Uncontrolled T2DM in India and Application of Trusted Molecules Empagliflozin, Sitagliptin, and Metformin Coming Together

Considering Early Combination Triple Therapy in Uncontrolled T2D: Rationale

Given the progressive nature of β-cell dysfunction and insulin resistance in T2DM, initiating early combination therapy can help overcome the glycemic inertia commonly seen with stepwise treatment approaches. Landmark trials have demonstrated the long-term benefits of starting therapy early with multiple agents, indicating improved durability of glycemic control compared to metformin monotherapy. This article will shed light on the rationale behind early combination strategies, such as the combination of Metformin, Sitagliptin, and Empagliflozin. (4)

Each agent offers a distinct mechanism targeting different pathophysiologic defects in T2DM

• Metformin: Metformin, beyond its insulin-sensitizing effects, exerts direct protective actions on pancreatic β cells by preserving their function and viability, and on the heart by reducing oxidative stress-induced cardiomyocyte apoptosis and fibrosis. (5)
• Sitagliptin: Sitagliptin improves glycemic control and preserves β-cell function by enhancing the actions of GLP-1 and GIP, including GIP-mediated β-cell support, while being weight-neutral and CV safe. (6)
• Empagliflozin: Empagliflozin promotes glucosuria by selectively inhibiting SGLT2 in the renal proximal tubule, leading to sustained glucose lowering, weight loss through urinary caloric loss, and reduction in BP owing to its mild diuretic effect. Through its beta-cell independent mechanism, empagliflozin preserves pancreatic beta-cell function by reducing burden and glucotoxicity, and is also associated with lower rates of CV-related hospitalization and mortality. (7)

Clinical Snapshot: Triple Combination Evidence

Two-year prospective study of 170 drug-naïve patients with newly diagnosed T2DM (baseline HbA1c 11.0%±1.8%), initial triple therapy with metformin 1,000 mg/day, sitagliptin 100 mg/day, and empagliflozin 10 mg/day led to a significant HbA1c reduction to 7.0%±1.7% (P<0.05). HbA1c <7% was achieved by 72.5% at 12 months and 61.7% at 24 months. Insulin sensitivity (HOMA-IR: 5.1 to 2.6) and β-cell function (HOMA-β: 25.3 to 52.5) improved significantly (P<0.05). Triglycerides (↓195.8 to 153.4 mg/dL), LDL-C (↓119.9 to 104.9 mg/dL), and albuminuria (↓107.4 to 77.3 mg/g) decreased significantly (P<0.05), while muscle mass rose (+0.97%) and fat mass declined (−1.08%). No severe hypoglycemia or serious adverse events were reported. (8)

Empagliflozin, Sitagliptin, Metformin - Supportive Evidence

Empagliflozin has demonstrated consistent cardiorenal benefits across key trials. In EMPA-KIDNEY (n=6609), it reduced kidney disease progression or CV death by 28% (HR: 0.72; 95% CI: 0.64–0.82; p<0.001), with benefits across eGFR and albuminuria levels. (9) In EMPEROR-Preserved (n=5988), it lowered CV death or HF hospitalization by 21%, first HF hospitalization by 27%, and slowed eGFR decline across the LVEF spectrum. (10) EMPA-REG OUTCOME (n=7020) showed reductions of 38% in CV death, 32% in all-cause mortality, 35% in HF hospitalization, and 14% in 3-point MACE. (11) EMPEROR-Reduced (n=3730) confirmed a 25% reduction in CV death or HF hospitalization and slower eGFR decline (1.73 mL/min/1.73 m²/year), supporting use in high-risk T2DM. (12)

Sitagliptin, evaluated in the JAMP study (n=651) in adults with inadequately controlled T2DM despite lifestyle or oral therapy, significantly reduced HbA1c by −0.73% (95% CI: −0.80 to −0.67) at 3 months. Fasting plasma glucose decreased by 26.3 mg/dL, and 53.1% of patients achieved HbA1c <7.0% within 3 months. The effect was consistent across subgroups, and sitagliptin was well tolerated with a low hypoglycemia rate of 0.42%. (13)

Metformin, as shown in the UKPDS (n=753), demonstrated durable benefits in overweight T2DM patients over 10.7 years, reducing diabetes-related endpoints (including CV, renal, and retinopathy complications) by 32%, diabetes-related deaths by 42%, and all-cause mortality by 36%. Long-term follow-up over 24 years confirmed sustained risk reductions, including 33% for myocardial infarction, 12% for stroke, 45% for peripheral artery disease, and 27% for all-cause mortality, underscoring its legacy effect. (14)

Considering Combination Therapy in T2D - Guidelines Review

In a more recent regulatory development (May 2025), the recent CDSCO SEC committee report flagged the Glimiperide + Metformin + Sitagliptin triple combination for lacking added safety benefit and clinical justification.

In such context, the potential relevance of the Empagliflozin + Sitagliptin + Metformin combination seems possibly an appropriate consideration among other available newer triple FDC options. (19)

Key Takeaway

• Uncontrolled T2D remains a major challenge in India, with poor HbA1c, blood pressure, and cholesterol level (ABC) goal achievement and a high burden of complications requiring timely and multifactorial intervention.
• Early triple combination therapy with metformin, sitagliptin, and empagliflozin offers complementary mechanisms that target insulin resistance, robust blood glucose control, weight lowering, BP lowering, and cardiorenal protection, while preserving β-cell function.
• Clinical evidence shows significant HbA1c reduction, improved β-cell function, cardio-metabolic benefits and more patients achieving blood glucose control with this triple regimen among newly diagnosed patients.

Abbreviations: T2DM – Type 2 Diabetes Mellitus, HbA1c – Glycated Hemoglobin, BP – Blood Pressure, LDL – Low-Density Lipoprotein, VERIFY – Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes, FDC – Fixed-Dose Combination, β-cell – Beta Cell, GLP-1 – Glucagon-Like Peptide-1, GIP – Glucose-Dependent Insulinotropic Polypeptide, DPP-4i – Dipeptidyl Peptidase-4 Inhibitor, SGLT2i – Sodium-Glucose Cotransporter-2 Inhibitor, CV – Cardiovascular, HOMA-IR – Homeostatic Model Assessment of Insulin Resistance, HOMA-β – Homeostatic Model Assessment of Beta Cell Function, LDL-C – Low-Density Lipoprotein Cholesterol, RCT – Randomized Controlled Trial, FPG – Fasting Plasma Glucose, MACE – Major Adverse Cardiovascular Events, eGFR – Estimated Glomerular Filtration Rate, STREAM – Sitagliptin Trial for Elderly Asian Moderate Diabetics, UKPDS – United Kingdom Prospective Diabetes Study, ASCVD – Atherosclerotic Cardiovascular Disease, CKD – Chronic Kidney Disease, HF – Heart Failure, MASLD – Metabolic Dysfunction-Associated Steatotic Liver Disease, AGIs – Alpha-Glucosidase Inhibitors, TZDs – Thiazolidinediones, SU – Sulfonylurea, GLP-1/GIP RAs – GLP-1 and GIP Receptor Agonists, ADA – American Diabetes Association, AACE – American Association of Clinical Endocrinology, RSSDI – Research Society for the Study of Diabetes in India, IDF – International Diabetes Federation, CDSCO – Central Drugs Standard Control Organization, SEC – Subject Expert Committee