European Journal of Cardiovascular Medicine

Type 2 diabetes mellitus (T2DM) is one of the most pressing public health challenges in India, affecting over 77 million individuals and projected to rise sharply in the coming decades. Among Indian subpopulations, individuals from South India show a unique cardiometabolic profile characterized by early-onset insulin resistance, a higher prevalence of central obesity, and a dietary pattern dominated by high glycemic index foods such as white rice and refined carbohydrates. These factors, combined with physical inactivity and genetic predisposition, make effective management of T2DM particularly challenging in this region.

Traditional glucose-lowering agents, while effective in reducing blood glucose levels, often lack significant impact on body weight and may even contribute to weight gain—worsening the insulin resistance cycle. This has created a clinical need for agents that not only lower glucose levels but also promote weight reduction, improve metabolic flexibility, and reduce cardiovascular risk.

Semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), has emerged as a transformative therapy in this domain. Clinical trials such as the SUSTAIN and STEP series have demonstrated robust effects of Semaglutide on both glycemic control (HbA1c reduction up to 1.5–1.8%) and body weight reduction (up to 15%), with an acceptable safety profile [1, 2, 3]. It not only enhances insulin secretion and suppresses glucagon but also reduces appetite, delays gastric emptying, and induces satiety [4].

However, these trials were largely conducted in Western populations and may not directly translate to the Indian context due to differences in dietary habits, body composition, and pharmacogenomic factors. Real-world Indian and Asian data on Semaglutide, although emerging, remains limited. Some recent studies suggest promising outcomes in Indian populations, including significant weight loss and HbA1c reduction with both oral and subcutaneous forms of the drug [5, 6, 7].

There is therefore a notable gap in dose-specific, regionally contextualized data, particularly among South Indian patients whose diets are dominated by refined carbohydrates consisting of high glycemic load and low fibre content, and who may respond differently to GLP-1 RA therapy. This study aims to address this gap by comparing the effects of 3mg vs 7 mg  oral Semaglutide daily on weight loss and glycemic control in a South Indian cohort.

Study Design

This was a prospective, interventional, two-arm comparative study conducted at Vels Medical College and Hospital, Tamil Nadu. The study was conducted over a period of four months, encompassing patient recruitment, intervention, follow-up, and data analysis. Each participant was followed prospectively for 12 weeks from the initiation of Semaglutide therapy.

Clinical and biochemical assessments were performed at four time points: baseline, week 4, week 8, and week 12. The primary objective was to compare the effects of two different doses of once daily Semaglutide (3mg and 7 mg) on weight loss and glycemic control in patients with type 2 diabetes mellitus (T2DM).

Study Population

A total of 50 adult patients diagnosed with T2DM were enrolled based on eligibility criteria and were randomized into two equal groups of 25 each.
Randomization was performed using a computer-generated simple random number sequence to ensure equal allocation into the two treatment arms.

Inclusion Criteria

• Age between 30 and 65 years
• Diagnosed with T2DM for at least 1 year
• HbA1c between 7.0% and 10.0%
• Body Mass Index (BMI) ≥25 kg/m²
• On stable doses of oral antidiabetic therapy (e.g., metformin ± sulfonylureas) for at least 3 months prior to enrollment

Exclusion Criteria

• Type 1 diabetes mellitus or secondary diabetes
• Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m²
• History of medullary thyroid carcinoma or multiple endocrine neoplasia type 2
• History of pancreatitis
• Prior treatment with any GLP-1 receptor agonist
• Pregnancy or lactation

Intervention Protocol

Patients were randomized into two treatment groups:

• Group A (Low-Dose Arm):
• Week 1–4: 3 mg Semaglutide once daily
• Week 5–12: 3 mg Semaglutide once daily

• Group B (High-Dose Arm):
• Week 1–4: 3 mg Semaglutide once daily
• Week 5–6: 7 mg once daily
• Week 7–12: 14 mg once daily.

Variables and Data Collection

The following clinical and biochemical variables were recorded at each time point:

• Demographic: Age, sex, BMI
• Clinical: Duration of diabetes, comorbidities, current medications
• Glycemic Parameters: Fasting Blood Sugar (FBS), Postprandial Blood Sugar (PPBS), HbA1c
• Anthropometric: Body weight (kg)
• Adverse Effects: Gastrointestinal symptoms (nausea, vomiting), hypoglycemia, injection site reactions

Outcomes Measured

Primary Outcomes

• Change in body weight (kg) from baseline to week 12
• Change in HbA1c (%) from baseline to week 12

Secondary Outcomes

• Change in FBS and PPBS from baseline to week 12
• Proportion of patients achieving:
• ≥5% reduction in baseline weight
• Target HbA1c <7.0%
• Incidence of reported adverse effects

Statistical Analysis

All data were initially entered into Microsoft Excel and subsequently analyzed using:

• IBM SPSS Statistics for Windows, Version 26.0 (IBM Corp., 2019)
• R version 4.1.2 (R Core Team, 2021)

SPSS was utilized for descriptive statistics, group comparisons using t-tests, and Chi-square tests for categorical variables. R software was used for advanced graphical visualization and exploratory subgroup analysis.

Continuous variables were expressed as mean ± standard deviation. Comparisons between groups were made using the independent t-test or Mann–Whitney U test as appropriate. A p-value <0.05 was considered statistically significant.

Ethical Considerations

The study protocol was reviewed and approved by the Institutional Ethics Committee of Vels Medical College and Hospital. Written informed consent was obtained from all participants prior to enrollment. The study was conducted in accordance with the Declaration of Helsinki and adhered to Good Clinical Practice (GCP) guidelines.

Baseline Characteristics

A total of 50 patients with type 2 diabetes mellitus were enrolled and randomized into two groups: Group A (Semaglutide 3 mg) and Group B (Semaglutide 7 mg), with 25 participants in each group. Baseline demographic and clinical characteristics were compared between the two groups to assess group equivalence before intervention.

There was no statistically significant difference between the groups in terms of age, sex distribution, BMI, HbA1c, fasting blood sugar (FBS), or postprandial blood sugar (PPBS) at baseline. An independent samples t-test showed no significant difference in mean age between Group A and Group B (t (48) = −0.58, p = 0.56, Cohen’s d = 0.16).The difference in baseline HbA1c was also nonsignificant (t (48) = −0.87, p = 0.39, Cohen’s d = 0.25).BMI was comparable across groups (t (48) = −0.58, p = 0.57, Cohen’s d = 0.17).For sex distribution, a Chi-square test revealed no significant association between group allocation and gender (χ² (1) = 0.08, p = 0.78, Cramer’s V = 0.04).

Table1:  Baseline Characteristics of Study Participants

Notes:

• Continuous variables presented as mean ± standard deviation.
• Categorical variable (sex) presented as count and percentage.
• Statistical tests: Independent t-tests for continuous variables, Chi-square for categorical.
• p < 0.05 considered statistically significant.
• Effect sizes: Cohen’s d for mean comparisons, Cramer’s V for categorical comparison.

2. Primary Outcomes

At the end of 12 weeks, both treatment groups showed statistically significant improvements in weight reduction and glycemic control compared to their respective baselines. However, participants in Group B (7mg Semaglutide) experienced significantly greater improvements than those in Group A (3 mg Semaglutide).

• The mean reduction in body weight was −3.2 ± 1.1 kg in Group A versus −5.9 ± 1.3 kg in Group B.
  An independent samples t-test confirmed this difference was statistically significant (t (48) = 8.03, p < 0.001, Cohen’s d = 2.27).
• Mean HbA1c reduction was −0.8 ± 0.3% in Group A and −1.4 ± 0.4% in Group B.
  This difference was also statistically significant (t (48) = 6.29, p < 0.001, Cohen’s d = 1.78).

These findings indicate that the higher dose of Semaglutide  7 mg) is more effective in achieving both weight loss and improved glycemic control in South Indian patients with type 2 diabetes over a 12-week period.

Table 2: Change in Primary Outcomes at 12 Weeks

Figure1: Comparison of Weight loss and HbA1c Reduction After 12 Weeks

Figure 1. Mean reduction in body weight (kg) and HbA1c (%) after 12 weeks of once daily Semaglutide therapy in Group A (3mg) and Group B (7mg). Bars represent mean values with standard deviation. Group B showed significantly greater improvements in both outcomes (p < 0.001 for both comparisons).

3. Secondary Outcomes

In addition to primary outcomes, both groups showed improvements in secondary metabolic parameters at 12 weeks.

• The reduction in fasting blood sugar (FBS) was −22.5 ± 8.4 mg/dL in Group A and −35.1 ± 10.2 mg/dL in Group B. This difference was statistically significant (t (48) = 4.43, p < 0.001, Cohen’s d = 1.25).
• Postprandial blood sugar (PPBS) declined by −35.6 ± 12.3 mg/dL in Group A and −52.4 ± 13.1 mg/dL in Group B. The between-group difference was significant (t (48) = 4.53, p < 0.001, Cohen’s d = 1.29).
• The proportion of patients achieving HbA1c <7.0% was 36% in Group A vs. 68% in Group B.
  A Chi-square test confirmed this difference to be significant (χ²(1) = 5.02, p = 0.025, Cramer’s V = 0.32).
• Similarly, the proportion of patients achieving ≥5% weight loss was 28% in Group A and 64% in Group B (χ² (1) = 6.45, p = 0.011, Cramer’s V = 0.36).

These results indicate that the higher dose of Semaglutide not only improved primary endpoints but also enhanced overall metabolic control and goal attainment in a greater proportion of patients.

Table 3: Secondary Outcome Measures at 12 Weeks

Figure2: Proportion of Patients Achieving Target Outcomes at 12 Weeks

Percentage of patients in each treatment group who achieved (A) HbA1c <7.0% and (B) ≥5% reduction in baseline body weight at the end of 12 weeks. Patients in the  7 mg Semaglutide group showed a significantly higher achievement of both metabolic targets compared to the 3mg group (p = 0.025 and p = 0.011, respectively).

 4: Adverse Events

Both treatment groups were monitored for adverse events throughout the 12-week intervention period. Overall, Semaglutide was well-tolerated in both dosing groups, with no serious or life-threatening complications reported.

• The most common adverse effects were mild gastrointestinal symptoms, including nausea and vomiting.
• Nausea was reported in 3 patients (12%) in Group A and 6 patients (24%) in Group B.
  The difference was not statistically significant (χ²(1) = 1.04, p = 0.31, Cramer’s V = 0.14).
• Vomiting occurred in 1 patient (4%) in Group A and 3 patients (12%) in Group B (χ²(1) = 1.07, p = 0.30, Cramer’s V = 0.15).
• A single case (4%) of mild hypoglycaemia was observed in Group B; no episodes occurred in Group A. This difference was not statistically significant (χ²(1) = 1.02, p = 0.31, Cramer’s V = 0.14).

No participants discontinued the study due to adverse effects, and all events were self-limiting or managed conservatively. Overall, adverse events were mild, dose-dependent, and did not result in treatment discontinuation. The slightly higher frequency of gastrointestinal symptoms in the 7mg group is consistent with known pharmacological tolerability patterns of Semaglutide.

Table 4: Adverse Events Reported During 12 Weeks

In this prospective two-arm comparative study, we observed that both doses of once-daily Semaglutide—3 mg and 7 mg—led to significant reductions in body weight and HbA1c over a 12-week period. However, the 7 mg dose was associated with superior outcomes across all endpoints, including fasting and postprandial glucose levels, proportion of patients achieving HbA1c <7%, and those achieving ≥5% weight loss.

These findings are in line with the global SUSTAIN program, where Semaglutide has demonstrated dose-dependent efficacy in both weight loss and glycemic control. In a pooled analysis of SUSTAIN 1–5, Ahrén et al. reported consistent weight loss across all BMI subgroups, with only a minor contribution from gastrointestinal symptoms such as nausea and vomiting [8]. This was further supported by Lingvay et al., who found that nausea- or vomiting-mediated weight reduction contributed less than 0.1 kg in SUSTAIN 3, 7, and 10 [12].

In our cohort, the higher 7 mg dose led to more than twice the number of patients achieving targeted glycemic control (HbA1c <7%) compared to the 3mg group. This mirrors the findings of Okamoto et al., who reported significantly improved glycemic outcomes and weight loss even in patients switched from other GLP-1 receptor agonists [9]. These data reinforce the clinical utility of Semaglutide not only as an initial agent but also as a superior replacement for other GLP-1 RAs.

Importantly, our study also confirmed the favourable tolerability profile of Semaglutide. Mild gastrointestinal symptoms were more frequent in the 7 mg group, consistent with dose escalation trends; however, all were self-limiting, and no treatment discontinuations occurred. This aligns with broader safety findings from Trujillo et al., who reviewed 30 GLP-1 RA trials and concluded that adverse events, particularly gastrointestinal, were generally transient and non-serious [11].

Beyond metabolic benefits, the cardiovascular safety and efficacy of Semaglutide have been established in large-scale outcome trials. In the SUSTAIN-6 trial, Semaglutide significantly reduced the composite of cardiovascular death, nonfatal MI, and nonfatal stroke in high-risk T2DM patients, confirming both efficacy and noninferiority to placebo [10]. These findings emphasize the multidimensional role of Semaglutide in modern diabetes management.

 Clinical Implications

Our findings provide real-world validation that once-weekly Semaglutide 7 mg is more effective than the 3mg dose for short-term improvements in glycemic control and weight loss. This has particular relevance in the South Indian population, where high-carbohydrate diets and central adiposity are common challenges in diabetes care. These results support a personalized, dose-optimized approach to GLP-1 RA therapy in clinical practice.

 Limitations

While the sample size was modest, it was adequate to detect significant differences between dosing arms. The study duration of 12 weeks provides insight into early-phase therapeutic response but does not capture long-term outcomes such as treatment durability, cardiovascular endpoints, or renal parameters. The study was conducted at a single centre, which may limit the generalizability to broader populations.

 Future Directions

Further multicentre studies involving larger and more diverse patient populations are needed to confirm these findings over longer treatment durations. Exploring the effects of Semaglutide on additional biomarkers, quality of life, and adherence in Indian cohorts will provide a more holistic understanding of its role in personalized diabetes management.

This prospective comparative study demonstrated that both 3mg and 7mg once daily Semaglutide significantly improved glycemic control and induced meaningful weight loss in patients with type 2 diabetes mellitus. However, the 7 mg dose was consistently more effective across all measured outcomes, including HbA1c reduction, fasting and postprandial glucose levels, and the proportion of patients achieving ≥5% weight loss.

Both doses were well tolerated, with only mild and self-limiting gastrointestinal symptoms observed, and no treatment discontinuations. These findings reinforce the clinical utility of Semaglutide 7 mg as a superior therapeutic option for short-term metabolic optimization, particularly in South Indian populations characterized by high-carbohydrate dietary patterns and central adiposity.

Given its dual benefit of glycemic control and weight reduction, Semaglutide should be considered a cornerstone in individualized diabetes management strategies, especially in patients requiring more intensive metabolic intervention. Further long-term studies are warranted to assess durability, cardiovascular risk reduction, and real-world adherence in diverse Indian populations.

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