The accelerated reduction Method of glycated haemoglobin in patients with type 2 diabetes mellitus and hypertension: a comparative clinical trial

The accelerated reduction Method of glycated haemoglobin in patients with type 2 diabetes mellitus and hypertension: a comparative clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The accelerated reduction Method of glycated haemoglobin in patients with type 2 diabetes mellitus and hypertension: a comparative clinical trial Kuat Oshakbayev, Aigul Durmanova, Nurzhan Bikhanov, Altay Nabiyev, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8096250/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aim: to compare different weight-loss methods such as pharmacologic, bariatric surgery, and very-low-calorie diet (VLCD) in accelerated decline in HbA1c in patients with T2D and hypertension. Methods. Design: a 30-day open label, prospective, multicenter, comparative clinical trial including 102 adult patients with T2D and hypertension were divided in three groups: Drug group; Surgical group; and VLCD. Primary endpoints: HbA1c; body weight. Results. At 30 days, body weight in the patients decreased significantly in Surgery group (-10.5%; P =0.009) and in VLCD group (-12.2%; P =0.003), while in Drug group the decrease was unsignificant (-1.2%; P =0.39). In all comparison groups the decrease in body weight occurred due to both fat and lean mass. SBP in Drug group decreased by -6.5%, DBP decreased by -3.4%. SBP/DBP in Surgical group changed by -1.6% and -2.9%, respectively. SBP/DBP in VLCD group significantly decreased by -24.3% and 18.6% ( P <0.0001), respectively. Correlation-regression analysis revealed a correlation between weight loss and a decrease in HbA1c (r=0.53; P <0.0001). Conclusions. The fastest method to reduce HbA1c in patients with T2D and hypertension was in VLCD group. The greater the weight loss, the lower the HbA1c. The great reduction in HbA1c led to a decrease in symptomatic drugs up to its complete abolition. Trial Registration: ClinicalTrials.gov NCT06410352 (05/08/2024): https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000EG8K&selectaction=Edit&uid=U0006MBT&ts=56&cx=-vph5l9 Health sciences/Diseases Health sciences/Endocrinology Health sciences/Medical research Glycated haemoglobin Weight loss Type two diabetes Semaglutide Blood pressure Very-low-calorie diet Bariatric surgery Figures Figure 1 Figure 2 1. INTRODUCTION The total number of adults with type two diabetes mellitus (T2D) has more than quadrupled worldwide over the past 30 years (from 200 million in 1990 to 830 million in 2022; NCD Risk Factor Collaboration), [ 1 ] while the total world population has increased only 1.3-fold. [ https://www.worldometers.info/world-population/ ] High incidence of T2D associated with obesity pandemic in all countries. [ 2 – 4 ] Approximately 60% of adults in the US have obesity. [ 5 ] In Kazakhstan every fifth of adult men (21.4%) is now obese. [ www.globalnutritionreport.org ] Obesity increases the incidence and mortality from chronic diseases. [ 6 , 7 ] T2D associated with obesity is characterized by long-term, slowly progressive cardiovascular complications that today cause the greatest harm to the population of all countries in the world, both developing and developed, accounting for about 70% of all annual deaths. [ 8 ],[ 9 ] Overweight and obesity are the cause of chronic diseases including T2D. [ 10 – 13 ] One of the current and modern methods of diagnostics and regular monitoring of treatment of patients with T2D is the determination of glycated haemoglobin (HbA1c). [ 14 ] Relatively recently, HbA1c has been included in the main diagnostic criteria for T2D and prediabetes. [ 15 ] According to the American Diabetes Association, changes in HbA1c occur no earlier than 3 months with drug treatment. [ 16 ] Weight loss methods improve cardiovascular risks, reduce medication requirements, and improve glycemic and lipid metabolism. [ 17 , 18 ] Moderate weight loss (5–10%) is clinically significant for reducing HbA1c in patients with metabolic syndrome. [ 19 ] Greater weight loss may be required to achieve improvement or remission of certain weight-related complications. Reducing excess weight improves the glycemic profile of patients with T2D; reducing fat mass is one of the main goals for combating hyperglycemia. [ 20 , 21 ] The results of many studies show that the beneficial effects of weight-loss treatment on HbA1c depend on the amount of weight lost. [ 22 – 24 ] We have recently demonstrated weight loss with good clinical outcomes in patients with T2D and CVD. [ 25 – 27 ] Nowadays, there are many known methods for reducing overweight, but they are all grouped into three main areas of weight loss: pharmacologic, surgical, and dietary. [ 28 – 31 ] Every weight loss method provides health benefits independently of others, but there is still debate about which method provides the greatest benefit for clinical and laboratory outcomes, particularly for HbA1c in patients with T2D. Improvements in glucose metabolism and cardiovascular risk factors were observed in patients who achieved large weight loss through lifestyle interventions or pharmacotherapy. [ 20 , 32 ] Bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality, [ 33 ] and bariatric surgery could be the effective currently available treatment for T2D despite his side-effects. [ 20 , 33 ] Currently, we have accumulated positive results in the weight loss treatment of patients with T2D and CVD by pharmacologic [ 34 , 35 ], very-low-calorie diet (VLCD), [ 25 , 26 , 36 ] and surgical (Vertical Sleeve Gastrectomy or Minigastric bypass, etc.) weight loss [ 37 , 38 ] more than 10% from baseline weight. The aim of this study was: to compare the three weight-loss treatment methods such as pharmacologic (semaglutide + empagliflozin), bariatric surgery (mini-gastro bypass), and VLCD (analimentary detoxication (ANADETO)) in accelerated decline in HbA1c in patients with T2D and hypertension. 2. METHODS 2.1 Study Design : A 30-day open label, prospective, multicenter, comparative clinical trial with the intention-to-treat analysis. 2.2 Participants A total of 107 participants screened in the study, and 82 adults (45 females) aged 30 to 60 years with T2D and hypertension were included to determine eligibility; 25 were excluded due to inclusion criteria. Of the 82 patients included in the study, six patients were excluded due to the inclusion/ exclusion criteria as described below. (Fig. 1 ) The patients were unevenly and voluntarily allocated into three groups: Drug group (pharmacological); Surgical group (surgery); and in VLCD. Of the 76 patients included in the treatment groups, three patients (two from drug group and one from VLCD group) were excluded due to drug intolerance and noncompliance. Finally, 73 patients (89%) were included in the study for analysis. Inclusion criteria 1) written informed consent; 2) T2D ≥ 3-year with glucose lowering therapy including insulin; 3) hypertension ≥ 3 years of treatment; 4) 30–60 years old; 5) BMI ≥ 27 kg/m2 for both sexes, for Asian ethnicity; 6) weight loss at baseline. All included patients before recruiting to the study received standard-of-care treatment for T2D and hypertension.[ 39 , 40 ] Exclusion criteria 1) T1D; 2) 61 years old; 3) patients after bariatric surgery; 4) unstable cardiac disorders (New York Heart Association class IV heart failure, refractory angina, uncontrolled arrhythmias, critical valvular heart disease, or severe uncontrolled hypertension); 5) glomerular filtration rate < 40 mL/min and/or dialysis within 14 days before screening; 6) ejection fraction 30 g/day within the past 3 years; 8) malignancy within the past 5 years; 9) gestation or lactation; 10) hereditary diseases; 11) known hypersensitivity to any of the test substances. Patient recruitment and randomization. Patient recruitment was carried out at three different clinical centers (Department for Internal medicine, Center for Endocrinology Center for Surgery). Then the patients were consulted by two doctors (surgeon and therapist) so that the patient could choose the appropriate type of treatment. Each patient was explained the pros and cons of each treatment method. After the patient's condition was assessed and all indications/contraindications, inclusion/exclusion criteria were met, he/she was referred to the appropriate center to receive the appropriate type of weight loss treatment. Randomization and blinding among patients were not possible within the study due to the study design. Comparative methods involve different interventions, patient allocation cannot be done ethically, informed consent cannot be concealed; results may not always be consistent with comparative treatments; randomization requires clinical equipoise. [ 41 , 42 ] Because of the trial was non-randomized, the patients were 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 were allocated to each group based on the patient and two physicians (surgeon and therapist) decisions to avoid the risk of "selection bias". Parameter normalization focused on the work needed to integrate processes into statistics. The data were collected by three different research teams who were blinded to the data of individuals other than their own. All data (antropometric, body composition analysis, clinical, laboratory, instrumental data) was collected in the same place. laboratories, instrumentalists, and laboratory, instrumental and statistician were blinded to which patient belonged to which group/arm. The statistician could only work with the data across study groups once, when all the data had been collected and the database was locked, and only then could we break the code and see which treatment was best. A combination of in-person conversations and telephone calls conduct during the study period. Outcome measures. Primary endpoints : HbA1c; reduction in body weight; fasting blood glucose. Secondary endpoints : systolic/diastolic BP; lipids; adverse events. Interventions. (Fig. 1 ) The drug group (n = 26) received subcutaneous Semaglutide (GLP-1RA) 1 mg once a 7 day with oral Empagliflozin (SGLT-2i) 25 mg once a day additionally to standard medical treatment including antihypertensive (metformin), lipid-lowering, symptomatic therapy. [ 35 , 43 , 44 ] The surgery group (n = 21) received a laparoscopic bariatric operation – minigastric bypass (MGB) that is endovideoscopic techniques with the intraperitoneal using of synthetic/biological materials 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. [ 37 , 45 , 46 ] These patients pass through additional pre-operation examination (blood tests and electrocardiography, esophagogastroscopy, ultrasound, and other necessary standard methods). The VLCD group (n = 26) received a fast weight loss program named ‘Analimentary-detoxication’ (ANADETO) including < 100 kcal/day with fat-free vegetables (tomato/cucumber) and salt intake (5–6 g/day), optimum physical activity, and sexual self-restraint. [ 25 , 47 , 48 ] The program is aimed at the following outputs: a) use of own fatty store (autolipophagy); b) control endogen metabolic intoxication; c) reuse of interim metabolic substrates. [ 25 , 49 , 50 ] Due to the presence of many known contraindications to use the drugs [ 51 , 52 ] and make surgery interventions, [ 53 , 54 ] the pharmacologic and surgery groups had patients with a milder clinical and laboratory course, but baseline body weight and HbA1c levels did not differ significantly between the comparison groups. (Table 1 ) Table 1 Comparative changes of body weight, glycemia, HbA1c, lipids, and blood pressure in the drug, surgery and VLCD clinical groups at baseline and 30 days after weight loss treatment (n = 73) (M ± SEM) Variables Drug group (n = 26) Surgery group (n = 21) VLCD group (n = 26) Baseline 30 days Baseline 30 days Baseline 30 days Age (years) 47.6 ± 1.4 - 44.1 ± 2.1 - 48.9 ± 1.7 - Body weight (kg) 105.2 ± 3.1 103.9 ± 3.2 110.1 ± 3.3 98.6 ± 3.0** 106.8 ± 3.2 93.7 ± 2.9** Fat mass (kg) 42.8 ± 1.9 41.7 ± 1.9 45.2 ± 1.9 39.3 ± 1.8* 44.8 ± 2.1 36.4 ± 1.9** Fat free mass (kg) 62.4 ± 2.1 62.1 ± 2.1 64.9 ± 2.1 59.2 ± 2.1 61.9 ± 2.2 57.8 ± 2.1 HbA1c (%) (% from Baseline) 8.95 ± 0.29 8.9 ± 0.3 (-0.56%) 9.36 ± 0.34 7.73 ± 0.28** (-17.41%) 9.93 ± 0.38 7.61 ± 0.31** (-23.36%) Fasting blood glucose (mmol/L) 8.49 ± 0.32 7.31 ± 0.35** 9.53 ± 0.52 7.33 ± 0.34** 9.89 ± 0.49 5.47 ± 0.36*** Cholesterol (mmol/L) 5.83 ± 0.12 5.79 ± 0.13 5.95 ± 0.09 5.23 ± 0.11*** 6.12 ± 0.11 4.66 ± 0.08*** Triglycerides (mmol/L) 1.98 ± 0.09 1.84 ± 0.10 2.27 ± 0.08 1.91 ± 0.07** 2.40 ± 0.1 0.82 ± 0.08*** HDL (mmol/L) 0.98 ± 0.04 1.05 ± 0.05 0.97 ± 0.04 1,10 ± 0.05 0.88 ± 0.04 1.33 ± 0.06*** Blood haemoglobin (g/L) 135.1 ± 2.3 136.3 ± 1.42 136.8 ± 2,2 128.4 ± 2,1** 125.6 ± 2.1 137.4 ± 1.5*** SBP (mm.Hg) 143.5 ± 2.3 134.1 ± 2.4** 148.1 ± 2.8 145.8 ± 2.8 161.8 ± 2.8 122.4 ± 2.1*** DBP (mm.Hg) 92.4 ± 2.0 89.2 ± 2.1 97.2 ± 2.4 94.4 ± 2.2 102.5 ± 2.0 83.2 ± 1.3*** * P -values < 0.025, ** P < 0.01 и *** P < 0.0001 were significant compared with baseline (before treatment) in all groups. Abbreviations : HbA1c, glycated haemoglobin; HDL, high density lipoprotein; M, mean; SBP/DBP, systolic/diastolic blood pressure; SEM, standard error of the mean; VLCD, very-low-calorie diet. 2.3 Analytical Assessment Anthropometrical indicators included age (years), weight (kg), BMI (kg/m 2 ), waist circumference (cm). Body composition parameters including fat mass (in % of total body weight), fat free mass, total body water, muscle mass, bone mass were measured using a Tanita MC-780MA Body Composition Analyzer (Tanita Corp., Tokyo, Japan). Physical activity was 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, bilirubin, hepatic enzyme activities. Imaging. Ultrasound imaging (GE Vivid 7 Ultrasound; GE Healthcare Worldwide USA, Michigan) used for abdominal organs and kidneys. We carried out anthropometrical, laboratory, and instrumental examinations two times: at baseline and after 30 days. Criteria for the diagnosis. Diagnosis of T2D according to the criteria of WHO and International Diabetes Federation (WHO/IDF consultation in 2006) [Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. Geneva, Switzerland, 2006]: HbA1c ≥ 6,5%, fasting plasma glucose level ≥ 7.0 mmol/l, or a patient receives antidiabetic therapy [ADA, 2023]. [ 55 ] Hypertension: systolic-BP ≥ 130 and/or their diastolic-BP ≥ 90 mm.Hg following repeated examination, or a patient receives antihypertensive-drugs. 2.4 Statistics Justification of the sample size. The estimated treatment difference between comparison groups was set to 10% with a standard deviation of 8% and the superiority margin of 2.5% (δ = 0.025) [ 56 ] based on two-sided hypothesis testing. Using SPSS,Sample-Power,V23.0, the number of evaluable individuals needed per treatment arm ≥ 20. At least 107 patients we screened and recruited, and 73 patients were assessed for eligibility in the comparative clinical trial (Fig. 1 ). [ 57 ] To increase in the power of the statistical analysis and receive significant results we used two-sided Student’s t tests with Bonferroni correction ( P- value/2); where P values of < 0.025 were set as significant differences in intra groups, and < 0.025 between groups to compensate for the small number of the groups. The study used SPSS Statistics v23 (SPSS Inc., Illinois, USA) and Microsoft Excel-2023 with normality assessed using histograms and box plots. Given the pilot nature of the study and firm hypotheses, were used. The study data is presented in Tables as Mean ± Standard Error of the Mean (M ± SEM) for normally distributed data. All analyses were intention-to-treat. Correlation-regression analysis was used to find statistical relationship between body weight and HbA1c levels before and after the intervention (in percent); it quantifies how changes in one variable correspond to changes in another, indicating the direction and strength of their relationship, including determining of the type of correlation, such as positive (variables change in the same direction), negative (variables change in opposite directions), or no correlation (no apparent relationship). We used electronic databases (Web of Science/ Medline, EBSCO/Medline Complete, Scopus/Science Direct, Google Scholar, EndNoteClick/Kopernio, PubMed, and Ovid/Wolter Kluwer) for finding research literature. 3. RESULTS The treatment results for patients in the three compared groups are presented in Table 1 . According to the data obtained, body weight decreased significantly in Surgery group (-10.5%; P = 0.009) and in VLCD group (-12.2%; P = 0.003), while in Drug group the decrease was unsignificant (-1.2%; P = 0.39). The decrease in body weight in all comparison groups occurred due to both fat and lean mass. However, in Surgery and VLCD groups, the decrease in fat mass was significantly ( P = 0.017 and P = 0.003, respectively). Fat free mass also decreased, but not significantly, in Surgery and VLCD groups by -8.8% ( P = 0.034) and 6.6% ( P = 0.09) from baseline, respectively. The decrease in fat mass and fat-free mass in Surgical group was almost the same: -5.9% and − 5.7%, respectively. FBG was decreased in Drug group by -13.9% ( P = 0.01), in Surgery group by -23.1% ( P = 0.001), and in VLCD group by -44.7% ( P < 0.0001). HbA1c was non-significantly decreased in Drug group by -0.56% ( P = 0.45), significantly decreased in Surgery group by -17.4% ( P = 0.008), and significantly decreased in VLCD group by -23.4% ( P < 0.0001). Lipids also improved partially significantly in Surgery group (-12.1% for cholesterol, P = 0.00012; -15.9% for triglycerides, P = 0.0014; +13.4% for HDL, P = 0.026) and in VLCD group (-23.8% for cholesterol, P < 0.0001; -65.8% for triglyceride, P < 0.0001; +51.1% for HDL, P < 0.0001), while in Drug group cholesterol, triglyceride, and HDL changed insignificantly (-0.7%, P = 0.41 and − 7.1%, P = 0.15, and + 7.4%, P = 0.14, respectively). Blood haemoglobin in Drug group changed insignificantly (+ 0.9%, P = 0.36), in Surgery group it significantly decreased (-6.1%, P = 0.0058), but in VLCD group blood haemoglobin significantly increased (+ 9.4%, P < 0.0001). SBP in Drug group significantly decreased by -6.5% ( P = 0.0043), but DBP non-significantly decreased by -3.4% ( P = 0.14). SBP/DBP in Surgical group did not change significantly: -1.6% ( P = 0.28) and − 2.9% ( P = 0.2), respectively. SBP/DBP in VLCD group significantly decreased by -24.3% ( P < 0.0001) and 18.6% ( P < 0.0001), respectively (Table 1 ). It was noted that in all three compared groups, HbA1c levels also decreased during weight loss. Therefore, we conducted a correlation-regression analysis to identify a statistical relationship between the dynamics of weight loss and changes in the HbA1c level. Correlation-regression analysis of the differences in percent between changes (body weight and HbA1c levels before and after the intervention) revealed a strong direct positive correlation between weight loss and a decrease in HbA1c (r = 0.53; F = 28.4, P < 0.0001): the greater the weight loss, the lower the HbA1c level (Fig. 2 ). According to the data, if body mass decreases by 10%, then HbA1c decreases by 20%; if body mass decreases by 25%, then HbA1c decreases by almost 40%. During the 30 days in Surgical group antidiabetic medications were gradually reduced and discontinued during 2–10 days in all patients, and antihypertensive medications also gradually reduced and discontinued during 7–30 days after MGB in 17 patients (81%). This effect varied depending on postoperative condition and level of weight loss. Patients in Drug group were unable to reduce the dosage of previously taken medications. In VLCD group, the need for antidiabetic and antihypertensive medications decreased due to improvements in metabolic and cardiovascular health. Starting from the 3–5 day of weight loss, it was necessary to reduce and completely stop taking the previous antidiabetic, antihypertensive, and other symptomatic medications; by 6–10 days the drugs were stopped completely (including all patients with T2D in the insulin-dependent stage), and at 30 days there was no evidence of T2D and hypertension. Adverse effects (AE). In Drug group were usual short-term gastrointestinal issues like nausea, vomiting, diarrhea, but after diet adjusting the AE were disappeared. In Surgical group were usual AE like inability to eat certain foods, dysgeusia, lack of appetite, flatulence, simplified bacterial overgrowth, anemia. There were no complications directly related to the surgical technic intervention. AE in VLCD were dizziness, weakness, nausea, and diarrhea within the first 2–6 days, then turbid/dark urine on 3–10 days, an increase in sputum expectoration in 2–3 times more than usually, which were disappeared after two weeks. Thus, it can be argued that significant weight loss was the main reason for the reduction in HbA1c levels and clinical outcomes, drug discontinuation, and improvement in glycemic, metabolic, and cardiovascular health. 4. DISCUSSION This study presents comparative results of three weight loss methods over one month to identify the fastest method to reduce HbA1c in patients with T2D and hypertension: pharmacological (Semaglutide + Empagliflozin), surgical (MGB) and VLCD (by ANADETO technology). The fastest method to reduce HBA1c was the VLCD (-23.4% from baseline), then the surgical method (-17.4% from baseline), and the last one was the pharmacological method (-0.6% from baseline). Every presented method for weight loss in patients with T2D and hypertension have the pros and cons.[ 58 ] This study design was non-randomized clinical trial. Despite the many advantages of randomized trial design, there are several misconceptions particularly in interdisciplinary comparing very different treatment methods as surgical, drug, non-drug. 41,42 These misconceptions include: heterogeneity of study interventions, the length of treatment, different compared methods, appraisal and critique, pharmaceutical industry influence, ethical standards, etc. [ 41 , 42 , 59 , 60 ] It should be noted that the more weight is lost, the better the blood pressure is reduced, the lipid levels are improved (cholesterol and triglyceride levels are reduced, HDL levels are increased) and the blood haemoglobin is increased. Significant improvements in these parameters were clearly observed in Surgery and VLCD groups, i.e. the faster the weight loss, the better these parameters were. These weight loss methods had antihyperglycemic, antihypertensive, and hypolipidemic effects, with their effectiveness depending on the level of weight loss. A decrease in total body weight was significant, mainly due to body fat mass, especially in VLCD group. A decrease in fat free mass was also observed, but this decrease was not significant in all compared groups. The reduction in fat and fat-free mass was almost the same in Surgical group. It could be because patients in Surgical group were unable to exercise enough to maintain muscle mass in the postoperative period, and therefore they also lost fat-free mass.[ 61 ] The decrease in muscle mass within the fat free mass is logically justified: the muscle mass that mechanically supported and carried this fat mass (which is part of the total body mass) will also logically decrease as the fat mass decreases.[ 62 ] Although there is also an opinion that the body, when in a calorie deficit, can turn to muscle tissue for energy when it does not receive enough of it from food.[ 63 ] The body must have muscle mass to overcome not only gravity, but also to ensure the mechanical carrying of excess fat along with the body.[ 64 ] For instance, the body muscle mass in the open space greatly reduces. [ 65 ] [ 66 ] The body fat consumes body energy because muscle mass is required to move/transport excess fat mass; the more fat mass, the more muscle mass in healthy young people.[ 67 ] Guidelines on hyperglycemic management recommend either GLP-1RAs or SGLT-2is as second-line treatments for patients with T2D on metformin monotherapy. The use of both antidiabetic drugs in combination is rare in the literature. [ 44 ] [ 39 , 58 , 68 ] Despite this, their effect on the reduction of HbA1c during one month was comparatively and significantly lower than in Surgical and VLCD groups. The study demonstrated that the more weight lost the better were parameters in fasting blood glucose, lipids, and blood pressure. Interesting changes occurred in blood haemoglobin in the compared groups, since ambiguous changes occurred there. Blood haemoglobin in Drug group changed insignificantly; but it reduced in Surgery group because in these patients after MGB often develop anemia due to the impaired absorption of iron in the gastrointestinal tract.[ 69 ] In VLCD group blood haemoglobin increased significantly possibly due to better improving in metabolism in hematopoiesis tissue and organs.[ 70 ] The results confirm and extend similar previous studies.[ 71 ] It is evident that the large weight loss improved anabolic processes, as haemoglobin, HDL levels increased significantly that confirmed other studies. [ 72 – 75 ] For instance, abstaining from fatty foods and meat has an antiosteoporosis effect improving bone metabolism. [ 76 , 77 ] Some other studies also confirm that weight loss results to increase haemoglobin and bone mineral density. [ 72 – 75 ] Weight loss methods decrease in multiple cardiovascular risks, reduce in medication, improve glycemic metabolism. [ 17 , 78 ] Weight loss in patients leads to cost savings by reducing the number of doctor visits, prescription drug tests, sick days, emergency visits and hospitalizations, but also has more long-term economic benefits, and reducing a risk for a wide range of chronic diseases. [ 79 ] After bariatric surgery, the need for antidiabetic and antihypertensive medications often gradually decreases (under strict medical supervision) due to improvements in metabolic and cardiovascular health during 10–30 days. In the VLCD group, a reduction and complete discontinuation of previous antidiabetic, antihypertensive and other symptomatic medications were observed by 6–10 days of weight loss. Our study also found that a large significant weight loss allows for the discontinuation of symptomatic drugs by reason of the need to reduce and completely discontinue previous medications.[ 80 , 81 ] Large weight loss should be the main treatment target on obesity-related complications. The ability to accumulate fat mass is one of the foundations for survival in conditions of food shortage. Food shortages always accompanied mankind. But, the survival rule “eat any time, any place, any opportunity” definitely led to overweight. [ 82 , 83 ] Currently, the ability to survive leads to an obesity epidemic. [ 84 , 85 ] Weight gain is unfavorable for the body’s energy. Overweight increases the total amount of metabolites. [ 86 , 87 ] Overweight correlates with the development of diseases such as T2D, hypertension, allergic and inflammatory diseases, urolithiasis and cholelithiasis, liver steatosis and fibrosis, and tumors. [ 84 , 88 ] Overweight increases metabolic pressure on the body and increases both basal metabolic rate and active metabolism. [ 89 ] Over-metabolism regime over-consumes the body’s ‘vital energy’. [ 90 , 91 ] Weight loss creates ‘body potential power to weight gain’ that increases physical/mental activity, recovers from diseases, or weight regain. Individual body weight and individual limit of weight gain mode may explain the ‘obesity paradox’. [ 11 , 92 , 93 ] Some weight-loss methods are useless for recovering from diseases. Weight loss due to chronic and neoplastic diseases (unintentional) results in energy expenditure, while weight loss due to intentional, for example, restrictive diet, results in energy savings. [ 94 – 96 ] There should use weight loss methods that can allow the body to save energy and burn body old fat at the same time. [ 79 ] During weight loss, old fat absorbs intermediate and end metabolic products that induce metabolic intoxication, [ 97 ] which should be managed.[ 25 , 49 ] Restriction diet improves gut microbiota, and intestinal function to synthesize gut vitamin. [ 98 , 99 ] 5. CONCLUSIONS Thus, the fastest method to reduce HbA1c in patients with T2D and hypertension was in VLCD group (based on autolipophagy with simultaneous control of endogen metabolic intoxication, ANADETO). HbA1c decreases by 20% if body mass decreases by 10%, and if body mass decreases by 25%, HbA1c decreases by almost 40%. Along with a reduction in HbA1c by more than 20% within 30 days, there was also a disappearance of clinical and laboratory symptoms of T2D, hypertension, hyperlipidemia and dyslipidemia. The fast weight loss helps reduce the need for antidiabetic and antihypertensive drugs in patients with T2D and hypertension. Strengths and limitations A strength of our study was that it was the first to show that different weight loss methods can have different effects on reducing HbA1c level. For the first time, the fact of the colossal influence of excess body weight on the level of HbA1c is presented. Published studies about positive role of fast weight loss on HbA1c in people with T2D and hypertension are very limited in scope and number. This study has several limitations. First, the study included the relatively small number of patients with T2D and hypertension. Second, the clinical trial had approximately 11% of the randomly assigned population dropped out prior to completion. There was only 30-day study that not enough to observe T2D and hypertension outcomes. Further high-quality multicenter clinical trials with a large sample size and longer-term follow-up are needed to confirm and extend the results of the study. Abbreviations AE: adverse effects ANADETO: analimentary detoxication CVD: cardiovascular disease FBG: fasting blood glucose GLP-1RA: glucagon-like peptide-1 receptor agonists HbA1c: glycated haemoglobin HDL or LDL: high- or low-density lipoprotein MGB: minigastric bypass SBP or DBP: systolic or diastolic blood pressure SGLT-2i: sodium-glucose cotransporter-2 inhibitor T1D or T2D: type one or two diabetes mellitus VLCD: very-low-calorie diet. Declarations The study was carried out in the Republic of Kazakhstan from September 1, 2024, through August 31, 2025. Participants were recruited gradually as they arrived in Center for Surgery, Clinical Academic Department of Internal Medicine, Center for Endocrinology at University Medical Center (Astana). Consent for publication. Our manuscript does not contain any individual person’s data in any form. All authors of the manuscript affirm that they had access to the study data and reviewed and approved the final manuscript. Conflict of interest disclosures: The authors declare that they have no competing interests (financial, professional, or personal) relevant to the manuscript. We have read and understood the journal policy on the declaration of interests and have no interests to declare. Ethics approval and consent to participate . The Ethical Committee of the University Medical Center (phone: +7 7172 69-25-86; Web: https://umc.org.kz/en/?ethics-commission=post-2) approved the study (approval protocol #8/2024/ПЭ of 28.08.2024; monitoring and re-approval protocol #1/2025/ПЭ of 12.02.2025. Board Affiliation: University Medical Center). The committee confirms that all methods were performed in accordance with the Declaration of Helsinki and guidelines of the Council for International Organizations of Medical Sciences (CIOMS) and that informed consent was obtained from all participants. Availability of data and materials. The data are available from the authors upon reasonable request. Those wishing to request the study data should contact Principal Investigator of a research grant: Dr. Oshakbayev Kuat (Emails: [email protected] ; [email protected] , phone + 77013999394). Funding: This research was prepared under a research grant from the Ministry of Science and Higher Education of the Republic of Kazakhstan (grant for 2024-2026 years with trial registration AP23488544, National Center for Scientific and Technical Information of the Republic of Kazakhstan). Authors' contributions: KO: design and performance, patient recruitment and treatment, data collection, bibliography review, scientific analysis, statistical advancing, scientific executor, writing draft, editing, and revision. AD: study design, patient recruitment and treatment, writing the methods and discussion, bibliography, paper review, and print. NB: study design, patient recruitment and treatment, writing the discussion, bibliography and paper review. AN: study design, research executor, writing the methods, editing, and revision. TS: patient recruitment and treatment, preparation of e-version data collection, bibliography, and paper review. AI: patient recruitment and treatment, preparation e-version data collection in Excel, bibliography and paper review, statistical advancing, writing the methods. GD: paper scientific review, writing the methods, and print. D K: patient recruitment and treatment, preparation e-version data collection in Excel, bibliography and paper review. MS : patient recruitment and treatment, preparation e-version data collection in Excel, bibliography and paper review. GK: design and performance, bibliography review, data collection, scientific analysis, writing methods/results/discussion, editing, and paper review. All authors have read and agreed to the published version of the manuscript. Acknowledgments. The authors thank the Diagnostic Center of University Medical Center and ANADETO Medical Center for recruiting patients, collecting data for the study, and providing technical assistance. Declaration of Generative AI and AI-assisted technologies in the writing process : During the preparation of this work the authors did not use AI-assisted technologies. Authors will provide an appropriate point-by-point response to the reviewer(s) which addresses their comments. References Zhou, B. et al. 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12:23:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8096250/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8096250/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97706137,"identity":"96d5f64e-b9fd-416d-88cc-60c5f40470ce","added_by":"auto","created_at":"2025-12-08 12:54:57","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":251249,"visible":true,"origin":"","legend":"","description":"","filename":"22025.11Manuscript100Ref.docx","url":"https://assets-eu.researchsquare.com/files/rs-8096250/v1/8bb6d25e57ae0e09fbbd64f9.docx"},{"id":97706128,"identity":"d943b9b7-f9a8-4ec8-a09c-3dd685224067","added_by":"auto","created_at":"2025-12-08 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12:54:57","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":208782,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8096250/v1/bb8a680e0fc1834004d10dcd.html"},{"id":97892908,"identity":"47278363-93cb-4236-9fef-dbaf62a95dae","added_by":"auto","created_at":"2025-12-10 15:24:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":312886,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u0026nbsp;\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8096250/v1/a456e1571bd22d042fa417e7.png"},{"id":97706125,"identity":"0432f585-03ce-417b-b7e8-40e35a3534e6","added_by":"auto","created_at":"2025-12-08 12:54:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":265120,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u0026nbsp;\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8096250/v1/69f3e3ae8d5c51b4fd93b930.png"},{"id":101634495,"identity":"f14e5cc3-a04c-47ee-aebf-4005ac7af01c","added_by":"auto","created_at":"2026-02-02 06:12:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1613809,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8096250/v1/bb6972f0-54fb-440b-b5e1-f074a48cb62b.pdf"},{"id":97706124,"identity":"b2c91702-bfc1-41c3-819d-ee5d8b5b7e04","added_by":"auto","created_at":"2025-12-08 12:54:56","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":67072,"visible":true,"origin":"","legend":"","description":"","filename":"6CONSORTExtensionTreatmentChecklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-8096250/v1/2ec52ddbfaa811ce8c8c5f38.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eThe accelerated reduction Method of glycated haemoglobin in patients with type 2 diabetes mellitus and hypertension: a comparative clinical trial\u003c/p\u003e","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eThe total number of adults with type two diabetes mellitus (T2D) has more than quadrupled worldwide over the past 30 years (from 200\u0026nbsp;million in 1990 to 830\u0026nbsp;million in 2022; NCD Risk Factor Collaboration), [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e] while the total world population has increased only 1.3-fold. [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.worldometers.info/world-population/\u003c/span\u003e\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eHigh incidence of T2D associated with obesity pandemic in all countries. [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e] Approximately 60% of adults in the US have obesity. [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e] In Kazakhstan every fifth of adult men (21.4%) is now obese. [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.globalnutritionreport.org\u003c/span\u003e\u003c/span\u003e] Obesity increases the incidence and mortality from chronic diseases. [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eT2D associated with obesity is characterized by long-term, slowly progressive cardiovascular complications that today cause the greatest harm to the population of all countries in the world, both developing and developed, accounting for about 70% of all annual deaths. [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e],[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e] Overweight and obesity are the cause of chronic diseases including T2D. [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eOne of the current and modern methods of diagnostics and regular monitoring of treatment of patients with T2D is the determination of glycated haemoglobin (HbA1c). [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e] Relatively recently, HbA1c has been included in the main diagnostic criteria for T2D and prediabetes. [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e] According to the American Diabetes Association, changes in HbA1c occur no earlier than 3 months with drug treatment. [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eWeight loss methods improve cardiovascular risks, reduce medication requirements, and improve glycemic and lipid metabolism. [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e] Moderate weight loss (5\u0026ndash;10%) is clinically significant for reducing HbA1c in patients with metabolic syndrome. [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e] Greater weight loss may be required to achieve improvement or remission of certain weight-related complications. Reducing excess weight improves the glycemic profile of patients with T2D; reducing fat mass is one of the main goals for combating hyperglycemia. [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eThe results of many studies show that the beneficial effects of weight-loss treatment on HbA1c depend on the amount of weight lost. [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e] We have recently demonstrated weight loss with good clinical outcomes in patients with T2D and CVD. [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eNowadays, there are many known methods for reducing overweight, but they are all grouped into three main areas of weight loss: pharmacologic, surgical, and dietary. [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e] Every weight loss method provides health benefits independently of others, but there is still debate about which method provides the greatest benefit for clinical and laboratory outcomes, particularly for HbA1c in patients with T2D. Improvements in glucose metabolism and cardiovascular risk factors were observed in patients who achieved large weight loss through lifestyle interventions or pharmacotherapy. [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e] Bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality, [\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e] and bariatric surgery could be the effective currently available treatment for T2D despite his side-effects. [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eCurrently, we have accumulated positive results in the weight loss treatment of patients with T2D and CVD by pharmacologic [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e], very-low-calorie diet (VLCD), [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e] and surgical (Vertical Sleeve Gastrectomy or Minigastric bypass, etc.) weight loss [\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e] more than 10% from baseline weight.\u003c/p\u003e\n\u003cp\u003eThe aim of this study was: to compare the three weight-loss treatment methods such as pharmacologic (semaglutide\u0026thinsp;+\u0026thinsp;empagliflozin), bariatric surgery (mini-gastro bypass), and VLCD (analimentary detoxication (ANADETO)) in accelerated decline in HbA1c in patients with T2D and hypertension.\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cp\u003e\u003cspan\u003e\u003cstrong\u003e2.1 Study Design\u003c/strong\u003e: A 30-day open label, prospective, multicenter, comparative clinical trial with the intention-to-treat analysis.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e\u003cstrong\u003e2.2 Participants\u003c/strong\u003e A total of 107 participants screened in the study, and 82 adults (45 females) aged 30 to 60 years with T2D and hypertension were included to determine eligibility; 25 were excluded due to inclusion criteria. Of the 82 patients included in the study, six patients were excluded due to the inclusion/ exclusion criteria as described below. (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) The patients were unevenly and voluntarily allocated into three groups: Drug group (pharmacological); Surgical group (surgery); and in VLCD. Of the 76 patients included in the treatment groups, three patients (two from drug group and one from VLCD group) were excluded due to drug intolerance and noncompliance. Finally, 73 patients (89%) were included in the study for analysis.\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003cp\u003e1) written informed consent; 2) T2D\u0026thinsp;\u0026ge;\u0026thinsp;3-year with glucose lowering therapy including insulin; 3) hypertension\u0026thinsp;\u0026ge;\u0026thinsp;3 years of treatment; 4) 30\u0026ndash;60 years old; 5) BMI\u0026thinsp;\u0026ge;\u0026thinsp;27 kg/m2 for both sexes, for Asian ethnicity; 6) weight loss at baseline. All included patients before recruiting to the study received standard-of-care treatment for T2D and hypertension.[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003cp\u003e1) T1D; 2)\u0026thinsp;\u0026lt;\u0026thinsp;30 age\u0026thinsp;\u0026gt;\u0026thinsp;61 years old; 3) patients after bariatric surgery; 4) unstable cardiac disorders (New York Heart Association class IV heart failure, refractory angina, uncontrolled arrhythmias, critical valvular heart disease, or severe uncontrolled hypertension); 5) glomerular filtration rate\u0026thinsp;\u0026lt;\u0026thinsp;40 mL/min and/or dialysis within 14 days before screening; 6) ejection fraction\u0026thinsp;\u0026lt;\u0026thinsp;40%; 7) history of alcohol consumption\u0026thinsp;\u0026gt;\u0026thinsp;30 g/day within the past 3 years; 8) malignancy within the past 5 years; 9) gestation or lactation; 10) hereditary diseases; 11) known hypersensitivity to any of the test substances.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003ePatient recruitment and randomization.\u003c/b\u003e Patient recruitment was carried out at three different clinical centers (Department for Internal medicine, Center for Endocrinology Center for Surgery). Then the patients were consulted by two doctors (surgeon and therapist) so that the patient could choose the appropriate type of treatment. Each patient was explained the pros and cons of each treatment method. After the patient's condition was assessed and all indications/contraindications, inclusion/exclusion criteria were met, he/she was referred to the appropriate center to receive the appropriate type of weight loss treatment. Randomization and blinding among patients were not possible within the study due to the study design. Comparative methods involve different interventions, patient allocation cannot be done ethically, informed consent cannot be concealed; results may not always be consistent with comparative treatments; randomization requires clinical equipoise. [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eBecause of the trial was non-randomized, the patients were 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 were allocated to each group based on the patient and two physicians (surgeon and therapist) decisions to avoid the risk of \"selection bias\". Parameter normalization focused on the work needed to integrate processes into statistics.\u003c/p\u003e\u003cp\u003eThe data were collected by three different research teams who were blinded to the data of individuals other than their own. All data (antropometric, body composition analysis, clinical, laboratory, instrumental data) was collected in the same place. laboratories, instrumentalists, and laboratory, instrumental and statistician were blinded to which patient belonged to which group/arm. The statistician could only work with the data across study groups once, when all the data had been collected and the database was locked, and only then could we break the code and see which treatment was best.\u003c/p\u003e\u003cp\u003eA combination of in-person conversations and telephone calls conduct during the study period.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcome measures.\u003c/b\u003e \u003cem\u003ePrimary endpoints\u003c/em\u003e: HbA1c; reduction in body weight; fasting blood glucose. \u003cem\u003eSecondary endpoints\u003c/em\u003e: systolic/diastolic BP; lipids; adverse events.\u003c/p\u003e\u003cp\u003e\u003cb\u003eInterventions.\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) \u003cem\u003eThe drug group\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;26) received subcutaneous Semaglutide (GLP-1RA) 1 mg once a 7 day with oral Empagliflozin (SGLT-2i) 25 mg once a day additionally to standard medical treatment including antihypertensive (metformin), lipid-lowering, symptomatic therapy. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/p\u003e\u003cp\u003e\u003cem\u003eThe surgery group\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;21) received a laparoscopic bariatric operation \u0026ndash; minigastric bypass (MGB) that is endovideoscopic techniques with the intraperitoneal using of synthetic/biological materials 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. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] These patients pass through additional pre-operation examination (blood tests and electrocardiography, esophagogastroscopy, ultrasound, and other necessary standard methods).\u003c/p\u003e\u003cp\u003e\u003cem\u003eThe VLCD group\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;26) received a fast weight loss program named \u0026lsquo;Analimentary-detoxication\u0026rsquo; (ANADETO) including\u0026thinsp;\u0026lt;\u0026thinsp;100 kcal/day with fat-free vegetables (tomato/cucumber) and salt intake (5\u0026ndash;6 g/day), optimum physical activity, and sexual self-restraint. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e] The program is aimed at the following outputs: a) use of own fatty store (autolipophagy); b) control endogen metabolic intoxication; c) reuse of interim metabolic substrates. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eDue to the presence of many known contraindications to use the drugs [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e] and make surgery interventions, [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e] the pharmacologic and surgery groups had patients with a milder clinical and laboratory course, but baseline body weight and HbA1c levels did not differ significantly between the comparison groups. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparative changes of body weight, glycemia, HbA1c, lipids, and blood pressure in the drug, surgery and VLCD clinical groups at baseline and 30 days after weight loss treatment (n\u0026thinsp;=\u0026thinsp;73) (M\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eDrug group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eSurgery group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eVLCD group\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 days\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e30 days\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e30 days\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e47.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e44.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e48.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBody weight (kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e105.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e103.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e110.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e98.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e106.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e93.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFat mass (kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e42.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e45.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e39.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e44.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e36.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFat free mass (kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e62.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e62.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e64.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e59.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e61.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e57.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHbA1c (%)\u003c/p\u003e\u003cp\u003e(% from Baseline)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e8.95\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\u003cp\u003e(-0.56%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e9.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28**\u003c/p\u003e\u003cp\u003e(-17.41%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e9.93\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31**\u003c/p\u003e\u003cp\u003e\u003cb\u003e(-23.36%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFasting blood glucose (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e8.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e9.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.34**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e9.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.36***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCholesterol (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e5.83\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e5.95\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e6.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTriglycerides (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e1.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.84\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e2.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e2.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHDL (mmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e0.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e0.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1,10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e0.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood haemoglobin (g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e135.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e136.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e136.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2,2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e128.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2,1**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e125.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e137.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSBP (mm.Hg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e143.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e134.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e148.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e145.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e161.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e122.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBP (mm.Hg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e92.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e89.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e97.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e94.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e102.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e83.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e* \u003cem\u003eP\u003c/em\u003e-values\u0026thinsp;\u0026lt;\u0026thinsp;0.025, ** \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01 и *** \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 were significant compared with baseline (before treatment) in all groups.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eAbbreviations\u003c/em\u003e: HbA1c, glycated haemoglobin; HDL, high density lipoprotein; M, mean; SBP/DBP, systolic/diastolic blood pressure; SEM, standard error of the mean; VLCD, very-low-calorie diet.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Analytical Assessment\u003c/h2\u003e\u003cp\u003e\u003cb\u003eAnthropometrical indicators\u003c/b\u003e included age (years), weight (kg), BMI (kg/m\u003csup\u003e2\u003c/sup\u003e), waist circumference (cm). Body composition parameters including fat mass (in % of total body weight), fat free mass, total body water, muscle mass, bone mass were measured using a Tanita MC-780MA Body Composition Analyzer (Tanita Corp., Tokyo, Japan).\u003c/p\u003e\u003cp\u003e\u003cem\u003ePhysical activity\u003c/em\u003e was assessed as the number of steps taken by patients, as determined by individual pedometers from Hoffmann-La-Roche(Switzerland) or other individual digital system.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLaboratory study.\u003c/b\u003e 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, bilirubin, hepatic enzyme activities.\u003c/p\u003e\u003cp\u003e\u003cb\u003eImaging.\u003c/b\u003e Ultrasound imaging (GE Vivid 7 Ultrasound; GE Healthcare Worldwide USA, Michigan) used for abdominal organs and kidneys.\u003c/p\u003e\u003cp\u003eWe carried out anthropometrical, laboratory, and instrumental examinations two times: at baseline and after 30 days.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCriteria for the diagnosis.\u003c/b\u003e Diagnosis of T2D according to the criteria of WHO and International Diabetes Federation (WHO/IDF consultation in 2006) [Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. Geneva, Switzerland, 2006]: HbA1c\u0026thinsp;\u0026ge;\u0026thinsp;6,5%, fasting plasma glucose level\u0026thinsp;\u0026ge;\u0026thinsp;7.0 mmol/l, or a patient receives antidiabetic therapy [ADA, 2023]. [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e] Hypertension: systolic-BP\u0026thinsp;\u0026ge;\u0026thinsp;130 and/or their diastolic-BP\u0026thinsp;\u0026ge;\u0026thinsp;90 mm.Hg following repeated examination, or a patient receives antihypertensive-drugs.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.4 Statistics\u003c/b\u003e \u003cem\u003eJustification of the sample size.\u003c/em\u003e The estimated treatment difference between comparison groups was set to 10% with a standard deviation of 8% and the superiority margin of 2.5% (δ\u0026thinsp;=\u0026thinsp;0.025) [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e] based on two-sided hypothesis testing. Using SPSS,Sample-Power,V23.0, the number of evaluable individuals needed per treatment arm\u0026thinsp;\u0026ge;\u0026thinsp;20. At least 107 patients we screened and recruited, and 73 patients were assessed for eligibility in the comparative clinical trial (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e] To increase in the power of the statistical analysis and receive significant results we used two-sided Student\u0026rsquo;s t tests with Bonferroni correction (\u003cem\u003eP-\u003c/em\u003evalue/2); where \u003cem\u003eP\u003c/em\u003e values of \u0026lt;\u0026thinsp;0.025 were set as significant differences in intra groups, and \u0026lt;\u0026thinsp;0.025 between groups to compensate for the small number of the groups. The study used SPSS Statistics v23 (SPSS Inc., Illinois, USA) and Microsoft Excel-2023 with normality assessed using histograms and box plots. Given the pilot nature of the study and firm hypotheses, were used. The study data is presented in Tables as Mean \u0026plusmn; Standard Error of the Mean (M\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM) for normally distributed data. All analyses were intention-to-treat.\u003c/p\u003e\u003cp\u003eCorrelation-regression analysis was used to find statistical relationship between body weight and HbA1c levels before and after the intervention (in percent); it quantifies how changes in one variable correspond to changes in another, indicating the direction and strength of their relationship, including determining of the type of correlation, such as positive (variables change in the same direction), negative (variables change in opposite directions), or no correlation (no apparent relationship).\u003c/p\u003e\u003cp\u003eWe used electronic databases (Web of Science/ Medline, EBSCO/Medline Complete, Scopus/Science Direct, Google Scholar, EndNoteClick/Kopernio, PubMed, and Ovid/Wolter Kluwer) for finding research literature.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003eThe treatment results for patients in the three compared groups are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. According to the data obtained, body weight decreased significantly in Surgery group (-10.5%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009) and in VLCD group (-12.2%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), while in Drug group the decrease was unsignificant (-1.2%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.39). The decrease in body weight in all comparison groups occurred due to both fat and lean mass. However, in Surgery and VLCD groups, the decrease in fat mass was significantly (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003, respectively). Fat free mass also decreased, but not significantly, in Surgery and VLCD groups by -8.8% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034) and 6.6% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.09) from baseline, respectively. The decrease in fat mass and fat-free mass in Surgical group was almost the same: -5.9% and \u0026minus;\u0026thinsp;5.7%, respectively.\u003c/p\u003e\u003cp\u003eFBG was decreased in Drug group by -13.9% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01), in Surgery group by -23.1% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and in VLCD group by -44.7% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\u003cp\u003eHbA1c was non-significantly decreased in Drug group by -0.56% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.45), significantly decreased in Surgery group by -17.4% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008), and significantly decreased in VLCD group by -23.4% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\u003cp\u003eLipids also improved partially significantly in Surgery group (-12.1% for cholesterol, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.00012; -15.9% for triglycerides, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0014; +13.4% for HDL, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026) and in VLCD group (-23.8% for cholesterol, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; -65.8% for triglyceride, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; +51.1% for HDL, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), while in Drug group cholesterol, triglyceride, and HDL changed insignificantly (-0.7%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.41 and \u0026minus;\u0026thinsp;7.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.15, and +\u0026thinsp;7.4%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.14, respectively).\u003c/p\u003e\u003cp\u003eBlood haemoglobin in Drug group changed insignificantly (+\u0026thinsp;0.9%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.36), in Surgery group it significantly decreased (-6.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0058), but in VLCD group blood haemoglobin significantly increased (+\u0026thinsp;9.4%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\u003cp\u003eSBP in Drug group significantly decreased by -6.5% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0043), but DBP non-significantly decreased by -3.4% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.14). SBP/DBP in Surgical group did not change significantly: -1.6% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.28) and \u0026minus;\u0026thinsp;2.9% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2), respectively. SBP/DBP in VLCD group significantly decreased by -24.3% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and 18.6% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), respectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIt was noted that in all three compared groups, HbA1c levels also decreased during weight loss. Therefore, we conducted a correlation-regression analysis to identify a statistical relationship between the dynamics of weight loss and changes in the HbA1c level. Correlation-regression analysis of the differences in percent between changes (body weight and HbA1c levels before and after the intervention) revealed a strong direct positive correlation between weight loss and a decrease in HbA1c (r\u0026thinsp;=\u0026thinsp;0.53; F\u0026thinsp;=\u0026thinsp;28.4, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001): the greater the weight loss, the lower the HbA1c level (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). According to the data, if body mass decreases by 10%, then HbA1c decreases by 20%; if body mass decreases by 25%, then HbA1c decreases by almost 40%.\u003c/p\u003e\u003cp\u003eDuring the 30 days in Surgical group antidiabetic medications were gradually reduced and discontinued during 2\u0026ndash;10 days in all patients, and antihypertensive medications also gradually reduced and discontinued during 7\u0026ndash;30 days after MGB in 17 patients (81%). This effect varied depending on postoperative condition and level of weight loss. Patients in Drug group were unable to reduce the dosage of previously taken medications.\u003c/p\u003e\u003cp\u003eIn VLCD group, the need for antidiabetic and antihypertensive medications decreased due to improvements in metabolic and cardiovascular health. Starting from the 3\u0026ndash;5 day of weight loss, it was necessary to reduce and completely stop taking the previous antidiabetic, antihypertensive, and other symptomatic medications; by 6\u0026ndash;10 days the drugs were stopped completely (including all patients with T2D in the insulin-dependent stage), and at 30 days there was no evidence of T2D and hypertension.\u003c/p\u003e\u003cp\u003eAdverse effects (AE). In Drug group were usual short-term gastrointestinal issues like nausea, vomiting, diarrhea, but after diet adjusting the AE were disappeared. In Surgical group were usual AE like inability to eat certain foods, dysgeusia, lack of appetite, flatulence, simplified bacterial overgrowth, anemia. There were no complications directly related to the surgical technic intervention. AE in VLCD were dizziness, weakness, nausea, and diarrhea within the first 2\u0026ndash;6 days, then turbid/dark urine on 3\u0026ndash;10 days, an increase in sputum expectoration in 2\u0026ndash;3 times more than usually, which were disappeared after two weeks.\u003c/p\u003e\u003cp\u003eThus, it can be argued that significant weight loss was the main reason for the reduction in HbA1c levels and clinical outcomes, drug discontinuation, and improvement in glycemic, metabolic, and cardiovascular health.\u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eThis study presents comparative results of three weight loss methods over one month to identify the fastest method to reduce HbA1c in patients with T2D and hypertension: pharmacological (Semaglutide\u0026thinsp;+\u0026thinsp;Empagliflozin), surgical (MGB) and VLCD (by ANADETO technology). The fastest method to reduce HBA1c was the VLCD (-23.4% from baseline), then the surgical method (-17.4% from baseline), and the last one was the pharmacological method (-0.6% from baseline). Every presented method for weight loss in patients with T2D and hypertension have the pros and cons.[\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThis study design was non-randomized clinical trial. Despite the many advantages of randomized trial design, there are several misconceptions particularly in interdisciplinary comparing very different treatment methods as surgical, drug, non-drug. \u003csup\u003e41,42\u003c/sup\u003e These misconceptions include: heterogeneity of study interventions, the length of treatment, different compared methods, appraisal and critique, pharmaceutical industry influence, ethical standards, etc. [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eIt should be noted that the more weight is lost, the better the blood pressure is reduced, the lipid levels are improved (cholesterol and triglyceride levels are reduced, HDL levels are increased) and the blood haemoglobin is increased. Significant improvements in these parameters were clearly observed in Surgery and VLCD groups, i.e. the faster the weight loss, the better these parameters were. These weight loss methods had antihyperglycemic, antihypertensive, and hypolipidemic effects, with their effectiveness depending on the level of weight loss.\u003c/p\u003e\u003cp\u003eA decrease in total body weight was significant, mainly due to body fat mass, especially in VLCD group. A decrease in fat free mass was also observed, but this decrease was not significant in all compared groups. The reduction in fat and fat-free mass was almost the same in Surgical group. It could be because patients in Surgical group were unable to exercise enough to maintain muscle mass in the postoperative period, and therefore they also lost fat-free mass.[\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThe decrease in muscle mass within the fat free mass is logically justified: the muscle mass that mechanically supported and carried this fat mass (which is part of the total body mass) will also logically decrease as the fat mass decreases.[\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e] Although there is also an opinion that the body, when in a calorie deficit, can turn to muscle tissue for energy when it does not receive enough of it from food.[\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThe body must have muscle mass to overcome not only gravity, but also to ensure the mechanical carrying of excess fat along with the body.[\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e] For instance, the body muscle mass in the open space greatly reduces. [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e] [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e] The body fat consumes body energy because muscle mass is required to move/transport excess fat mass; the more fat mass, the more muscle mass in healthy young people.[\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]\u003c/p\u003e\u003cp\u003e Guidelines on hyperglycemic management recommend either GLP-1RAs or SGLT-2is as second-line treatments for patients with T2D on metformin monotherapy. The use of both antidiabetic drugs in combination is rare in the literature. [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e] Despite this, their effect on the reduction of HbA1c during one month was comparatively and significantly lower than in Surgical and VLCD groups. The study demonstrated that the more weight lost the better were parameters in fasting blood glucose, lipids, and blood pressure.\u003c/p\u003e\u003cp\u003eInteresting changes occurred in blood haemoglobin in the compared groups, since ambiguous changes occurred there. Blood haemoglobin in Drug group changed insignificantly; but it reduced in Surgery group because in these patients after MGB often develop anemia due to the impaired absorption of iron in the gastrointestinal tract.[\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e] In VLCD group blood haemoglobin increased significantly possibly due to better improving in metabolism in hematopoiesis tissue and organs.[\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e] The results confirm and extend similar previous studies.[\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eIt is evident that the large weight loss improved anabolic processes, as haemoglobin, HDL levels increased significantly that confirmed other studies. [\u003cspan additionalcitationids=\"CR73 CR74\" citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e] For instance, abstaining from fatty foods and meat has an antiosteoporosis effect improving bone metabolism. [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e] Some other studies also confirm that weight loss results to increase haemoglobin and bone mineral density. [\u003cspan additionalcitationids=\"CR73 CR74\" citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eWeight loss methods decrease in multiple cardiovascular risks, reduce in medication, improve glycemic metabolism. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e] Weight loss in patients leads to cost savings by reducing the number of doctor visits, prescription drug tests, sick days, emergency visits and hospitalizations, but also has more long-term economic benefits, and reducing a risk for a wide range of chronic diseases. [\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eAfter bariatric surgery, the need for antidiabetic and antihypertensive medications often gradually decreases (under strict medical supervision) due to improvements in metabolic and cardiovascular health during 10\u0026ndash;30 days. In the VLCD group, a reduction and complete discontinuation of previous antidiabetic, antihypertensive and other symptomatic medications were observed by 6\u0026ndash;10 days of weight loss.\u003c/p\u003e\u003cp\u003eOur study also found that a large significant weight loss allows for the discontinuation of symptomatic drugs by reason of the need to reduce and completely discontinue previous medications.[\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e] Large weight loss should be the main treatment target on obesity-related complications.\u003c/p\u003e\u003cp\u003eThe ability to accumulate fat mass is one of the foundations for survival in conditions of food shortage. Food shortages always accompanied mankind. But, the survival rule \u0026ldquo;eat any time, any place, any opportunity\u0026rdquo; definitely led to overweight. [\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e] Currently, the ability to survive leads to an obesity epidemic. [\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e] Weight gain is unfavorable for the body\u0026rsquo;s energy. Overweight increases the total amount of metabolites. [\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e, \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eOverweight correlates with the development of diseases such as T2D, hypertension, allergic and inflammatory diseases, urolithiasis and cholelithiasis, liver steatosis and fibrosis, and tumors. [\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e] Overweight increases metabolic pressure on the body and increases both basal metabolic rate and active metabolism. [\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e] Over-metabolism regime over-consumes the body\u0026rsquo;s \u0026lsquo;vital energy\u0026rsquo;. [\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e] Weight loss creates \u0026lsquo;body potential power to weight gain\u0026rsquo; that increases physical/mental activity, recovers from diseases, or weight regain. Individual body weight and individual limit of weight gain mode may explain the \u0026lsquo;obesity paradox\u0026rsquo;. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e, \u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e] Some weight-loss methods are useless for recovering from diseases. Weight loss due to chronic and neoplastic diseases (unintentional) results in energy expenditure, while weight loss due to intentional, for example, restrictive diet, results in energy savings. [\u003cspan additionalcitationids=\"CR95\" citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThere should use weight loss methods that can allow the body to save energy and burn body old fat at the same time. [\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e] During weight loss, old fat absorbs intermediate and end metabolic products that induce metabolic intoxication, [\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e] which should be managed.[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e] Restriction diet improves gut microbiota, and intestinal function to synthesize gut vitamin. [\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e]\u003c/p\u003e"},{"header":"5. CONCLUSIONS","content":"\u003cp\u003eThus, the fastest method to reduce HbA1c in patients with T2D and hypertension was in VLCD group (based on autolipophagy with simultaneous control of endogen metabolic intoxication, ANADETO). HbA1c decreases by 20% if body mass decreases by 10%, and if body mass decreases by 25%, HbA1c decreases by almost 40%. Along with a reduction in HbA1c by more than 20% within 30 days, there was also a disappearance of clinical and laboratory symptoms of T2D, hypertension, hyperlipidemia and dyslipidemia. The fast weight loss helps reduce the need for antidiabetic and antihypertensive drugs in patients with T2D and hypertension.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eStrengths and limitations\u003c/strong\u003e\u003cp\u003eA strength of our study was that it was the first to show that different weight loss methods can have different effects on reducing HbA1c level. For the first time, the fact of the colossal influence of excess body weight on the level of HbA1c is presented. Published studies about positive role of fast weight loss on HbA1c in people with T2D and hypertension are very limited in scope and number. This study has several limitations. First, the study included the relatively small number of patients with T2D and hypertension. Second, the clinical trial had approximately 11% of the randomly assigned population dropped out prior to completion. There was only 30-day study that not enough to observe T2D and hypertension outcomes. Further high-quality multicenter clinical trials with a large sample size and longer-term follow-up are needed to confirm and extend the results of the study.\u003c/p\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAE:\u0026nbsp;adverse effects\u003c/p\u003e\n\u003cp\u003eANADETO: analimentary detoxication\u003c/p\u003e\n\u003cp\u003eCVD:\u0026nbsp;cardiovascular disease\u003c/p\u003e\n\u003cp\u003eFBG:\u0026nbsp;fasting blood glucose\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGLP-1RA: glucagon-like peptide-1 receptor agonists\u003c/p\u003e\n\u003cp\u003eHbA1c: glycated haemoglobin\u003c/p\u003e\n\u003cp\u003eHDL or LDL: high- or low-density lipoprotein\u003c/p\u003e\n\u003cp\u003eMGB:\u0026nbsp;minigastric bypass\u003c/p\u003e\n\u003cp\u003eSBP or DBP: systolic or diastolic blood pressure\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSGLT-2i: sodium-glucose cotransporter-2 inhibitor\u003c/p\u003e\n\u003cp\u003eT1D or T2D:\u0026nbsp;type one or two diabetes mellitus\u003c/p\u003e\n\u003cp\u003eVLCD: very-low-calorie diet.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe study was carried out in the Republic of Kazakhstan from September 1, 2024, through August 31, 2025. Participants were recruited gradually as they arrived in Center for Surgery, Clinical Academic Department of Internal Medicine, Center for Endocrinology at University Medical Center (Astana).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication.\u003c/strong\u003e Our manuscript does not contain any individual person\u0026rsquo;s data in any form. All authors of the manuscript affirm that they had access to the study data and reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest disclosures:\u003c/strong\u003e The authors declare that they have no competing interests (financial, professional, or personal) relevant to the manuscript. We have read and understood the journal policy on the declaration of interests and have no interests to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e The Ethical Committee of the University Medical Center (phone: +7 7172 69-25-86; Web: https://umc.org.kz/en/?ethics-commission=post-2) approved the study (approval protocol #8/2024/ПЭ of 28.08.2024; monitoring and re-approval protocol #1/2025/ПЭ of 12.02.2025. Board Affiliation: University Medical Center). The committee confirms that all methods were performed in accordance with the Declaration of Helsinki and guidelines of the Council for International Organizations of Medical Sciences (CIOMS) and that informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials.\u0026nbsp;\u003c/strong\u003eThe data are available from the authors upon reasonable request. Those wishing to request the study data should contact Principal Investigator of a research grant: Dr. Oshakbayev Kuat (Emails: [email protected]; [email protected], phone + 77013999394).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research was prepared under a research grant from the Ministry of Science and Higher Education of the Republic of Kazakhstan (grant for 2024-2026 years with trial registration AP23488544, National Center for Scientific and Technical Information of the Republic of Kazakhstan).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/strong\u003e\u003cem\u003eKO:\u003c/em\u003e design and performance, patient recruitment and treatment, data collection, bibliography review, scientific analysis, statistical advancing, scientific executor, writing draft, editing, and revision. \u003cem\u003eAD:\u0026nbsp;\u003c/em\u003estudy design, patient recruitment and treatment, writing the methods and discussion, bibliography, paper review, and print. \u003cem\u003eNB:\u0026nbsp;\u003c/em\u003estudy design, patient recruitment and treatment, writing the discussion, bibliography and paper review. \u003cem\u003eAN:\u0026nbsp;\u003c/em\u003estudy design, research executor, writing the methods, editing, and revision. \u003cem\u003eTS:\u003c/em\u003e patient recruitment and treatment, preparation of e-version data collection, bibliography, and paper review.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003eAI:\u003c/em\u003e patient recruitment and treatment, preparation e-version data collection in Excel, bibliography and paper review, statistical advancing, writing the methods. \u003cem\u003eGD:\u0026nbsp;\u003c/em\u003epaper scientific review, writing the methods, and print.\u003cem\u003e\u0026nbsp;D\u003c/em\u003e\u003cem\u003eK:\u0026nbsp;\u003c/em\u003epatient recruitment and treatment, preparation e-version data collection in Excel, bibliography and paper review. \u003cem\u003eMS\u003c/em\u003e\u003cem\u003e:\u0026nbsp;\u003c/em\u003epatient recruitment and treatment, preparation e-version data collection in Excel, bibliography and paper review. \u003cem\u003eGK:\u003c/em\u003e design and performance, bibliography review, data collection, scientific analysis, writing methods/results/discussion, editing, and paper review. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments.\u0026nbsp;\u003c/strong\u003eThe authors thank the Diagnostic Center of University Medical Center and ANADETO Medical Center for recruiting patients, collecting data for the study, and providing technical assistance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Generative AI and AI-assisted technologies in the writing process\u003c/strong\u003e: During the preparation of this work the authors did not use AI-assisted technologies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors will provide an appropriate point-by-point response to the reviewer(s) which addresses their comments.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZhou, B. et al. 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Individuals with Metabolically Healthy Overweight/Obesity Have Higher Fat Utilization than Metabolically Unhealthy Individuals. \u003cem\u003eNutrients\u003c/em\u003e ;\u003cb\u003e8\u003c/b\u003e(1). (2016).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePurdel, C., Margina, D., Adam-Dima, I. \u0026amp; Ungurianu, A. The Beneficial Effects of Dietary Interventions on Gut Microbiota-An Up-to-Date Critical Review and Future Perspectives. \u003cem\u003eNutrients\u003c/em\u003e ;\u003cb\u003e15\u003c/b\u003e(23). (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSeyfried, F. et al. Roux-en-Y gastric bypass surgery in Zucker rats induces bacterial and systemic metabolic changes independent of caloric restriction-induced weight loss. \u003cem\u003eGut Microbes\u003c/em\u003e ;\u003cb\u003e13\u003c/b\u003e(1). (2021).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Glycated haemoglobin, Weight loss, Type two diabetes, Semaglutide, Blood pressure, Very-low-calorie diet, Bariatric surgery","lastPublishedDoi":"10.21203/rs.3.rs-8096250/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8096250/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eAim:\u003c/strong\u003e to compare different weight-loss methods such as pharmacologic, bariatric surgery, and very-low-calorie diet (VLCD) in accelerated decline in HbA1c in patients with T2D and hypertension.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods. \u003c/strong\u003eDesign: a 30-day open label, prospective, multicenter, comparative clinical trial including 102 adult patients with T2D and hypertension were divided in three groups: Drug group; Surgical group; and VLCD. Primary endpoints: HbA1c; body weight.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults. \u003c/strong\u003eAt 30 days, body weight in the patients decreased significantly in Surgery group (-10.5%; \u003cem\u003eP\u003c/em\u003e=0.009) and in VLCD group (-12.2%; \u003cem\u003eP\u003c/em\u003e=0.003), while in Drug group the decrease was unsignificant (-1.2%; \u003cem\u003eP\u003c/em\u003e=0.39). In all comparison groups the decrease in body weight occurred due to both fat and lean mass.\u003c/p\u003e\n\u003cp\u003eSBP in Drug group decreased by -6.5%, DBP decreased by -3.4%. SBP/DBP in Surgical group changed by -1.6% and -2.9%, respectively. SBP/DBP in VLCD group significantly decreased by -24.3% and 18.6% (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.0001), respectively. Correlation-regression analysis revealed a correlation between weight loss and a decrease in HbA1c (r=0.53; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.0001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions. \u003c/strong\u003eThe fastest method to reduce HbA1c in patients with T2D and hypertension was in VLCD group. The greater the weight loss, the lower the HbA1c. The great reduction in HbA1c led to a decrease in symptomatic drugs up to its complete abolition.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration:\u003c/strong\u003e ClinicalTrials.gov NCT06410352 (05/08/2024): https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000EG8K\u0026amp;selectaction=Edit\u0026amp;uid=U0006MBT\u0026amp;ts=56\u0026amp;cx=-vph5l9\u003c/p\u003e","manuscriptTitle":"The accelerated reduction Method of glycated haemoglobin in patients with type 2 diabetes mellitus and hypertension: a comparative clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-08 12:54:52","doi":"10.21203/rs.3.rs-8096250/v1","editorialEvents":[{"type":"communityComments","content":1}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bc5d44f1-3744-4477-b57e-3c18bdb18341","owner":[],"postedDate":"December 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":59275735,"name":"Health sciences/Diseases"},{"id":59275736,"name":"Health sciences/Endocrinology"},{"id":59275737,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-02-02T06:10:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-08 12:54:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8096250","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8096250","identity":"rs-8096250","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}