Efficacy and Safety of Dapagliflozin, Glimepiride, and Metformin Fixed-Dose Combination Tablet in Type 2 Diabetes: A Phase III Trial

The global burden of type 2 diabetes mellitus (T2DM) is rapidly increasing, with India contributing significantly to the disease prevalence and associated economic burden. Despite metformin being the first-line therapy, many patients require combination treatment due to the progressive and multifactorial nature of T2DM. Fixed-dose combinations (FDCs) of drugs with complementary mechanisms may improve glycemic control, adherence, and treatment outcomes. This study has evaluated efficacy and safety of FDC of dapagliflozin (DAPA), glimepiride (GLIM), and metformin (MET) immediate release (IR) tablet versus co-administration of GLIM and MET tablets in patients with T2DM. This phase 3, randomized, open-label study included 536 Indian patients with T2DM [glycated hemoglobin (HbA1c) ≥ 8.0% and ≤ 11%], randomized (1:1:1:1) into four arms in primary treatment period (up to Week 16): FDC of DAPA + GLIM + MET [5 mg+1 mg+500 mg (Test 1)] or [5 mg+1 mg+1000 mg (Test 2)] twice-daily, or co-administration of GLIM and MET (1 mg and 500 mg) (Comparator 1) or GLIM and MET (1 mg and 1000 mg) (Comparator 2) twice-daily. Patients with HbA1c ≥ 7.0% at week 16 entered an uptitration period (increased GLIM dose to 2 mg; Weeks 16–28). Change in HbA1c from baseline to Week 16 was the primary endpoint. At Week 16, least-square mean HbA1c reduction was significantly greater with Test 1 (− 2.17%) versus Comparator 1 (− 1.64%, p = 0.0047) and Test 2 (− 2.25%) versus Comparator 2 (− 1.72%, p < 0.0001). Similarly, the proportion of patients achieving HbA1c < 7.0% at Week 16 was significantly greater in Test 1 versus Comparator 1 and Test 2 versus Comparator 2 ( p < 0.0002 and p < 0.0001, respectively). Reduction in HbA1c, fasting, and postprandial blood glucose from baseline to Weeks 12, 16, and 28 was significant in all arms. Overall, treatments were well tolerated. The FDC of DAPA + GLIM + MET IR tablet demonstrated superior glycemic control over co-administration of glimepiride and metformin and acceptable safety profile, making it an effective therapeutic option for T2DM management. Clinical Trials Registry India, CTRI/2022/06/043249.