Dapagliflozin and Sitagliptin FDC in T2D with Heart Failure: 2025 Indian Practice Review

Among India's 89.8 million people with T2D [1], heart failure incidence reaches approximately 50%, with 33% higher hospitalization risk versus non-diabetics; with undiagnosed HF further adding to this brunt. [2] Poor glycemic control incrementally increases HF risk with each 1% HbA1c elevation. [3] The clinical challenge lies in achieving glycemic targets while avoiding agents that may worsen cardiac function. A consideration shaping pertinent clinical decisions today is the need for therapies that also offer cardio protection, such as the SGLT2i (dapagliflozin) & DPP-4i (sitagliptin) fixed-dose combination (FDC).

Why SGLT2i and DPP4i Combinations Seem Clinically Appropriate Fit in T2D-HF Overlap?

SGLT2i in HF- Outcomes Redefined: SGLT2 inhibitors as a class have consistently demonstrated robust benefits in heart failure. Among SGLT2i, Dapagliflozin addresses the HF and T2D nexus through SGLT2 inhibition, reducing glucose reabsorption while inducing osmotic diuresis that alleviates volume overload, enhancing myocardial energy metabolism via fatty acid oxidation in insulin-resistant cardiomyocytes, and reducing myocardial fibrosis. In T2D patients with HFrEF (n=51), dapagliflozin decreased HbA1c by 2.54% (from 8.62% to 6.08%), improved HOMA-IR by 1.49 (4.47 to 2.98), improved LVEF by 39.42% (from 33.82% to 73.24%), decreased LVESD by 13.24mm (from 44.71mm to 31.47mm), reduced cTnI by 43.5% (from 0.62 to 0.35 μg/L), CK-MB by 32.2% (from 28.35 to 19.24 U/L), and NT-proBNP by 21.1% (from 673.53 to 531.76 ng/L) all P<0.001, validating cardioprotective benefits alongside glycemic control. [4]

DPP4i’s Cardioprotection & Cardio-Safety: DPP-4 inhibitors show differential effects on HF outcomes, sitagliptin has demonstrated cardiovascular neutrality in clinical trials. Sitagliptin enhances incretin-mediated insulin secretion while remaining weight-neutral with favorable effects on lipid profiles and blood pressure. Beyond glycemic control, it exhibits cardioprotective properties by reducing cardiac apoptosis, hypertrophy, and fibrosis. Real-world evidence from 7,620 T2D patients with HF demonstrated sitagliptin users (n=887) had no increased risk for all-cause hospitalization or death versus non-users (7.1% vs. 9.2%, aOR: 0.84, 95% CI: 0.69–1.03), highlighting sitagliptin's value in mitigating HF risks in T2D. [5]

Dapagliflozin & Sitagliptin FDC-Synergistic Benefits in T2D with HF: Latest Indian Experience

A recently published 2025 Indian multicentric observational study (n=168 T2DM with HF) demonstrated real-world efficacy of Dapagliflozin & Sitagliptin FDC, showing significant improvements after 3 months in Indian T2D patients with HF. HbA1c decreased by 1.5% (from 8.9% to 7.4%), NT-proBNP reduced from 306.7 to 184 pg/ml, ejection fraction improved by 6.7% (from 43.1% to 45.99%), and eGFR increased by 17.2% (from 63.08 to 73.96 ml/min/1.73m²), all P<0.0001. Additionally, SBP declined from 151.6 to 133.6 mmHg, and DBP declined from 98.8 to 87.4 mmHg, respectively, demonstrating comprehensive cardiometabolic benefits with good tolerability in this high-risk population. [6]

Another Indian retrospective electronic medical records-based study (n=3,112 T2DM patients) evaluated Dapagliflozin & Sitagliptin FDC real-world effectiveness. In patients with baseline HbA1c ≥8% (n=838), HbA1c reduced from 9.29% to 7.98% at 3 months (p<0.001), which sustained at 6 months from 9.19% to 7.86% (n=146, p<0.001). FBG decreased from 167.9 to 133.7 mg/dL, PPBG decreased from 249.4 to 200.1 mg/dL (both p<0.0001). Weight decreased from 76.31 to 75.65 kg in patients with BMI >25 kg/m² (p<0.0001). Benefits were consistent across age, gender, and CV comorbidities. [7]

Emerging 2025 Cardiology Conferences’ Evidence: DAPA ACT HF-TIMI 68 and DAPAHEART Trial Updates

Dapagliflozin in Hospitalized Heart Failure: The DAPA ACT HF-TIMI 68 trial, presented at ESC 2025 Congress, Madrid (n=2,401 hospitalized HF patients, 71.5% LVEF ≤40%), demonstrated that dapagliflozin reduced all-cause mortality by 34% (HR 0.66), CV death by 22%, and HF rehospitalization by 15%. Meta-analysis of three in-hospital SGLT2i trials (n=3,527) confirmed reductions in CV death/worsening HF by 29% (HR 0.71, p=0.012) and all-cause mortality by 43% (HR 0.57, p=0.001). [8]

Dapagliflozin Long-Term Cardiac Benefits: Along similar lines, the DAPAHEART 4-year follow-up study, presented at EASD 2025 (in T2D with stable CAD), showed dapagliflozin improved coronary flow reserve by 34.4% (2.15 to 2.85, p=0.001) and reduced epicardial adipose tissue thickness by 29% (p=0.03), highlighting sustained cardiovascular benefits beyond acute management. [9]

Applying Dapagliflozin & Sitagliptin FDC in T2D Patients with HF: Guidelines & Consensus Review

Multiple international and Indian guidelines recognize the clinical value of considering dapagliflozin & sitagliptin in managing T2D patients with cardiovascular comorbidities:

Key Messages

• Among India's 89.8 million people with T2D, approximately 50% develop heart failure with 33% higher hospitalization risk, requiring therapies that control glucose with cardio-safety and cardio-protective effects.
• Dapagliflozin improves LVEF by 39.42%, reduces NT-proBNP by 21.1%, and decreases myocardial injury markers through SGLT2 inhibition that alleviates volume overload and enhances myocardial metabolism; while sitagliptin allows for cardiovascular-neutral, weight-neutral glycemic control.
• Dapagliflozin & sitagliptin FDC in Indian T2D-HF patients reduced HbA1c by 1.5%, improved ejection fraction by 6.7%, decreased NT-proBNP, and increased eGFR by 17.2%.
• Global and Indian guidelines (ADA, RSSDI, HFAI, iCARDIO Alliance) recommend SGLT2 inhibitors across the HF spectrum in T2D patients; with Indian expert consensus suggesting early consideration of dapagliflozin & sitagliptin FDC initiation for comprehensive cardio protection in T2D.

Abbreviations: ADA: American Diabetes Association, aOR: Adjusted Odds Ratio, ASCVD: Atherosclerotic Cardiovascular Disease, BMI: Body Mass Index, BP: Blood Pressure, CAD: Coronary Artery Disease, CI: Confidence Interval, CK-MB: Creatine Kinase-MB, CKD: Chronic Kidney Disease, cTnI: Cardiac Troponin I, CV: Cardiovascular, CVD: Cardiovascular Disease, DBP: Diastolic Blood Pressure, DKD: Diabetic Kidney Disease, DPP-4: Dipeptidyl Peptidase-4, eGFR: Estimated Glomerular Filtration Rate, FDC: Fixed-Dose Combination, HbA1c: Glycated Hemoglobin, HF: Heart Failure, HFAI: Heart Failure Association of India, HFmrEF: Heart Failure with Mildly Reduced Ejection Fraction, HFpEF: Heart Failure with Preserved Ejection Fraction, HFrEF: Heart Failure with Reduced Ejection Fraction, HOMA-IR: Homeostatic Model Assessment for Insulin Resistance, HOMA-IS: Homeostatic Model Assessment for Insulin Sensitivity, HR: Hazard Ratio, LDL-C: Low-Density Lipoprotein Cholesterol, LVEDD: Left Ventricular End-Diastolic Diameter, LVEF: Left Ventricular Ejection Fraction, LVESD: Left Ventricular End-Systolic Diameter, MACE: Major Adverse Cardiovascular Events, NT-proBNP: N-Terminal Pro-B-Type Natriuretic Peptide, RSSDI: Research Society for the Study of Diabetes in India, SBP: Systolic Blood Pressure, SGLT2i: Sodium-Glucose Co-Transporter-2 Inhibitor, T2D: Type 2 Diabetes