Dapagliflozin and Metformin in T2D: Three Important Indian Evidences Revisited- Dr Semanti Chakraborty

India's Type 2 diabetes(T2D) prevalence is increasing, with over half of affected individuals remaining undiagnosed.

More than 70% of Indian T2D are uncontrolled. Indian patients with diabetes tend to lose glycemic control earlier than the global diabetic population (~1.5 vs. ~3 years), frequently presenting late with poor HbA1c and multiple comorbidities. This has accelerated the need for earlier use of dual fixed-dose combinations, including dapagliflozin–metformin, which has emerged as one of the important considerations in early T2DM management. This article discusses key studies highlighting evidence on dapagliflozin and metformin across real-world, prospective, and interventional settings in India.[1,2,3]

Evidence 1. Dapagliflozin Add-On to Metformin- Real-World Effectiveness on Gluco-Cardio-Metabolic Parameters: A multicentre EMR-based retrospective study by Sethi et al. evaluated dapagliflozin added to metformin across 478 Indian centres, screening 3,616 patients with inadequately controlled T2DM. Among the HbA1c ≥8% subgroup, baseline values of 9.06% fell to 7.50% over a 60–140-day follow-up. Body weight dropped from 83.2 kg to 80.0 kg, while BMI declined from 32.7 to 31.9. Systolic blood pressure improved from 132 mmHg to 127 mmHg and diastolic pressure from 81 mmHg to 79 mmHg. Patients with poorer baseline glycemic control achieved larger absolute reductions in blood glucose parameters, highlighting the value of early intensification. These findings reinforce the effectiveness of dapagliflozin–metformin combinations in real-world Indian settings. (Figure 1)[4]

Figure 1: Comparison of baseline and follow-up values after dapagliflozin-metformin in type 2 Diabetes

Evidence 2. Dapagliflozin & Metformin - Durability of Glycaemic Control in Real-World Indian Practice (FOREFRONT): The FOREFRONT study, a pan-India prospective observational trial across 46 centres, enrolled 1,978 patients with uncontrolled T2DM and followed 1,941 (98.1%) through six months. Among the overall cohort on dapagliflozin-based therapy, with 92.3% receiving concomitant metformin, HbA1c declined from 9.11% at baseline to 8.11% at three months and further to 7.62% at six months, with the steepest reductions seen in the most uncontrolled patients (baseline HbA1c >10% falling from 11.32% to 8.53%)[Figure 2]. Body weight tracked downward from 78.15 kg to 77.01 kg and then 76.16 kg, while systolic blood pressure improved from 130.33 mmHg to 126.60 mmHg. Safety was favourable, with only 58 adverse events (2.9%) and no deaths or discontinuations. This longitudinal real-world evidence indicates that dapagliflozin–metformin combinations deliver durable, progressive glycaemic improvement across diverse Indian clinical settings.[5]

Figure 2: HbA1c trajectory over 6 months after treatment with Dapagliflozin & Metformin in T2D

Evidence 3. Dapagliflozin and Metformin in North Indian T2DM- Impact on Ectopic Fat and Insulin Sensitivity: A prospective interventional study evaluated dapagliflozin 10 mg added to stable metformin (500–2000 mg/day) in thirty Indian patients with T2DM over 120 days. Fasting blood glucose was reduced from 180.50 mg/dL to 121.9 mg/dL (−58.60 mg/dL) and HbA1c from 8.98% to 6.88% (-2.10%). Body weight declined from 83.6 kg to 79.81 kg (-3.7 kg), with waist circumference narrowing from 104.13 cm to 100.1 cm (-4.03 cm). MRI-derived proton density fat fraction revealed liver fat decreasing from 15.2% to 10.1% (-5.10%) and pancreatic fat from 7.5% to 5.99% (-1.51%), with the liver fat reduction persisting independent of weight loss. HOMA-IR improved from 13.95 to 7.06 (-6.89), while postprandial insulin sensitivity increased. This evidence demonstrates that dapagliflozin–metformin therapy in Indian patients addresses not only glycaemia and adiposity but also ectopic fat deposition, a key driver of insulin resistance in this population. (Figure 2) [6]

Figure 3: Changes in skinfold thickness (mm) from baseline to 120 days of dapagliflozin 10 mg added to stable metformin in Asian Indian patients with T2DM. Statistically significant reductions were seen in biceps, subscapular, suprailiac, lateral thoracic, calf, peripheral, and central skinfold thickness (all P < .05).

These improvements reflect the complementary mechanisms of the combination, metformin suppressing hepatic glucose output and, more recently, demonstrating glucose-regulating action in the brain via the VMH–Rap1 pathway, while dapagliflozin drives glucosuric caloric loss and ectopic fat mobilisation, a synergy particularly relevant to the Indian phenotype characterised by insulin resistance at lower BMI thresholds.[7]

Key Takeaways:

✔ The evolving Indian T2DM phenotype, characterised by earlier glycaemic deterioration, insulin resistance, and metabolic dysfunction at lower BMI thresholds, increasingly supports earlier use of combination therapy tackling these underlying defects.

✔ Across Indian real-world and interventional evidence, dapagliflozin–metformin therapy demonstrated consistent benefits extending beyond HbA1c reduction, including improvements in body weight, blood pressure, ectopic fat burden, and insulin sensitivity, reflecting broader metabolic benefits relevant to routine clinical practice needs.

✔ Dapagliflozin–metformin combination’s favourable safety profile, durability of glycaemic control, and mechanistic complementarity support its role as a practical and clinically sustainable early combination strategy in newly diagnosed & uncontrolled Indian T2D patients.

Abbreviations: ASCVD — Atherosclerotic cardiovascular disease, BMI — Body mass index, BP — Blood pressure, DBP — Diastolic blood pressure, EMR — Electronic medical record, FBG — Fasting blood glucose, FDC — Fixed-dose combination, FF — Fat fraction, HbA1c — Glycated haemoglobin, HOMA-IR — Homeostatic model assessment of insulin resistance, MRI — Magnetic resonance imaging, NAFLD — Nonalcoholic fatty liver disease, PDFF — Proton density fat fraction, RWE — Real-world evidence, SBP — Systolic blood pressure, SGLT2i — Sodium-glucose cotransporter-2 inhibitor, T2DM — Type 2 diabetes mellitus, WC — Waist circumference