinical Procedures: you will be given a medical history that includes a 
complete physical examination with the measurement of your weight and blood 
pressure. 
 
b) Laboratory procedures: we will take a blood sample from one of your 
arms, approximately 7ml equivalent to approximately 2 teaspoons of your blood, 
to perform some laboratory studies. 
 
The laboratory studies that we will perform include measurement of your 
glucose, creatinine, uric acid, and a lipid (fat) profile. For your safety and 
hygiene, all the material used in this study is sterile and disposable, and at the 
end of the planned analyzes, the rest of the sample will be destroyed. 
The purpose of conducting laboratory and clinical studies is to learn more 
about your general health conditions. It will take us approximately 20 minutes to 
perform these clinical and laboratory tests. We will give you the results of your 
lab studies within 3 days. 
 
In case of meeting the criteria to enter the study and once this letter of 
consent is signed, another day will be called to the Research Unit on a 12-hour 
fast at 8:00 a.m. where the following specific procedures will be performed: 
 
Specific procedures of this investigation: 
 
During the second visit, which will take place no more than 7 days after 
your first visit, a blood sample (4 ml) will be taken again to assess your 
lipid (blood fat) profile. 


On this second visit, you will be given the medicine, which you will take 2 
capsules in the morning, one in the afternoon and two at night. The medicine 
will be provided to you free of charge and in sufficient quantity. 
 
After this visit, you will be asked to come in three more times (every 30 
days) to assess your health, in addition to assessing your weight, waist, and 
blood pressure. 
 
The blood tests will be carried out at the beginning and will be repeated 
until the 90th day (3 months) according to the appointment calendar that will be 
given to you. At all appointments to the Research Unit, you will be questioned 
about your health. 
 
The results of the final laboratory tests will be delivered to you and 
explained to you by the medical staff in charge of this project. You will be given 
a clinical summary that includes recommendations for continuing your 
treatment. 
The knowledge that results from this research will help to know and 
propose treatment options for glucose intolerance. 
 
Profits 
 
You can get the benefit of knowing your metabolic profile, that is, the 
amount of sugar in your blood, uric acid, fats in your blood such as cholesterol 
and triglycerides (among others), as well as knowing the functioning of your 
liver and kidneys. 
 
You will receive professional guidance on what steps you should take to 
lower your risk of heart disease or diabetes. Nutrition recommendations will be 
offered to you in the hope that it will help you improve your disease control. 
 
Possible risks and annoyances 
 
Discomforts or risks associated with clinical evaluation procedures: 


Weight, height, waist, and blood pressure measurements are noninvasive 
clinical studies that do not cause pain, discomfort, or risk. 
 
Discomforts or risks associated with laboratory procedures: 
 
Discomfort during blood sampling is minimal. Sometimes the procedure to 
take a blood sample can cause a little pain or a slight discomfort, it is possible 
that a small bruise may form. 
 
Discomforts or risks associated with the administration of berberine: 
 
Berberine has been shown to be safe, however it can temporarily produce 
gastrointestinal symptoms such as gas, diarrhea or abdominal pain. 
 
Discomforts or risks associated with the administration of bezafibrate: 
 
Bezafibrate is generally well tolerated. Adverse effects may occur in 5-10% 
of patients. The main complaints are gastrointestinal such as loss of appetite, a 
feeling of fullness in the stomach and nausea. Other side effects that appear 
infrequently can include fatigue, headache, and increases in certain liver 
enzymes. 
 
If you experience any complications from your participation in this study, 
you will receive the necessary treatment and follow-up. Any complication will be 
attended by specialized personnel of this Unit. 
 
Participation or withdrawal 
 
Your participation in this study is completely voluntary. If you decide not to 
participate, you will continue to receive the medical care provided by the 
Research Unit. If you do not want to participate in the study, your decision will 
not affect your right to obtain the health or other services you receive. 
 
For the purposes of this research we will only use the information that you 
have provided us from the moment you agreed to participate until the moment 
you let us know that you no longer wish to participate, so if during the study you 
decide to withdraw, you can do so. without this representing an alteration in 
your medical care. 


However, you should only enter this study if your current plan is to continue until 
the end of the study (3 months). 
 
You can ponder your decision to agree to participate or not to participate in 
the research project and your answer can be provided at a subsequent 
appointment. 
 
You are free to ask any member of the research team as many questions 
as you like. 
 
If you wish to suspend your participation, please contact those responsible 
for the study: Dr. en C. Manuel González Ortiz (33 36764255), LN. Karina G. 
Pérez Rubio (33 10918297) LN. Juan Miguel León Martínez (33 15515550) 
Cardiovascular Research Unit (36173499) 
 
Some of the doctors responsible for the study will make a final visit to 
ensure your health. 
 
The study doctor may also discontinue your participation at any time 
without your consent for any of the following reasons: 
 
• 
If you do not follow the instructions for your participation in the study 
 
• 
If the treatment appears to be harmful or intolerable to you 
 
• 
If the study is canceled 
 
 
Contact staff for questions and clarifications 
 
If you have questions or want to talk to someone about this research 
study, you can communicate from 8:00 a.m. to 4:00 p.m., Monday through 
Friday, with Dr. Manuel González Ortiz, who is the researcher responsible for 
the study, at the aforementioned telephones. 
 
In the event of an emergency arising from the study, you can dial the 
previous phone numbers with Dr. Manuel González Ortiz, at any time of the day 
and on any day of the week. 


Compensation 
 
Your participation in this study is completely voluntary, both the beginning 
of the study and its follow-up will be done only with your consent. Your 
contribution to our work will be compensated with the benefits mentioned above 
in the benefits section, which do not include monetary or in-kind compensation. 
 
Privacy and confidentiality 
 
The information that you provide us that could be used to identify you 
(such as your name, telephone number and address) will be kept confidential 
and separately as well as your answers to the questionnaires and the results of 
your clinical tests, to guarantee your Privacy. 
The team of researchers, the people involved in your health care, and your 
family doctor will know that you are participating in this study. However, no one 
else will have access to the information that you provide us during your 
participation in this study, unless you wish to do so. We will only provide your 
information if it is necessary to protect your rights or well-being (for example, if 
you suffer physical harm or need emergency care), or if required by law. 
When the results of this study are published or presented at conferences, 
for example, no information that could reveal your identity will be released. Your 
identity will be protected and hidden. To protect your identity, we will assign you 
a password that we will use to identify your data, and we will use that password 
instead of your name in our databases. 
☺ 
 
 
Did 
you 
understand 
the 
proposed 
information? 
YES 
NOT 
 
 
 
 
Patient statement 


By signing this consent, I acknowledge that I have been informed about 
the study methods and the administration of the treatments, the disadvantages 
and benefits and adverse events that may occur due to the procedures and 
medications. 
 
I certify that I have had sufficient time to read and understand the above 
information. I also acknowledge that all the technical language used in the 
description of the research study was explained to me to satisfaction and that I 
received answers to all my questions. 
 
I confirm that I have received a copy of this consent form. I understand that 
I am free to withdraw from the study at any time, without losing any benefits or 
suffering any penalty. I freely and without reservation give my consent to 
participate as a patient in this study. 
COMPETITOR 
 
Participant signature 
Signature Date 
 
Participant name: 
 
Participant's address: 
 
Telephone numbers to locate it: 
 
 
 
 
WITNESS 1 
Signature of witness 1 
Signature Date 
Witness 1 Name: 
Address of witness 1: 
Relationship with the Partic pant: 
 
 
 
 
 
WITNESS 2 


Witness 2 Signature: 
Signature Date 
Witness 2 Name: 
Address of witness 2: 
Relationship with the Parti cipant: 
 
 
Investigator statement 
 
I or my authorized representative have discussed with the participant or their authorized legal representative, 
the nature and purpose of this study, as well as the possible risks and benefits of their participation. I believe 
that the participant and / or their legal representative have received the complete information in 
understandable and appropriate language and that the explanation was understood. 
 
 
 
Investigator's signature: 
Signature Date 
Investigator's name: 
 
Participant identification code: