CLINICAL EFFICACY AND SAFETY OF GLIMEPIRIDE, EMPAGLIFLOZIN AND SITAGLIPTIN WITH METFORMIN IN TYPE 2 DIABETES MELLITUS: A DOUBLE AND TRIPLE DRUG THERAPY

Abstract

Type 2 diabetes mellitus (T2DM) is a growing global health challenge, imposing significant disease burden and economic strain. In Pakistan, the situation is particularly alarming. According to the most recent IDF Atlas (2025), approximately 34.5 million adults (aged 20–79 years) are affected in Pakistan, with an age-standardized prevalence of 31.4%, the highest in the world. This escalating prevalence underscores the urgent need for effective treatment strategies tailored to the local population. The present study was designed to evaluate and compare the clinical efficacy and safety profiles of initial double and triple combination regimens in treatment-naïve patients with T2DM. After obtaining approval from the Institutional Review Board of Bahria University Health Sciences, Karachi (IRB- BUHSCK), this open-labeled, parallel-arm, randomized clinical trial was conducted at the Diabetic Clinic of the National Medical Center, Karachi. A total of 172 diagnosed type 2 diabetic patients (males and females, aged 30–55 years) meeting inclusion criteria were enrolled through randomization via the sealed-envelope method. Participants were allocated into four parallel treatment arms 43 in each: Group A received Metformin 500 mg + Glimepiride 2 mg (fixed-dose combination, FDC); Group B received Metformin 500 mg + Empagliflozin 12.5 mg (FDC); Group C received Metformin 500 mg + Sitagliptin 50 mg (FDC); and Group D received Metformin 500 mg + Empagliflozin 12.5 mg (FDC) + Sitagliptin 50 mg once daily, in addition to lifestyle modifications. 150 patients successfully completed the study (Group A: 34; Group B: 38; Group C: 37; Group D: 41). Of 90 days, with assessments at baseline, day 45, and day 90. The primary endpoint was a reduction in HbA1c of at least ≥1% from baseline to day 90, while secondary outcomes included changes in fasting and random blood sugar, body weight, and lipid profile. Safety outcomes were evaluated through hematological, hepatic, renal, and cardiovascular profiles, while adverse effects were also monitored. Results demonstrated that all four groups achieved statistically significant glycemic improvement (p < 0.001). The greatest HbA1c reduction was observed in Group D (–1.57%), followed by Group A (–1.34%), Group B (–1.11%), and Group C (– 1.00%). Participants maintained self-monitoring weekly diaries, and assessments was done on week 6 and 12. It was hypothesized that initial triple therapy would viii

achieve superior glycemic reduction and metabolic benefits compared with double- drug combinations. The triple combination (Group D: metformin + empagliflozin + sitagliptin) provided the most comprehensive benefits, improving anthropometric, glycemic, lipid, hepatic, and renal parameters. Among the dual regimens, Group A (metformin + glimepiride) achieved superior glycemic control with modest lipid improvements, while Group B (metformin + empagliflozin) was more effective for weight and triglyceride reduction with favorable effects on HDL and renal function. Group C (metformin + sitagliptin) showed the least efficacy but remained well tolerated. Overall, treatment effects followed: Group D > Group A ≈ Group B > Group C, confirming triple therapy as the most balanced strategy while dual therapies offer targeted benefits that can be individualized