Effectiveness of Weight Loss Methods on Lifespan for Metabolic Syndrome

NCT ID: NCT06410352

Last Updated: 2025-11-26

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 220 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-03-01
• Study Completion Date: 2026-07-31

Brief Summary

Background. The prevalence of type 2 diabetes mellitus (T2D) in the world is constantly increasing. Treatment of T2D is complicated by arterial hypertension and obesity (metabolic syndrome - MS). Cardiovascular complications are the main cause of death in patients with MS. Objective weight loss improves clinical and laboratory parameters in patients with T2D and hypertension.

Purpose: To study lifespan, glycemic and lipid metabolism, quality of life, and cost-effectiveness of pharmacologic, surgical, and dietetic weight loss methods in obese patients with MS at 24 weeks in a comparative clinical trial.

Methods:

1. st stage - Study design: An open pilot prospective clinical trial. The study included 71 adult patients with T2D and hypertension for the Ramadan fast's (RF) weight loss.

2. nd stage - Study design: A 24-week open label, prospective, multicenter, comparative clinical trial with the intention-to-treat analysis.

Participants. Totally 150 adult patients with MS aged 35-65 years and with BMI≥27 kg/m2 for Asian will be included. They will be distributed in three comparative groups: drug treatment, surgery and diet.

Primary endpoints: weight loss, fasting blood glucose, blood insulin level, systolic/diastolic BP.

Secondary endpoints: blood lipids, heel bone mineral density (HBMD), and ejection fraction (EF).

Expected results:

A prospective multicenter clinical study will provide comparative results on life expectancy, glycemic and lipid metabolism, quality of life, cost-effectiveness of pharmacological, bariatric and dietary methods of weight loss in patients with obesity, T2D and hypertension. As a result of the research, the following will be published:

1. at least three articles and/or reviews in peer-reviewed scientific publications indexed in the Science Citation Index Expanded of the Web Of Science database and/or having a Cite Score percentile in the Scopus of at least 50;

2. at least 1 patent for an invention (including a positive decision on it).

Detailed Description

At the 1 st stage of the study will screen 71 adult patients for eligibility aged 35 to 65 years with T2D and hypertension for the RF. T2D was treated with Metformin, Sulfonylurea, GLP-1 agonists (exenatide, liraglutide), Glitazones in different combinations; hypertension was treated with beta-blockers, calcium channel blockers, diuretics, SGLT-2 Inhibitors (empagliflozin, canagliflozin) in different combinations. Patients with heart failure (HF) in their medical records and anamnesis with reduced ejection fraction <55% also will be included; I-II stages of the NYHA functional classification.

Inclusion criteria: 1) written informed consent; 2) 35≤ age <65 years old; 2) any BMI and WC; 3) diagnosis of T2D and hypertension ≥3 years and treatment with non-hormonal conventional pharmacological medications; 4) any level of triglycerides, cholesterol, body fat%; 5) weight loss on the RF for 30 days.

Exclusion criteria: 1) age <35 or ≥65 years old; 1) Insulin-depended T2D and uncontrolled high BP; 2) patients taking gastrointestinal lipase inhibitors, etc.; 3) presence of acute infection diseases or exacerbation of chronic diseases; 4) ejection fraction <30%; 5) history of alcohol consumption >30 g/day within the past 5 years; 6) malignancy within the past 5 years; gestation or lactation; kidney failure; hereditary diseases; or known hypersensitivity to any of the test substances.

Outcome measures: Primary endpoints: weight loss, fasting blood glucose, blood insulin level, systolic/diastolic BP. Secondary endpoints: blood lipids, heel bone mineral density (HBMD), and EF.

Intervention. The participants adhered to fasting on RF season. They strictly adhered to two principles of nutrition during RF: 1) "no blood, no smell of fat" which means "don't eat meat and don't eat fatty foods"; 2) the 'Sehri time' (a meal eaten before dawn) included just 1.5-2.0 glass of water and fruits of 80-100 gr (apple, dates, and persimmon). Indeed, the patients followed a diet in which they ate one meal a day - participants have a meal during 'Iftar time' (a meal eaten after sunset). The participants also adhered to walking at least 3,000 steps/day, sexual self-restraint.

A combination of in-person conversations and telephone calls conductes during the 30-day study period: the baseline/7-day/14-day and 30-day RF.

At the 2nd stage of the study will include totally 150 adult patients with MS distributed in three comparative groups: drug treatment, surgery and diet therapy.

The study design is prospective because the investigators have to comparatively measure TL before/after interventions; the study may not be an observation study. Because of the trial will non-randomized patients will be allocated to each group based on equal baseline characteristics according to the inclusion/exclusion criteria and including adjustments for baseline and confounding characteristics.

The patients will be allocated to each group based on the patient and two physicians (surgeon and therapist) decisions to avoid the risk of "selection bias". Normalization of parameters will focuse on the work required to embed processes into statistics.

Inclusion criteria: 1) written informed consent; 2) T2D≥3-year with glucose lowering therapy including insulin; 3) 35-55 years old; 4) BMI≥27 kg/m2 for both sex, for Asian ethnicity; 5) ongoing treatment with antihypertensive treatment; 6) weight loss 15-20% at baseline and dynamic follow-up up to 24 weeks.

All included patients before recruiting to the study received standard-of-care treatment for T2D and AH according to regional guidelines.

Exclusion criteria: T1D; <34 age >56 years old; unstable cardiac disorders (New York Heart Association class IV heart failure, refractory angina, uncontrolled arrhythmias, critical valvular heart disease, or severe uncontrolled hypertension); glomerular filtration rate <30 mL/min and/or dialysis within 14 days before screening; malignancy within the past 5 years; gestation or lactation; hereditary diseases; known hypersensitivity to any of the test substances.

The 1st group (n=50) receives subcutaneous Semaglutide (GLP-1RA) 1 mg once a 7 day with oral Empagliflozin (SGLT-2i) 25 mg once a day that is a novel combination additionally to standard medical treatment including anti-diabetes, antihypertensive, lipid-lowering, symptomatic therapy.

The 2nd group (n=50) receives surgical method (laparoscopic MGB). These patients pass through additional pre-operation examination (blood tests and electrocardiography, esophagogastroscopy, ultrasound, and other necessary standard methods).

The 3rd group (n=50) receives very-low-calorie-restriction diet ('Analimentary-detoxication') including <100 kcal/day with fat-free vegetables (tomato/cucumber) and salt intake (5-6 g/day), optimum physical activity, and sexual self-restraint. The program goals the next outputs: a) use of own fatty store; b) control endogen intoxication; c) reuse of interim metabolic substrates.

A combination of in-person conversations and telephone calls conduct during the study period.

Justification of the sample size. The estimated treatment difference will set to 10% with a standard deviation of 8% and the superiority margin of 5% (δ=0.05) based on two-sided hypothesis testing. Using SPSS,Sample-Power,V23.0, the number of evaluable individuals needed per treatment arm >32. At least 150 patients will be screened and recruited in the comparative clinical trial.

End Points: The primary endpoints: reduction in body weight 15-20% from baseline; leukocyte TL. The secondary endpoints: HbA1c; fasting blood glucose and 2-hour oral glucose tolerance test (OGTT); systolic/diastolic BP; lipid profile; immunoassay insulin in blood; adverse events.

Methods:

• Criteria for the diagnosis of MS. Diagnosis of MS (IDF-2005). Diagnosis T2D: HbA1c≥6,5%, fasting plasma glucose level ≥7.0 mmol/l, or a patient receives antidiabetic therapy [ADA, 2023]. [55] AH: systolic-BP≥130 and/or their diastolic-BP≥90 mm.Hg following repeated examination, or a patient receives antihypertensive-drugs.
• General obesity will be measured by determining of BMI (kg/m2). Abdominal obesity is assessed by waist circumference using the standards for the Asian nationality by IDF(2018). [56]
• Body composition parameters including fat mass, visceral fat, fat-free mass, total body-water, muscle/bone mass, metabolic age, basal-metabolic-rate, and bioimpedance will be evaluated by Tanita-MC-980MA Multi-Frequency Segmental Body-Composition-Analyzerer(TanitaCorp,Japan).
• Physical activity will be assessed as the number of steps taken by patients, as determined by individual pedometers from Hoffmann-La-Roche(Switzerland) or other individual digital system.
• Laboratory study. On the same blood samples, standard laboratory a complete blood count, erythrocyte sedimentation rate, urea, creatinine, glucose, electrolytes, HbA1c, lipid profile (total-cholesterol, HDL/LDL, triglycerides), total proteins, coagulation profile, bilirubin, hepatic enzyme activities, blood/ urine ketone bodies.
• Hormones assay. Fasting serum insulin by immunoassay method (CzechRepublic). The Homeostasis Model Assessment insulin resistance indexes (HOMA-IR) will be used as a surrogate measure of insulin sensitivity as follows: HOMA-IR=((fasting insulin in nU/L)×(fasting glucose in mmol/l)/22.5).
• Measurement of TL. TL will be measured in T/S ratio with an adaptation of the quantitative polymerase chain reaction (q-PCR) methods. The intraassay and interassay variability (CV) for quantitative polymerase chain reaction will be shown.

Blood samples for measurement of TL will be collected in sterile vacutainer and delivered to the Genom and personalized medicine laboratory (Nazarbayev University). DNA was purified using Promega Wisard DNA system in -20 С. In short, for measurement of telomere repeat copies, primers will be added. Two control samples will be run in each experiment to allow for normalization between experiments, and periodical reproducibility experiments will be performed to guarantee correct measurements. The ratio calculated is proportional to average TL per cell.

• Quality of life assesses with international questionnaire BAROS Bariatric Analysis and Reporting Outcome System, EuroQoL.
• Cost-effectiveness analysis conductes using as outcomes both clinical as well as EuroQol to estimate the incremental cost-effectiveness of the three alternative interventions. Analysis considers specific costs (a) direct medical costs (including the intervention itself and follow-up care to the condition), (b) indirect nonmedical costs, and (c) additional non-medical costs. Costs of medical care obtaines from economic departments of participating medical centers identifying resources consumed during the interventions. Indirect costs obtaines from patients. The limited time horizon of this study will make it necessary to use a model to extrapolate the observed effect of the treatments assessed in the long term.
• Consultations of specialists conductes before/during/after the study 24-week period.
• Imaging methods: Ultrasound of internal organs (GE Vivid 7 Ultrasound; GE Healthcare Worldwide USA, Michigan); ECG.

Interpretation of the data. The primary hypothesis is that patients treated with the comparative methods would experience a greater weight reduction and improving in the primary/secondary endpoints; then the groups selects to compare between themselves in the aggregate using multiple linear regression analysis. To establish the effectiveness of the comparative methods based on the principle: H0 (null hypothesis) one method doesn't differ from another/other; and Ha (alternative) one method differs from another/other.

Statistical analysis. The statistical analysis plan considers non-compliance, loss-of-follow-up, and missing-data. Multiple-logistic-regression-models, ANOVA/ANCOVA uses to predict the probability of specific variables. Mixed-effect-models or generalized-estimating-equations (GEE) evaluates with statisticians. The Student's two-factor-t-test, OR (95%,CI), Pearson's criterion-χ2 will be used to assess differences in proportions. Mann-Whitney U-test and Kruskal-Wallis test are used for nonparametric. Pearson or Spearman correlation coefficient (r). To determine dependent/independent variables and to control confounders discusses between the team using literature data.

Regression analysis performs using state of the art machine learning algorithms in python code. These include application of algorithms such as KNN, SVM and Random Forests. Additionally, the investigators will apply deep learning methodology for creating a model to test the hypothesis testing as a binary classifier. This learning model uses neural network, given new data will be able to make personalized effects of the three treatment methods. Study data presentes in tables as M±SE or median (25-75%) based on distribution of variables. Survival analysis (Kaplan-Meier or Cox-regression) uses to assess mortality in the three comparative treatments. Statistical analysis using SPSS for Windows,ver.28.0.

Ethics. The appropriate national and institutional regulatory authorities and ethics committees will approve the study design, and all participants will provide written informed consent. The study will fulfilled in University Medical Center together with Nazarbayev University School of Medicine and National Laboratory Astana and Astana Medical University.

Conditions

Metabolic Syndrome

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Pharmacologic weight loss (Combination Product)

The 1st group (n=50) receives subcutaneous Semaglutide (GLP-1RA) 1 mg once a 7 day with oral Empagliflozin (SGLT-2i) 25 mg once a day that is a novel combination additionally to standard medical treatment including anti-diabetes, antihypertensive, lipid-lowering, symptomatic therapy.

Group Type: ACTIVE_COMPARATOR

Semaglutide, Empagliflozin

Intervention Type: DRUG

subcutaneous Semaglutide (GLP-1RA) 1 mg once a 7 day with oral Empagliflozin (SGLT-2i) 25 mg once a day

Surgical weight loss

The 2nd group (n=50) receives surgical method (laparoscopic MGB). These patients pass through additional pre-operation examination (blood tests and electrocardiography, esophagogastroscopy, ultrasound, and other necessary standard methods).

Group Type: ACTIVE_COMPARATOR

Minigastric bypass

Intervention Type: PROCEDURE

Endovideososcopic techniques with the intraperitoneal using of synthetic/biological materials. MGB is performed to reduce the absorption surface of the gastrointestinal tract by shunting the greater part of the stomach, the duodenum and the initial section of the small intestine, which reduces the absorption of food and leads to a decrease in the production of gastrointestinal hormones.

Very-low-calorie-restriction diet

The 3rd group (n=50) receives very-low-calorie-restriction diet ('Analimentary-detoxication') including \<100 kcal/day with fat-free vegetables (tomato/cucumber) and salt intake (5-6 g/day), optimum physical activity, and sexual self-restraint. The program goals the next outputs: a) use of own fatty store; b) control endogen intoxication; c) reuse of interim metabolic substrates.

Group Type: EXPERIMENTAL

Analimentary detoxication

Intervention Type: DIETARY_SUPPLEMENT

very-low-calorie-restriction diet ('Analimentary-detoxication') including \<100 kcal/day with fat-free vegetables (tomato/cucumber) and salt intake (5-6 g/day), optimum physical activity, and sexual self-restraint.

Ramadan fast's weight loss

The 4th group (n=30) adheres to fasting on Ramadan fast (RF) season. They strictly adhered to two principles of nutrition during RF: 1) "no blood, no smell of fat" which means "don't eat meat and don't eat fatty foods"; 2) the 'Sehri time' (a meal eaten before dawn) included just 1.5-2.0 glass of water and fruits of 80-100 gr (apple, dates, and persimmon). Indeed, the patients followed a diet in which they ate one meal a day - participants have a meal during 'Iftar time' (a meal eaten after sunset).

Group Type: EXPERIMENTAL

Ramadan fast's weight loss

Intervention Type: BEHAVIORAL

The participants adhered to fasting on RF season. They strictly adhered to two principles of nutrition during RF: 1) "no blood, no smell of fat" which means "don't eat meat and don't eat fatty foods"; 2) the 'Sehri time' (a meal eaten before dawn) included just 1.5-2.0 glass of water and fruits of 80-100 gr (apple, dates, and persimmon). Indeed, the patients followed a diet in which they ate one meal a day - participants have a meal during 'Iftar time' (a meal eaten after sunset).

Interventions

Semaglutide, Empagliflozin

subcutaneous Semaglutide (GLP-1RA) 1 mg once a 7 day with oral Empagliflozin (SGLT-2i) 25 mg once a day

Intervention Type: DRUG

Minigastric bypass

Endovideososcopic techniques with the intraperitoneal using of synthetic/biological materials. MGB is performed to reduce the absorption surface of the gastrointestinal tract by shunting the greater part of the stomach, the duodenum and the initial section of the small intestine, which reduces the absorption of food and leads to a decrease in the production of gastrointestinal hormones.

Intervention Type: PROCEDURE

Analimentary detoxication

very-low-calorie-restriction diet ('Analimentary-detoxication') including \<100 kcal/day with fat-free vegetables (tomato/cucumber) and salt intake (5-6 g/day), optimum physical activity, and sexual self-restraint.

Intervention Type: DIETARY_SUPPLEMENT

Ramadan fast's weight loss

The participants adhered to fasting on RF season. They strictly adhered to two principles of nutrition during RF: 1) "no blood, no smell of fat" which means "don't eat meat and don't eat fatty foods"; 2) the 'Sehri time' (a meal eaten before dawn) included just 1.5-2.0 glass of water and fruits of 80-100 gr (apple, dates, and persimmon). Indeed, the patients followed a diet in which they ate one meal a day - participants have a meal during 'Iftar time' (a meal eaten after sunset).

Intervention Type: BEHAVIORAL

Other Intervention Names

Semaglutide (GLP-1RA), Empagliflozin (SGLT-2i); bariatric operation; Very-low-calorie diet; Ramadan fast

Eligibility Criteria

Inclusion Criteria

• written informed consent;
• T2D≥3-year with glucose lowering therapy including insulin;
• 35-55 years old;
• BMI≥27 kg/m2 for both sex, for Asian ethnicity;
• ongoing treatment with antihypertensive treatment;
• weight loss 15-20% at baseline and dynamic follow-up up to 24 weeks.

Exclusion Criteria

• T1D;
• <34 age >56 years old;
• unstable cardiac disorders (New York Heart Association class IV heart failure, refractory angina, uncontrolled arrhythmias, critical valvular heart disease, or severe uncontrolled hypertension);
• glomerular filtration rate <30 mL/min and/or dialysis within 14 days before screening; • malignancy within the past 5 years;
• gestation or lactation;
• hereditary diseases;
• known hypersensitivity to any of the test substances.

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Medical Center, Kazakhstan

OTHER

Sponsor Role: lead

Nazarbayev University School of Medicine

UNKNOWN

Sponsor Role: collaborator

Nazarbayev University

OTHER

Sponsor Role: collaborator

Astana Medical University

OTHER

Sponsor Role: collaborator

Public Association "Eurasian Society of Personalized Medicine"

UNKNOWN

Sponsor Role: collaborator

Ministry of Science and Higher Education of the Republic of Kazakhstan

OTHER_GOV

Sponsor Role: collaborator

Responsible Party

Kuat Oshakbayev

full-Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kuat Oshakbayev, professor

Role: PRINCIPAL_INVESTIGATOR

University Medical Center, Kazakhstan

Locations

Kuat Pernekulovich Oshakbayev

Astana, Astana, Kazakhstan

Site Status: RECRUITING

Countries

Kazakhstan

Central Contacts

full-professor Kuat Oshakbayev

Role: CONTACT

okp.kuat@gmail.com

+77013999394

Facility Contacts

Kuat P Oshakbayev, professor

Role: primary

okp.kuat@gmail.com

+77013999394 ext. +77172421946

Other Identifiers

AP23488544

Identifier Type: -

Identifier Source: org_study_id