India has an estimated 90 million people living with T2D [1] amid rising obesity and doubled management costs. Uncontrolled T2DM and early-onset complications—including neuropathy, chronic kidney disease (CKD), cardiovascular disease, dyslipidaemia, and hypertension remains challenging. [2] This highlights the need to move beyond glucose-centric strategies toward therapies addressing both glycaemic control and organ protection, often requiring combination therapy to achieve early and effective management.[3] This article discusses how the empagliflozin, sitagliptin, and metformin combination addresses these multifaceted advancing needs in Indian T2D care.
Complementary Roles of Empagliflozin, Sitagliptin & Metformin in T2D Care
Empagliflozin, Sitagliptin, and metformin have complementary mechanisms of action that target multiple pathophysiologic defects in T2DM.SGLT2i (Empagliflozin) blocks renal glucose reabsorption, increases urinary glucose excretion, and provides cardiovascular and renal protection.DPP-4i (Sitagliptin) prevents incretin hormone breakdown, enhances insulin secretion, and suppresses glucagon without hypoglycemia risk. Metformin reduces hepatic glucose production, improves insulin sensitivity, and decreases intestinal glucose absorption. [4] (Figure 1)
Figure 1: Organ-Specific Pharmacological Effects of Empagliflozin, Sitagliptin, and Metformin
For HbA1c ≥1.5% above target, combination therapy with Empagliflozin, Sitagliptin, and/or Metformin may be initiated based on patient-specific needs.
Clinical Evidence Supporting Empagliflozin + Sitagliptin + Metformin in Uncontrolled T2D
Effect on Glucose Control in Indian T2D: A 24-week, prospective, randomized, open-label, parallel-group trial (n=150) conducted at a tertiary care center evaluated the efficacy and safety of adding empagliflozin or sitagliptin to metformin in Indian T2DM patients with inadequate glycemic control. Both combinations reduced HbA1c effectively: Metformin+Sitagliptin achieved reduction from 8.5 ± 0.6% to 7.2% (change: -1.3 ± 0.5%), while Metformin+Empagliflozin achieved reduction from 8.6 ± 0.7% to 7.1% (change: -1.5 ± 0.4%; p<0.001 for both vs. monotherapy; p=0.041 between combinations). Metformin+Empagliflozin demonstrated substantial weight loss from 90.1 ± 12.8 kg to 87.3 kg (change: -2.8 ± 1.5 kg), while Metformin+Sitagliptin remained weight-neutral from 89.2 ± 13.0 kg to 88.8 kg (change: -0.4 ± 1.2 kg; p<0.001). FBG decreased significantly with Metformin+Sitagliptin from 170.1 ± 23.9 to 131.9 mg/dL (change: -38.2 ± 18.5 mg/dL) and Metformin+Empagliflozin from 173.0 ± 26.2 to 131.5 mg/dL (change: -41.5 ± 19.0 mg/dL; p<0.001). The synergistic benefits provide a rationale for combination therapy, including empagliflozin, sitagliptin, and metformin, addressing both glycemic control and organ protection. [5]
Effect of Glucose Control & Kidney Markers in T2D: A 3-month cross-sectional observational study (n=155) evaluated the efficacy and safety of adding empagliflozin or sitagliptin to metformin in uncontrolled T2DM patients. Sitagliptin add-on Metformin achieved HbA1c reduction from 9.5 ± 2.0% to 7.4 ± 1.5%, while Empagliflozin add-on Metformin achieved reduction from 9.4 ± 1.5% to 7.6 ± 1.2% (both groups p<0.001). Empagliflozin add-on Metformin reduced serum creatinine from 1.08 ± 0.24 to 1.03 ± 0.2 mg/dL (p=0.01) and improved eGFR from 75.4 ± 23.7 to 78.1 ± 23.1 mL/min/1.73m² (p=0.006). Sitagliptin add-on Metformin showed changes in serum creatinine from 0.96 ± 0.13 to 0.94 ± 0.12 mg/dL (p=0.06) and eGFR from 79.8 ± 16.1 to 81.9 ± 19.3 mL/min/1.73m² (p=0.06). The findings support combination therapy benefits on glycemic control and renal protection, with empagliflozin demonstrating superior renal outcomes. [6]
Implementation in Routine Practice: Navigating Guidelines and Indian Expert Consensus
A recently published Indian expert consensus (December 2025) highlights that 95% experts favored empagliflozin as a foundational therapy for T2DM patients with ASCVD, while 93% supported its use for HF prevention across all ejection fractions, and 93% endorsed its role in slowing the progression of diabetic kidney disease and suggested considering empagliflozin-based combination therapy for better glycemic control, weight management and systolic blood pressure. [7]
The recently released ADA 2026 guideline strongly recommends considering combination therapy for initial treatment to shorten the time to attainment of individualized glycemic goals (Level of Recommendation A). While metformin remains the cornerstone of first-line T2DM management, the guideline advocates for considering SGLT2 inhibitors in patients requiring cardiovascular protection and CKD risk reduction in non-dialysis patients, while DPP-4 inhibitors in those prioritizing low hypoglycemia risk and weight neutrality. [8]
Key Takeaways
- Uncontrolled T2DM with early cardio-renal complications in India necessitates therapies beyond glucose-centric control.
- Empagliflozin, sitagliptin, and metformin provide complementary mechanisms targeting glycemia, weight, blood pressure, and organ protection.
- Clinical studies demonstrate clinically meaningful HbA1c reductions with metformin-based combinations of empagliflozin or sitagliptin, along with favorable effects on body weight and renal parameters, supporting the potential role of empagliflozin, sitagliptin, and metformin in combination therapy.
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