Type 2 diabetes mellitus (T2DM) is a major public health challenge in India, with an estimated 101 million individuals affected and 39.4 million living with undiagnosed diabetes. (1) Of all patients with T2DM in India, 69% have not achieved target HbA1c levels, highlighting the urgent need for effective glycemic management strategies. (2)
Due to the progressive nature of T2DM, achieving optimal glycemic control often necessitates combination therapy. A fixed-dose combination (FDC) of antidiabetic agents offers a rational and synergistic approach, leveraging complementary mechanisms of action to enhance efficacy. FDCs also provide advantages such as reduced pill burden and improved adherence, making them a valuable consideration in clinical practice. (3) Certain FDCs offer advantages by including agents with established cardiovascular benefits and a lower risk of hypoglycemia due to their beta-cell-independent action. One such combination includes sodium-glucose cotransporter-2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i). (4)
Pharmacological Profile of Dapagliflozin and Sitagliptin
Dapagliflozin, a selective SGLT2 inhibitor, lowers blood glucose insulin independently by blocking renal glucose reabsorption, offering cardiovascular and renal benefits (DECLARE–TIMI 58 trial). Sitagliptin, the first approved and most experienced DPP-4 inhibitor for T2DM in over 60 countries (5), enhances incretin-stimulated insulin secretion, suppresses glucagon, and improves fasting and postprandial glycemic control. (6)
Complementary Benefits of the Combination: The dapagliflozin-sitagliptin combination targets six of the eight components of the ominous octet, addressing key pathophysiological defects in T2DM. The dual action reduces HbA1c, improves β-cell function, supports weight reduction, lowers blood pressure, and enhances adherence optimizing therapeutic outcomes without increasing hypoglycemia risk, making it a valuable option for T2DM management. (4)
Clinical Efficacy and Safety of Dapagliflozin-Sitagliptin FDC
Dapagliflozin Sitagliptin FDC Provides Potent Glycemic Benefits: Real-World Indian Experience: A retrospective study evaluated the efficacy and safety of dapagliflozin-sitagliptin FDC in 358 T2DM patients in India. The mean age was 56.2 years, with 68.2% males and a baseline HbA1c of 8.9%. At 12 weeks, HbA1c significantly decreased to 7.2 (p < 0.0001), fasting glucose from 178.8 to 124.0 mg/dL (p < 0.0001), and postprandial glucose from 273.9 to 176.0 mg/dL (p < 0.0001). No serious adverse events were reported. These findings support dapagliflozin-sitagliptin FDC as an effective and well-tolerated option for T2DM management in India. (7)
Dapagliflozin Sitagliptin FDC Benefits Cardio-Metabolic Parameters in Indian T2DM Patients: A real-world, retrospective study across 111 Indian centers evaluated sitagliptin-dapagliflozin FDC in 328 T2DM patients (mean age: 51.14 years, 77.74% male). At 12 weeks, HbA1c dropped 1.05% (p < 0.0001), with FPG (-22.98 mg/dL) and PPBG (-40.94 mg/dL) reductions. In CAD patients, HbA1c decreased by 1.02%, FPG reduced by 54.52 mg/dL, and PPBG reduced by 88.73 mg/dL. SBP, DBP, and LDL-C decreased by 14.61 mm Hg, 7.80 mm Hg, and 18.14 mg/dL respectively thus highlighting cardiometabolic benefits. The FDC was well-tolerated, with only mild, transient adverse effects, supporting its efficacy in glycemic control and cardiovascular risk reduction. (8)
Dapagliflozin-Sitagliptin FDC – The Preferred SGLT2i-DPP4i Combination among Indian Clinicians
The DiSi Survey, a nationwide knowledge, attitude, and practice (KAP) study, provided critical insights into the prescribing patterns of DPP4i-SGLT2i FDCs in India. Conducted among 185 physicians across various states, the survey highlighted that among the available generic DPP4i-SGLT2i FDCs, dapagliflozin-sitagliptin was the most preferred combination (36.2%), surpassing linagliptin-dapagliflozin and vildagliptin-dapagliflozin.
Physicians reported frequent use of these FDCs in treatment-naïve patients with HbA1c >8%, those uncontrolled on metformin with HbA1c >8.5%, and as add-on therapy to insulin. Additionally, 85% of physicians noted a reduction in SGLT2i-associated genitourinary tract infections when SGLT2i and DPP4i were co-administered, reinforcing the clinical advantage of Dapagliflozin and Sitagliptin FDC in optimizing glycemic control and safety profiles for Indian patients with T2DM. (9)
Guideline Recommendations
The Indian Expert Consensus Group (2024) recommends the dapagliflozin-sitagliptin FDC for T2DM patients with HbA1c ≥7.5%, especially those intolerant to metformin, at high CV risk, or with HF, CKD, or ASCVD. It offers once-daily dosing, CV and renal safety, and lower genitourinary infection risk due to DPP4 enzyme inhibition. The consensus emphasized that dapagliflozin reduces the risk of GFR decline by at least 50%, end-stage kidney disease, and renal mortality, while sitagliptin may help prevent diabetic neuropathy, supporting their role in diabetes-related renal protection. (10)
The American Diabetes Association 2025 recommends combination therapy at T2DM onset to expedite glycemic control. SGLT2 inhibitors are included in treatment for high ASCVD-risk patients due to their proven cardiovascular benefits, reducing major adverse events and heart failure risk, independent of A1C levels; DPP-4 inhibitors for glucose-lowering effects without causing weight gain. (11)
The RSSDI Clinical Practice Recommendations emphasize glycemic efficacy, safety, weight impact, and hypoglycemia risk in treatment selection. If targets are unmet, adding an SGLT2i or DPP-4i is recommended for their cardiovascular benefits, weight neutrality/reduction, and lower hypoglycemia risk. (12)
Conclusion/ Key Takeaways
- T2DM remains a major public health challenge in India, with a significant proportion of patients failing to achieve glycemic targets.
- Dapagliflozin-Sitagliptin FDC provides a synergistic approach to glycemic control, addressing multiple defects in T2DM pathophysiology and cardiovascular benefits and safety.
- Clinical and real-world evidence demonstrates the efficacy of Dapagliflozin and Sitagliptin in lowering HbA1c, improving cardiometabolic parameters, and ensuring renal safety.
- Supported by major guidelines, dapagliflozin and sitagliptin could be a clinically valuable option among uncontrolled T2DM and high CV-risk T2DM patients; improving adherence, safety, and treatment outcomes.
- Dapagliflozin/Sitagliptin is the most preferred SGLT2i/DPP4i FDC combination among Indian clinicians.
References:
1. Rathod, Lokendra et al. “Genetic variants and type 2 diabetes in India: a systematic review and meta-analysis of associated polymorphisms in case-control studies.” The Lancet regional health. Southeast Asia vol. 32 100518. 10 Dec. 2024.
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11. American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025. Diabetes Care 1 January 2025; 48 (Supplement_1): S181–S206. https://doi.org/10.2337/dc25-S009
12. Chawla R, Madhu SV, Makkar BM, Ghosh S, Saboo B, Kalra S RSSDI-ESI Consensus Group. RSSDI-ESI clinical practice recommendations for the management of type 2 diabetes mellitus 2020. Indian J Endocr Metab. 2020;24:1–122. doi: 10.4103/ijem.IJEM_225_20.
