Type 2 diabetes mellitus (T2DM) represents one of the foremost public health challenges of the 21st century, with the International Diabetes Federation estimating a global prevalence of approximately 537 million adults in 2021. India carries a disproportionate burden, with over 77 million people living with diabetes, a figure projected to exceed 134 million by 2045. Obesity is a major driver of T2DM pathogenesis and progression, contributing to insulin resistance, beta-cell dysfunction, and accelerated cardiovascular risk.

 

Despite the availability of numerous antidiabetic agents, achieving and maintaining optimal glycaemic targets (HbA1c <7%) remains challenging, particularly in obese patients where insulin resistance is more pronounced. Conventional therapies including metformin, sulfonylureas, and insulin are often associated with weight gain or inadequate glycaemic control in this subgroup, underscoring the need for effective agents capable of simultaneously improving glycaemia and reducing adiposity.

 

Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a major therapeutic advance in T2DM management. Semaglutide is a once-weekly, long-acting GLP-1 receptor agonist with 94% sequence homology to human GLP-1. It exerts its antidiabetic effects through glucose-dependent insulin secretion, suppression of glucagon release, slowing of gastric emptying, and central appetite suppression, leading to clinically meaningful reductions in both blood glucose and body weight. The SUSTAIN clinical trial programme has demonstrated robust HbA1c reductions of 1.2–1.8% and weight reductions of 3–6 kg with semaglutide in diverse populations.

 

However, data specifically addressing the efficacy and safety of semaglutide in obese Indian patients with T2DM remain limited. Indian patients exhibit distinct metabolic phenotypes including central obesity at lower BMI thresholds, earlier onset of T2DM, and a propensity for beta-cell failure. These characteristics may influence therapeutic response. The present study was therefore undertaken to evaluate the 12-month efficacy and safety of once-weekly subcutaneous semaglutide in obese adults with T2DM from a tertiary care centre in Bangalore, India.

2.1 Study Design and Setting This was a prospective, randomized, double-blind, placebo-controlled, parallel-group trial conducted at Shri Atal Bihari Vajpayee Medical College and Research Institute, Bangalore, India, from March 2025 to February 2026. 2.2 Study Participants Adults aged 30–65 years with a confirmed diagnosis of T2DM for at least one year, HbA1c between 8.0% and 11.0%, BMI ≥ 30 kg/m², and on stable metformin monotherapy (≥1500 mg/day) for at least 3 months were eligible for inclusion. Key exclusion criteria included: type 1 diabetes, estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m², active hepatic disease (alanine aminotransferase >3× upper limit of normal), personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, use of any antidiabetic agent other than metformin within the preceding 3 months, pregnancy or lactation, severe cardiovascular event within 6 months, and known hypersensitivity to any GLP-1 receptor agonist. 2.3 Randomization and Blinding Eligible participants were randomized in a 1:1 ratio to receive either subcutaneous semaglutide 0.5 mg once weekly or a matching subcutaneous placebo injection once weekly, using computer-generated block randomization (block size 4) stratified by baseline HbA1c (<9.5% or ≥9.5%) and sex. Allocation was concealed using sequentially numbered opaque sealed envelopes. Both participants and investigators (except the unblinded pharmacist dispensing study medication) were blinded to treatment assignment. Semaglutide was initiated at 0.25 mg/week for the first 4 weeks (dose escalation phase), then increased to 0.5 mg/week for the remainder of the study (maintenance phase). 2.4 Study Assessments All participants underwent standardized clinical and biochemical assessments at baseline and at 3, 6, 9, and 12 months. HbA1c was measured by high-performance liquid chromatography (HPLC). Fasting plasma glucose and lipid profile were measured after a minimum 10-hour fast using standard enzymatic colorimetric methods. The 2-hour post-prandial glucose was measured 2 hours after a standardized 75 g oral glucose load. Anthropometric measurements (weight, height, waist circumference) and blood pressure were recorded by trained personnel using standardized protocols. Body weight was measured on a calibrated digital scale in light indoor clothing without shoes. eGFR was estimated using the CKD-EPI creatinine equation. Adverse events were recorded at every visit and graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 2.5 Endpoints The primary endpoint was the change in HbA1c from baseline to 52 weeks. Secondary endpoints included: change in FPG, 2-h PPG, body weight, BMI, waist circumference, systolic and diastolic blood pressure, and lipid parameters (total cholesterol, LDL-C, HDL-C, triglycerides) from baseline to 52 weeks. Proportions of patients achieving HbA1c <7.0% and <7.5%, weight reduction ≥5% and ≥10%, and safety outcomes were also assessed. 2.6 Statistical Analysis Sample size was calculated assuming a mean difference of 1.0% in HbA1c reduction between groups, a standard deviation of 1.2%, 80% power, and a two-tailed alpha of 0.05, requiring 46 participants per group; allowing for 15% attrition, 55 participants per group (n=110 total) were enrolled. Continuous variables are expressed as mean ± standard deviation (SD). Between-group comparisons at endpoint were performed using Student's independent t-test. Within-group changes from baseline were assessed using paired t-tests. Categorical data were compared by chi-square or Fisher's exact test as appropriate. All analyses were performed on the intention-to-treat (ITT) population using last observation carried forward (LOCF) for missing data. A two-tailed p-value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA).