Therapeutic Application of Empagliflozin, Sitagliptin, and Metformin for Advancing Overall Wellness in T2D: Evidence Review for Practitioners in 2025

Hyperglycemia in T2D plays a pivotal role in diabetic microvascular complications; however, reducing HbA1c offers only modest benefit in mitigating cardio-renal complications, which are the major causes of T2DM-related mortality and morbidity. As 70–80% of individuals with T2DM, particularly those newly diagnosed, lack overt cardiovascular or renal disease, a significant proportion harbor undetected CVD or renal abnormalities, making disease management challenging and necessitating therapeutic strategies beyond glycemic control alone. Emerging therapeutic approaches therefore emphasize early combination therapy to achieve glycemic targets while potentially conferring organ-protective benefits. This article examines triple therapy with empagliflozin, sitagliptin, and metformin, evaluating therapeutic success beyond HbA1c to include metabolic stability, weight management and cardio-renal protection. [1]

Clinical Rationale for Using Empagliflozin, Sitagliptin, and Metformin Combination for Advancing T2D Care

The complementary mechanisms of action, potential synergistic benefits, gluco-metabolic and cardio-renal advantages of empagliflozin, sitagliptin, and metformin triple therapy [2,3,4,5]are illustrated in Figure 1.

Figure 1: Complementary Mechanisms, Synergistic Benefits of Empagliflozin, Sitagliptin, and Metformin Combination in T2DM

Empagliflozin Sitagliptin Metformin in T2D- Gluco-Metabolic & Cardio Renal Benefit Evidence Review:

Empagliflozin: The EMPA-REG OUTCOME trial demonstrated empagliflozin's multifaceted cardiorenal benefits beyond glycemic control in 7,020 patients with T2DM and CVD over 3.1 years. Empagliflozin achieved 14% reduction in MACE (10.5% vs. 12.1%; HR 0.86; 95% CI 0.74–0.99), primarily driven by 38% reduction in CV death, alongside 32% reduction in all-cause mortality (5.7% vs. 8.3%; HR 0.68; 95% CI 0.57–0.82) and 35% reduction in HF hospitalizations (2.7% vs. 4.3%; HR 0.65; 95% CI 0.50–0.85). Renal protection included 39% reduction in incident or worsening nephropathy, 44% reduction in serum creatinine doubling, and 55% reduction in renal replacement therapy (RRT) initiation. Additional benefits comprised sustained weight loss of approximately 2.99 kg over 24 months, SBP reduction of 2.5 mmHg, and decreased serum uric acid levels, establishing comprehensive organ-protective effects independent of glycemic control. [2]

Sitagliptin: Real-world evidence demonstrates sitagliptin's multifaceted benefits beyond glycemic control in T2DM patients. A retrospective study of 102 patients showed maintained renal function with no significant differences in serum creatinine (0.86 mg/dL baseline vs. 0.87 mg/dL at 18 months; p=0.484) and eGFR (82.69 ml/min/1.73 m² baseline vs. 82.63 ml/min/1.73 m² at 18 months; p=0.276), indicating slowed CKD progression. [3] Regarding β-cell preservation, a 24-week study in elderly patients demonstrated significant HOMA-β improvement from baseline 48.8 to 87.4 (p=0.01). The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) confirmed CV safety with no increase in major adverse CV events or HF hospitalizations compared to placebo in patients with CVD. Additionally, pooled analysis of 25 trials (n=14,611) demonstrated superior CV safety versus sulfonylureas (incidence rate ratio 0.0; 95% CI 0.00-0.31). Sitagliptin maintained weight neutrality with minimal hypoglycemia risk (0.3-9.5%) across various combination therapies, establishing comprehensive metabolic and organ-protective benefits. [4]

Metformin: The United Kingdom Prospective Diabetes Study demonstrated metformin's robust CV risk reduction, with subsequent large-scale studies confirming these benefits. A prospective observational study (n=19691) in T2DM patients with atherosclerosis reported 24% lower all-cause mortality with metformin use. A retrospective cohort study (n=253,690) showed >40% lower frequency of death or hospitalization due to MI or stroke compared to sulfonylureas. Additionally, a 4-year retrospective study (n=14856) demonstrated 60% lower stroke risk with metformin, while a 13-year study (n=645710) reported 20% lower atrial fibrillation risk compared to non-metformin users. In the Swedish Diabetes Registry, metformin use in patients with CKD stage 3 was associated with 13% lower all-cause mortality, demonstrating safety and efficacy across diverse populations. [5]

Combination Therapy in T2DM: Latest 2026 Guidelines & Indian Clinicians’ Perception on Empagliflozin-Based Combinations

The recently released Standards of Care in Diabetes 2026 by the American Diabetes Association (ADA) strongly suggests considering combination therapy for initial treatment to shorten time to attainment of individualized glycemic goals (Level of Recommendation A). The guideline also suggests use of SGLT2 inhibitors in T2DM patients with CVD or high-risk ASCVD, across HF spectrum and CKD; metformin as the first-line treatment for T2DM for its beneficial effects on HbA1c, weight neutrality, low-risk of hypoglycemia and CV mortality, and is safe to use in patients with eGFR ≥30 mL/min/1.73 m²; and also favored DPP-4i for their weight neutrality and effective glucose-lowering efficacy. [6]

Consistent with ADA guidelines, a recently released mapping survey (n=129 HCPs) indicated that over 82% of Indian physicians suggested initiating empagliflozin as a first-line therapy alongside metformin in T2DM with ASCVD; over 82% of physicians suggested its use in both HFpEF and HFrEF patients, and 86% of the physicians also stated that empagliflozin delays CKD progression and 79% stated that it reduces proteinuria. [7]

Key Messages

• While glycemic control remains fundamental, cardio-renal complications, the major causes of T2DM-related mortality and morbidity, require therapeutic strategies beyond HbA1c reduction alone, particularly as many patients harbor undetected CVD or CKD risks in the real-world.
• Early combination therapy achieves glycemic targets while conferring organ-protective benefits through complementary mechanisms of action with synergistic effects on metabolic stability, weight management and cardio-renal protection.
• Empagliflozin achieved 38% CV death reduction and 39% CKD events reduction, sitagliptin maintained renal function with β-cell preservation and CV safety, while metformin demonstrated 24% lower all-cause mortality including 13% reduction in CKD stage 3 patients.
• ADA 2026 recommends combination therapy for initial treatment (Level A) when indicated; while 82% of Indian physicians support empagliflozin as first-line therapy in ASCVD, with 86% affirming to delay in CKD progression.

Abbreviations: ADA - American Diabetes Association, ASCVD - Atherosclerotic Cardiovascular Disease, CI - Confidence Interval, CKD - Chronic Kidney Disease, CV – Cardiovascular, CVD - Cardiovascular Disease, DPP-4i - Dipeptidyl Peptidase-4 inhibitor, eGFR - estimated Glomerular Filtration Rate, HbA1c - Glycated Hemoglobin, HCPs - Healthcare Professionals, HF - Heart Failure, HFpEF - Heart Failure with preserved Ejection Fraction, HFrEF - Heart Failure with reduced Ejection Fraction, HOMA-β - Homeostasis Model Assessment β-cell function, HR - Hazard Ratio, MACE - Major Adverse Cardiovascular Events, MI - Myocardial Infarction, NT-proBNP - N-Terminal Pro-B-Type Natriuretic Peptide, SBP - Systolic Blood Pressure, SGLT2 - Sodium-Glucose Cotransporter 2, T2D - Type 2 Diabetes, T2DM - Type 2 Diabetes Mellitus, TECOS - Trial Evaluating Cardiovascular Outcomes with Sitagliptin, UKPDS - United Kingdom Prospective Diabetes Study