Patient case: 63-year-old female with aortic aneurysm; genetic feature: ACTA2

Clinical trial: Oral Administration of Cinnamomum Cassia as an Enhancer of the Insulin Response of IGF1 and Metabolic Control in Patients With DM2 Without Glycemic Control Treated With Metformin Diary.

Summary: Among the multiple treatment options for Diabetes Mellitus Type 2 (DM2), the influence on Insuline like growth factor 1 (IGF1) plays a causal role in diabetes but has shown similarities with insulin, both in its structure and in its function, including a rapid reduction in glucose levels in blood, could improve glycemic control in patients.
  Oral administration of 3 g of cinnamomum cassia for 90 days acts as an enhancer of the IGF1 insulin response and on metabolic control (fasting glucose, glycosylated hemoglobin (HbA1c), triglycerides, total cholesterol, high density cholesterol, low density cholesterol, very low density cholesterol, systolic and diastolic blood pressure (TAS and TAD), body weight) in patients with DM2 without glycemic control treated with metformin at doses ≤ 850 mg daily.

Detailed description: Introduction:
  DM2 is a chronic disease, considered a public health problem, scenario in which each year increases the number of people affected, has a high prevalence in the investigator's country, 9.4% (ENSANUT 2016), which causes a high morbidity and mortality. Conceptually it is defined as a heterogeneous syndrome originated by the genetic-environmental interaction and characterized by a chronic hyperglycemia, as a consequence of a deficiency in the secretion or action of insulin, which triggers acute complications (ketoacidosis and hyperosmolar coma), microvascular chronicles (retinopathies) and neuropathies) and macrovascular (coronary heart disease, cerebrovascular and peripheral vascular diseases).
  Growth hormones such as IGF1 with important biological effects on metabolism have been shown to promote the absorption of glucose in certain peripheral tissues. It has been shown that IGF1 binds to insulin receptors to stimulate the transport of glucose in fat and muscle, inhibiting the production of hepatic glucose by lowering blood glucose while at the same time suppressing insulin secretion, increasing sensitivity to insulin and improves the lipid profile.
  For the treatment of DM2 the use of botanical products can improve glucose metabolism by hypoglycemic effect, as well as that of lipids and antioxidant, aqueous extracts of cinnamomum cassia have been shown to enhance glucose uptake and glycogen synthesis in vitro and increase phosphorylation of the insulin receptor with possible effect on IGF1 receptor.
  The emergence of other therapies can generate new treatments for patients with DM2, which in turn reduce costs and help improve the quality of life.
  Justification:
  The prevalence of diabetes and metabolic decontrol is high both in Mexico and in the world and conditions the development of long-term complications. The concentrations of IGF1 in blood are diminished in the patients with diabetes mellitus and by its effects similar to the insulin in the metabolism of the glucose when normalizing this can produce control of the diabetes.
  In vitro studies have shown that cinnamomum cassia increases glucose uptake, glycogen synthesis and insulin receptor phosphorylation. In humans it has been confirmed that it increases the levels of glucagon-like peptide 1 (GLP-1), favors the activation of peroxisome proliferator-activated receptor (PPAR-γ and PPAR-α) promoting insulin sensitivity, as well as inhibits hepatic 3-hydroxy 3-methylglutaryl coenzyme A reductase to reduce the synthesis of cholesterol and has a vasodilator effect by activity on the enzyme nitric oxide synthase.
  Cinnamomum cassia also has a proposal on the signaling of IGF1 receptors (GRB2), which activated by phosphatidylinositol 3-kinase (PI3K) control the proliferation of IGF1, this IGF1 having reduced levels in patients with diabetes becomes a therapeutic target for improved control metabolic. However, the direct application of IGF1 has as main limitation important collateral effects which has inhibited its use, so it is intended to evaluate the stimulatory effect on IGF1 with cinnamomum cassia considering phytopharmaceutical of good quality and low side effects.
  General hypothesis:
  Cinnamomum cassia acts as an enhancer of the insulin response of IGF1 and metabolic control in patients with DM2 without glycemic control treated with metformin at low doses.
  Goals:
  GENERAL To evaluate the effect of cinnamomum cassia as an enhancer of the insulin response of IGF1 on metabolic control in patients with DM2 without glycemic control treated with metformin.
  SPECIFIC
  To analyze the effect before and after daily oral administration of 850mg of metformin plus 3g of cinnamomum cassia compared to placebo for 90 days on:
  -  Levels of IGF1.
  -  Fasting glucose value, HbA1c, triglycerides, total cholesterol, high density cholesterol, low density cholesterol, very low density cholesterol, systolic and diastolic blood pressure, body weight.
  SECONDARY
  To analyze the effect before and after daily oral administration of 850mg of metformin plus 3g of cinnamomum cassia compared to placebo for 90 days on:
  -  Insulin sensitivity, body mass index (BMI), waist circumference,% body fat.
  -  Determine the pharmacological attachment and tolerability of CC and placebo.
  Working universe:
  Patients with DM2, (men and women with a recent diagnosis, treated with 850 mg of metformin daily, without glycemic control). Residents of Guadalajara and metropolitan area and that for the development of the protocol they will go to the facilities of the National Medical Center of the West, Specialty Hospital.
  Sample size:
  It was calculated according to the following formula for clinical trials:
  n= 2 [ (Zα - Z1-β) (δ) / d] 2
  Where the following values were taken into account for the substitution of the equation:
  The Zα corresponding to the value of statistical confidence, which was prefixed by 95%; for a type I error of 5% expressed as an α value of 0.05 to two tails. For this confidence the value of the Z is 1.96.
  The Z1-β that expresses the statistical power and was prefixed in 80%; for a type II error of 20% that equals a β value of 0.20. For this statistical power and this type II error, the typified Z score is -0.842.
  The δ represents the value of the standard deviation of the primary outcome variables. In this way, a sample size was calculated for each of them, keeping the IGF1 criterion with a reference value for obese population of 16 μg / l.
  Finally d is the expected difference of the value of IGF1. The sample size calculated by this equation is, therefore, a minimum of 7 patients per study group in order to provide sufficient statistical power for the exploration of the primary primary variable, in this case the value of IGF1 .
  Two working groups will be formed at random, which will be integrated as follows: 1) a group of 14 patients (7 women and 7 men) with DM2 without adequate control, treated with metformin 850 mg daily, who will receive 1 g of cinnamomum cassia orally every 8 hours, for 90 days, and 2) a group of 14 patients (7 women and 7 men) with DM2 without adequate control, treated with metformin 850 mg daily, who will receive 1 g of placebo (calcined magnesia ) orally every 8 hours, for 90 days. In this way, the total number of participants required for the study will be, at least, 28 volunteers.
  Variables:
  Independent variable:
  Pharmacological intervention:
  -  Intervention group: Administration of metformin 850mg daily and cinnamomum cassia 1g orally before each meal, for 90 days.
  -  Control group: Administration of metformin 850mg daily and of placebo approved 1g (calcined magnesia) orally before each meal, for 90 days.
  Dependent variables:
  Primary outcome dependent variables:
  -  Laboratory determinations: IGF1, fasting glucose, HbA1c, lipid profile.
  -  Clinical determinations: systolic and diastolic blood pressure, body weight.
  Dependent secondary outcome variables:
  -  Laboratory determinations: serum creatinine, liver profile.
  -  Clinical determinations: Insulin sensitivity, body mass index, waist circumference and percentage of adiposity.
  Intervening variables:
  -  Diet.
  -  Exercise and physical activity.
  -  Phase of the menstrual cycle.
  -  Age.
  -  Gender.
  Operational definitions:
  The operational definitions that were used for each of the variables in the study as well as their measurement scale and, if applicable, the reference values are listed below.
  i. PHARMACOLOGICAL INTERVENTION The pharmacological intervention was defined as the oral administration of 1g three times a day and for 90 days of cinnamomum cassia or placebo according to the randomisation group. This is the primary independent variable, of a one-dimensional, qualitative, nominal and dichotomous nature. The possible values for this variable are: 1) cinnamomum cassia orally 1 g every 8 hours and; 2) placebo orally approved 1 g every 8 hours.
  ii. SERUM LEVELS OF IGF1 Serum levels of IGF1 vary from one individual to another, being dependent on age, sex, nutritional and hormonal status. Tables are used to define the normal range of IGF1 in healthy people, however, there is no information on the IGF1 levels adjusted for age and sex in the follow-up of patients with DM2. The record will be made in ng / ml. It is one of the primary, one-dimensional, quantitative and discrete dependent outcome variables.
  iii. GLUCOSE Glucose was defined as the serum glucose value after a minimum fast of 8 hours, this parameter is expressed in mg / dl. It is a primary dependent variable of a one-dimensional, quantitative and discrete type.
  iv. HbA1c The glycosylated hemoglobin is currently the best available test that reflects the glycemic control of the patient with DM2, it allows estimating the average level of glycemia 90 to 120 days prior to taking the sample. The percentage quantification of HbA1c allows a rapid and reliable estimation of the average quarterly glycemia, using the formula: (HbA1c% x 30) - 60. It is one of the primary outcome variables and is considered one-dimensional, quantitative and continuous.
  v. LIPID PROFILE The lipid profile was defined as the measurement of plasma lipid concentrations in the fasting state of 12 hours. For this, the value obtained in blood will be taken into account: total triglycerides, total cholesterol, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL). It is a primary, multidimensional, quantitative and continuous dependent variable.
  vi. SYSTOLIC AND DIASTOLIC ARTERIAL PRESSURE Systolic and diastolic blood pressure was defined as taking blood pressure expressed in millimeters of mercury (mmHg) after 15 minutes at rest, with empty bladder and at least 30 minutes of fasting. It is a variable of primary outcome, one-dimensional, quantitative and discrete.
  vii. BODY WEIGHT Body weight was defined as the measurement in grams of body mass, this measurement will be made in a TANITAMR TBF 300A, with the patient standing, wearing light clothes, barefoot and with empty bladder before the measurement. This is a variable of primary outcome, one-dimensional, quantitative and continuous.
  viii. SERUM CREATININE Serum creatinine was defined as a substance derived from the degradation of creatine at the level of muscle cells, being a function of lean body mass that appears increased in case of chronic and acute kidney disease, urinary tract obstruction, dehydration and rhabdomyolysis . It is expressed in mg / dl and it is a secondary, one-dimensional, quantitative and continuous dependent variable.
  ix. HEPATIC PROFILE The liver profile was defined as the biochemical evidence of hepatic or biliary cytotoxicity. It is a secondary, multidimensional, quantitative and continuous dependent variable that requires the determination of the following biochemical parameters: serum concentrations of aspartate aminotransferase (AST), alantate aminotransferase (ALT), lactic dehydrogenase (DHL), alkaline phosphatase (FA), gamma glutaril transpeptidase (GGT), direct bilirubin (BD) and total bilirubin (BT).
  x. SENSITIVITY TO INSULIN For the evaluation and / or quantification of insulin sensitivity, the triglycerides / glucose index surrogate formula will be used, based on the product of the natural logarithm between total triglycerides and fasting glucose divided by 2, whose formula is TyG = [( Ln TG (mg / dL) × FG (mg / dL)) / 2], using cut-off point of 4.68 for classification as sensitive ≥4.67 or resistant ≥4.68. It is a secondary, multidimensional, qualitative and dichotomous dependent variable.
  xi. BODY MASS INDEX
  The body mass index (BMI) or Quetelet Index is the relationship between body weight in kilograms between height in meters squared:
  BMI = kg / m2 It offers an indirect estimate for the diagnosis of obesity, validated and accepted by the World Health Organization (WHO) to identify subjects at risk of presenting comorbidities according to their BMI. It is a secondary variable, multidimensional, quantitative and continuous.
  xii. WAIST CIRCUMFERENCE The waist circumference was defined as the measurement in centimeters of the abdominal circumference at the level of the umbilicus. It is a secondary variable, one-dimensional, quantitative and continuous.
  xiii. PERCENTAGE OF ADIPOSITY The percentage of adiposity was defined as the measure of the percentage of total body mass that is composed of fat. It is a secondary, one-dimensional, quantitative, continuous variable.
  xiv. DIET The general nutrition recommendations will be explained to each patient according to the American Diabetes Association (ADA) guidelines. This is a confusing, qualitative, nominal and dichotomous variable.
  xv. EXERCISE AND PHYSICAL ACTIVITY Patients will be instructed to maintain physical activity as part of their daily routine to avoid interfering with the results. Considered variable of confusion, qualitative, nominal and dichotomous.
  xvi. PHASE OF THE MENSTRUAL CYCLE Because the levels of IGF1 vary according to the phase of the menstrual cycle, laboratory determinations in female patients will be made during the follicular phase that will be from day 3 to 8 of its cycle. This is a confusing variable, qualitative, nominal and dichotomous.
  xvii. AGE Age is defined as the total number of years elapsed from the patient's date of birth. Since IGF1 levels vary according to age, maintaining a plateau status during adulthood, it will be considered a confusing, qualitative, nominal and polytomous variable.
  xviii. GENDER The gender will be considered as the phenotypic sex of the patient at birth and registered as female or male. This variable is confusing, qualitative, nominal and dichotomous.
  Clinical procedures:
  All the anthropometric and vital signs determinations, as well as the procedures for the interrogation, physical examination and integration of the corresponding clinical history will be carried out by means of universally accepted methods and in accordance with the General Health Law, in its Regulation on the Provision of Medical Care Services.
  The history and clinical exploration will be performed at the first visit of the participant in order to establish eligibility to continue in the study. All positive and clinically interesting data will be recorded in the data collection notebook (CRD). The clinical examination and questioning will be carried out again in all the occasions required within the development of the study or in case of suspicion of adverse events. The data corresponding to: age, gender, diagnosis of DM2 will also be recorded directly in the CRD of each participant. The date of diagnosis of the disease, the time of evolution of the same and the laboratory tests with which the diagnosis.
  The weight, height, BMI, percentage of adiposity, TAS and TAD will be registered in the CRD, and in the database; determined according to the following criteria:
  -  Weight. The weight will be measured with the participant in standing position and wearing light clothes, without shoes, or socks and with the bladder evacuated before the measurement. A stationary TANITAMR electric bioimpedance scale will be used. The weight shall be recorded in kilograms with a minimum precision of 0.1 kg. Patients of the female gender should be in the period before the beginning of the menstrual period.
  -  Size. The height will be measured with a clinical flexometer. For its determination the participant will be asked to remove his footwear, maintain the position of standing with the heels together and a separation of around 5 cm between his first toes. In an upright position and with the look towards the horizon, the outer commissure of one of the eyes will be aligned with the hole of the external auditory canal ipsilateral. The size will be recorded in meters, with a minimum precision of 0.5 cm.
  -  Body mass index. The BMI is the relationship between the weight in kg and the square of the height in meters (kg / m2). This reading will be provided automatically by the TANITAMR electric bioimpedance scale.
  -  Blood pressure. Blood pressure will be determined by the auscultatory technique with a digital OMRON 705-T sphygmomanometer and a conventional stethoscope. The accuracy of the measurement will be established at no more than 3 mmHg and the blood pressure will be defined as the systolic and diastolic tensions average of 3 consecutive determinations.
  Paraclinical procedures:
  During each of the scheduled visits to the research unit it will be necessary to determine a clinical chemistry study, for this purpose it will be essential to collect blood samples and their subsequent processing. For the collection of all blood samples in each of the visits to the research center all participants will be cited at 8:00 am and will be an indispensable requirement in each of the collections of samples that come in a fasting state of 12 hours.
  Collection of blood samples for clinical analysis will be performed by simple venous puncture in the anterior ulnar region, at the height of the elbow fold. The total volume of blood required to collect during the entire fieldwork phase will be around 80ml per participant.
  Once the blood sample has been taken, the patient will be given general guidance and recommendations on diet and exercise for a healthy lifestyle. From the 3rd visit the attachment to the treatment will be evaluated, this determination will be made with the following formula, considering as acceptable a value ≥ 80%:
  Compliance rate (%) = Total number of capsules you ingested / Total number of capsules you should have ingested = Result multiplied by 100.
  Conservation and processing of samples:
  The serum should be processed routinely:
  The blood serum is obtained from a blood sample that is placed in dry test tubes (without any type of anticoagulant) to allow the formation of the blood clot by rest of the sample for a period no longer than 15 minutes, afterwards centrifuge the tube with whole blood at 3000 rpm for 10 min to obtain serum separation Strongly hemolyzed, lipemic or icteric samples should be repeated. The serum that must be frozen will be processed in a maximum time of 60 minutes (in the case of aliquots for IGF1 and insulin). Using a recovery criterion> 90% of the serum IGF1 concentration, the samples can be kept stable for 1 year at -80 ° C, 5 days at -20 to -4 ° C, and 3 days at 18 ° C.
  For determinations of: fasting glucose, Hb A1c, total cholesterol, high density cholesterol and triglycerides; it will proceed to its analysis on the same day that the medical history and clinical procedure of the patient is performed.
  Quality control in procedures:
  The quality and information management procedures will have the following quality control strategies:
  -  Review of the database in duplicate.
  -  Electronic comparison of duplicate database.
  -  Statistical review of the quality of the information.
  -  Statistical adjustment of the information.
  -  Calculation in duplicate of the statistical parameters of quality control.
  Instruments, techniques, materials and resources:
  i. Clinical chemistry analysis All the clinical chemistry measurements required in the study will be carried out with automated instruments for chemical analysis (Central Laboratory,Specialties Hospital of the National Medical Center of the West).
  -  The measurement of Hb A1c, will be performed using the high-resolution liquid chromatography technique with ion exchange with the automated equipment VARIANT II hemoglobin A1c Recorder Pack (Cat. No. 270-2102), with coefficient of variation of the low test precision 2.14% and high precision 1.68%.
  -  Serum measurements of glucose, total cholesterol, total triglycerides and HDL cholesterol will be performed using simple enzymes, multistep or electrometric methods, with an automated clinical chemistry analysis instrument Vitros System Chemistry 950, Ortho-Clinical Diagnostics Inc. NY, USA. The corresponding reagent kits are obtained from Ortho-Clinical Diagnostics Inc, through the Johnson-Johnson company, Rochester NY, USA. The equipment is operated by a single certified chemist assigned to this study in the clinical chemistry area of the central laboratory of the Specialties Hospital of the National Medical Center of the West. This equipment is calibrated routinely according to the general laboratory log.
  ii. Quantification of IGF1 IGF1 measurements will be performed with the MILLIPLEX® MAP HIGF-I, II Magnetic Bead in the Specialties Hospital of the National Medical Center of the West. This is a two-part kit used for the quantitative determination of IGF1 and / or IGF2 in serum, plasma, tissue extracts, cells or samples of culture media.
  Principle of the IGF1 assay: MILLIPLEX® MAP uses patented techniques to internally encode microspheres with two fluorescent dyes. Through precise concentrations of these dyes, magnetic microspheres can be created, each of which is coated with a specific capture antibody.
  After the analyte from a test sample is captured by the bead, a biotinylated antibody detection is introduced. The reaction mixture is then incubated with Streptavidin-PE conjugate, to complete the reaction on the surface of each microsphere. Each individual microsphere is identified and the result of the bioassay is quantified based on signals from fluorescent reporters.
  iii. Other equipment and instruments:
  The following equipment will be used during one or several stages of the study development:
  -  An Acer computer, with Windows 10 operating system.
  -  A medium format inkjet printer.
  -  A microcentrifuge with adjustable speed up to 7,200 g, with timer. Micro 7 model, by Fisher Scientific. National Labnet Company Inc. Made in USA.
  -  A digital clinical centrifuge with variable speed up to 6,000 rpm, brand Hetich, model EBA 20.
  -  A refrigerator-freezer for laboratory samples for freezing temperatures up to -30 ° C. Custom-Freezer model of 419 liters of storage. White-Westinghouse. Made in USA
  -  An analyzer of body composition TANITAMR TBF 300A, made in the United States by TANITA.
  -  A Littmann classic II stethoscope for adults, Littmann USA.
  -  A digital OMRON 705-T sphygmomanometer
  -  A diagnostic kit (otoscope and ophthalmoscope) with halogen lamps, Welch Allyn.
  -  A fiberglass clinical flexometer.
  -  A stationary fiberglass clinical flexometer for measuring height.
  Data management and analysis:
  Database All participants will have a complete clinical record during the development of the study. All the clinical and biochemical data that are submitted to statistical analysis must be registered in the corresponding CRD of each participant. The database will be developed from the CRDs, according to the coding included in said document, in * .xls format of the Microsoft Excel program. Updating and verification of the initial database will be done every time new data is obtained throughout the development of the field work. Once all the participants complete all the visits of the field work phase of the study, a review, verification and final validation of the initial database will be carried out. When the absence of errors in the initial database is verified, it will be converted to the format for analysis under the statistical package SPSS version 21 or higher for Windows. Before its analysis, the final database will be subject to verification and final correction by the principal investigator.
  Statistic analysis:
  The statistical analysis procedures will be carried out by means of a computer, using the final database and the software SPSS version 21 or higher for Windows. The coding of the interventions (in their two treatment groups) for the statistical analysis will be blinded to the analyst, coded only as intervention A or B.
  The most appropriate and reliable statistical procedures for the analysis of the data will be decided based on the result of the normality test. Overall the descriptive statistics used in the presentation of the data will include qualitative measures in frequency and percentage and quantitative measures of central tendency and dispersion (arithmetic mean and standard deviation), when considered appropriate it will also include median, minimum and maximum values or dispersion ranges.
  -  Identification of differences between the treatment groups in relation to variables of nominal nature using chi-square.
  -  Identification of differences between treatment groups in relation to quantitative data: anthropometric, metabolic and biosecurity in each of the study periods (pre-selection, start of intervention, closure of intervention), using the Student's T test or U of Mann Whitney.
  -  Identification of biosecurity profiles, between groups using chi-square.
  -  Identification of differences in paired samples (intra-group) between baseline and final measurements by paired Student's T test or Wilcoxon test.
  For all cases, the significance will be p ≤ 0.05. All patients receiving at least one dose of intervention treatment will be taken into account in the statistical analysis as part of the intention-to-treat analysis of the eliminated subjects.
  Ethical and legal framework:
  All the procedures and activities carried out during the development of this clinical trial will be carried out in full compliance with the legal provisions of the General Health Law of the United Mexican States, and in accordance with the ethical principles for pharmacological research on human beings detailed in the latest revision of the Helsinki Declaration and the International Harmonization Conference.
  The research protocol will be submitted for approval by the local Research Committee of the Specialties Hospital of the National Medical Center of the West. The study is classified within the General Health Law and its regulations on research in humans as of risk greater than the minimum, since it is a pharmacological study with potential risk; for which it is required to obtain a consent under written information signed at the beginning of the study. The document will be signed in duplicate by the participant, two witnesses from outside the research team and preferably relatives or friends of the participant, and by the principal investigator of the center. One of the duplicates of informed consent will remain with the principal investigator, while the other will be delivered to the study participant.
  According to the guidelines of good clinical practice all participants in the study will be identified only by initials and number in the database. The records and laboratory results will be available only to the principal investigators, and with the restrictions of law for the participant.
  Conflicts of interest:
  There are no conflicts of interest for the conduct of the study. The information obtained from this study will be made available to privileged researchers involved in the development of it.
  Diffusion:
  The results of the study will be presented in national and international congresses and will be published indexed in an impact factor magazine.

Eligibility: Inclusion Criteria:
  -  Signature of consent under written information prior to the completion of any procedure in the study.
  -  Men and women aged 40 to 59 years old, residents of Guadalajara, Jalisco and the metropolitan area.
  -  Ability to communicate and meet all the requirements of the study.
  -  BMI less than or equal to 34.9 kg / m2.
  -  Diagnosis of DM2 according to the ADA:
  -  Plasmatic glucose ≥126mg / dl (7.0 mmol / L) in an 8-hour fast.
  -  Plasmatic glucose ≥200mg / dl (11.1 mmol / L) at 2 hours after an oral glucose tolerance test.
  or HbA1C ≥6.5% (48 mmol / mol).
  o Plasmatic glucose ≥200mg / dl (11.1 mmol / L) in a random sample to the patient with classic symptoms of hyperglycemia.
  -  Evolution of DM2 less than 1 year.
  -  Be receiving pharmacological treatment with metformin in doses less than or equal to 850mg.
  -  Stable body weight within 3 months prior to the start of the study, defined as a variability in body weight of less than 10%.
  -  Eumenorrheic women with mechanical or definitive contraceptive method without hormonal treatment.
  Exclusion Criteria:
  -  Determination of HbA1c less than 6.5%, greater than 10% or fasting glucose greater than 250 mg / dL.
  -  Serum total cholesterol concentration greater than or equal to 240mg / dl.
  -  Serum triglyceride concentration greater than or equal to 400mg / dl.
  -  History of hypersensitivity to study drugs.
  -  Intake of drugs with known effects on glucose metabolism, lipids, and weight.
  -  Uncontrolled arterial hypertension, defined as systolic blood pressure values greater than or equal to 140mm / Hg and a diastolic blood pressure greater than or equal to 90mm / Hg.
  -  History of cardiovascular disease, blood disorders, kidney, pancreatic or thyroid disease.
  -  Women with suspicion or confirmation of pregnancy
  -  Women in breastfeeding period.
  -  History of smoking at any intensity within 12 months prior to the start of the study.
  -  History of drug abuse or alcoholism.
  -  Inability to attend or answer the evaluations made in each of the visits.
  -  Pacemaker bearing, or any other permanent bioelectronic element that can modify the electric bioimpedance reading or be affected by it.

Relevance to patient case: not relevant