Introduction

India bears a substantial burden of type-2 diabetes mellitus (T2DM), affecting over 101 million people. According to the findings of “The Impact India programme”, the average glycated hemoglobin (HbA1c) level in Indian patients with T2DM was 8.56%, indicating a poor glycemic control.   Poor awareness, treatment non-adherence, and polypharmacy contribute to uncontrolled diabetes and increased risk of cardiovascular and microvascular complications. Early intensive combination therapy is recommended for patients with high HbA1c levels (>8.5%). Fixed-dose combinations (FDCs) can reduce pill burden and improve adherence. The combination of metformin, glimepiride, and sitagliptin provides complementary glucose-lowering effects, with evidence suggesting that sitagliptin plus low-dose glimepiride may improve glycemic control while minimizing hypoglycemia and potentially preserving beta-cell function.

Aim

To determine the efficacy (establishing superiority) and safety of a triple FDC of sita­gliptin, metformin and low-dose glimepiride, as compared to co-administration of metformin and high-dose glimepiride in Indian patients with T2DM uncontrolled with metformin and glimepiride.

Patient Profile

• Adult patients diagnosed with T2DM (age: 18–65 years), having a body mass index (BMI) of < 45.0 kg/m² and following a diet and exercise regimen. 
• The study participants had HbA1c levels between 8% and 11% after being on a stable daily dose of glimepiride 4 mg and metformin ≥ 1500 mg for ≥ 10 weeks before screening. 

Methods

Study Design

• A phase 3, multicentre, randomised, parallel, active-controlled, double-blind, double-dummy study conducted across 16 hospitals in eight states in India.
• A 2-week screening period preceded a 16-week double-blind, double-dummy treatment period. This was followed by a 12-week, open-label treatment period.

Treatment Strategy

• Patients were randomized 1:1 to receive the following:
• SITA + MET + GLIM group:  Patients received a triple FDC of sitagliptin 50 mg, metformin 1000 mg and glimepiride 1 mg, twice daily (BID) 
• Coadministration group: Patients received metformin 1000 mg and glimepiride 2 mg BID (administered as, two tablets of metformin 500 mg and one tablet of glimepiride 2 mg). 

Outcomes

Primary Outcome

Secondary Efficacy Outcome

• The change in HbA1c from baseline to week 28.
• The proportion of pa­tients with HbA1c < 7% at weeks 12, 16 and 28.
• Changes in fasting blood glucose (FBG) and post-prandial blood glucose (PPBG) from baseline to weeks 12, 16, 24, and 28.
• The number of patients requiring hypoglycemia management or rescue medications.
• Hypoglycemia was defined as blood glucose ≤ 70 mg/dL or signs and symptoms of hypoglycemia. Mild hypoglycemia was defined as blood glucose ≥ 54 mg/dL but < 70 mg/dL
•  Assessments at Weeks 24 and 28 were conducted only in patients receiving sita­gliptin 50 mg/metformin 1000 mg/glimepiride 1 or 2 mg (triple FDCs) during the open-label treatment period.

Safety Outcomes

Results

• A total of 473 patients were screened, of these, 392 were randomised to receive study medications. The mean age of the study subjects was 47.29 ± 8.87 years and the mean baseline HbA1c was 9.16% ± 0.75%. 
• The study reported a treatment compli­ance of 96.8% and 98.0% the SITA + MET + GLIM and coadministration groups, respectively during the 16-week double-blind period.
• Among 190 randomized patients, 182 progressed to the 12-week open-label phase. Subsequently, 130 remained on the initial BID regimen, while 52 escalated to the higher glimepiride dose at week 16 (sitagliptin 50 mg/metformin 1000 mg/glimepiride 2 mg BID).
• Patients treated with triple FDC therapy (SITA + MET + GLIM) exhibited superior glycemic control vs. those in the coadministration group, with a significantly greater HbA1c reduction at week 16 (−1.79% vs −1.28%; p<0.0001) (Fig. 1)

Fig. 1: Reduction in HbA1c levels during the study     

                  

Fig. 2 Mean HbA1c, change from baseline to week 16

Fig. 3 Proportion of patients with HbA1c target of < 7% at weeks 12 & 16

           

• Both groups showed significant reductions in FBG and PPBG, with comparable effects between groups.
• During the open-label extension, glycemic improvements were sustained with triple FDC therapy (pooled population), resulting in a mean HbA1c reduction of −2.37% by week 28. 
• At week 28, 53.0% of patients, who had progressed to 12-week open label treatment period, achieved HbA1c <7%, accompanied by substantial reductions in PPBG (−72.8 mg/dL at week 24; −78.6 mg/dL at week 28) and FBG (−48.4 mg/dL at week 24; −53.6 mg/dL at week 28).
• Among patients continuing triple FDC therapy, HbA1c declined from 8.97% to 6.93% by week 16 and by −2.53% by week 28. In 52 patients, up-titrated to glimepiride 2 mg, HbA1c fell from 9.64% to 8.51% by week 16 and by 1.97% at week 28, this included an additional 0.84% reduction after dose escalation (p<0.0001).
• Incidence of hypoglycaemia was low and comparable between groups (1.6% vs. 0.5%), with only one additional event during the open-label phase. All events were mild, asymptomatic, laboratory-detected, required no intervention or rescue medication. No new safety concerns were reported during the study.
• The incidence of treatment-emergent AEs was comparable in both the study groups. Most of the AEs were of moderate severity.

Conclusions

• This first-in-world, large-scale study conducted in India demonstrated that the triple FDC of sitagliptin, metformin and glimepiride was effective and well-tolerated in T2DM patients in India.
• The FDC was superior to metformin 1000 mg and glimepiride 2 mg BID in terms of reduc­ing HbA1c from baseline to week 16 and has the potential to reduce pill bur­den and improve treatment adherence.

 Diabetes Obes Metab 2026; 28:6207–6216.