Uncontrolled T2D in India: Valuable Consideration for Dapagliflozin Sitagliptin Combination

India accounts for 1 in 7 adults living with diabetes globally. An estimated 89.8 million adults aged 20-79 years in India are living with diabetes, with 43% undiagnosed, according to the IDF Diabetes Atlas 2025 published in April 2025. (1) Only 20.8% achieve glycaemic control, leaving nearly 80% with uncontrolled diabetes. (2) India also ranks third in diabetes-related deaths [0.33 million per year] (1) This highlights the critical need for effective T2DM management strategies, including early screening for dysglycemia, cardio-metabolic risk factors, and targeted interventions to achieve stringent glycemic control and mitigate and manage complications effectively.

Clinically Relevant Treatment Option: Dapagliflozin + Sitagliptin

There is a paradigm shift in T2DM management from a glucose-centric approach to a broader focus on cardio-renal protection, additionally emphasizing early combination therapy to delay β-cell failure.(3) SGLT2 inhibitors, known for their β-cell independent mechanisms, have demonstrated significant cardiovascular and renal benefits, especially in patients with high cardiovascular and CKD risk. When combined with DPP4 inhibitors, the complementary actions enhance both glycemic control and cardio-renal outcomes, effectively reducing body weight and blood pressure, without increasing hypoglycemia risk and protecting the beta-cells, making this combination relevant for Indian T2DM, where poor cardio-metabolic risk factor control and treatment adherence are substantial concerns.(4,5)

Dapagliflozin & Sitagliptin: Clinical Relevance in Uncontrolled T2D

Weight Lowering: The dapagliflozin-sitagliptin combination effectively reduced body weight by 2.17 kg, decreasing from 74.92 ± 8.57 kg to 72.76 ± 7.89 kg at week 12 (p<0.0001).(5)

BP Lowering: The dapagliflozin-sitagliptin combination reduced SBP by 14.61 mmHg (from 147.00 ± 16.03 mmHg to 132.40 ± 10.14 mmHg) and DBP by 7.80 mmHg (from 90.31 ± 8.34 mmHg to 82.52 ± 8.07 mmHg) over 12 weeks [p<0.0001]. (5)

CV Protection: Dapagliflozin reduced the relative risk of major adverse cardiovascular events (MACE)—including cardiovascular death, myocardial infarction, or ischemic stroke—by 16%, and the absolute risk by 2.6% [15.2% vs. 17.8%; HR 0.84; 95% CI, 0.72–0.99].(6) Sitagliptin reduced the rate of total cardiovascular events by approximately 34% (3.41 vs. 5.17 per 1000 person-months; p < 0.001), with a 41% lower risk of coronary heart disease (HR 0.59), 25% lower risk of ischemic stroke (HR 0.75), and 44% lower risk of all-cause mortality (HR 0.56) after adjusting for covariates. (7)

CV Safety: Dapagliflozin significantly reduced hospitalization due to heart failure by 24% (RR = 0.76; 95% CI: 0.70–0.84; p<0.00001), and also improved their composite outcomes. (8) Sitagliptin use was not associated with increased hospitalization for heart failure during a 1.02-year follow-up (p = 0.795).In high-risk patients with recent ischemic stroke and CKD, sitagliptin did not elevate HF hospitalization risk and may offer added cardioprotection when combined with dapagliflozin. (3)

CKD Benefits: Dapagliflozin significantly slowed kidney disease progression, reducing eGFR decline by 1.81 mL/min/1.73 m² (p < 0.0001) and slowing the annual eGFR loss by 36%. It also lowered albuminuria by an average of 44.3 mg/g within 6 months (p < 0.0001), and reduced the risk of ≥50% eGFR decline, end-stage kidney disease, or death by 44% [HR = 0.56; p < 0.001]. (2)

In a prospective observational study on T2D outpatients, sitagliptin increased eGFR at 3 and 12 months in patients with baseline eGFR between 30–60 mL/min/1.73 m². Separately, in patients with baseline UACR ≥30 mg/g, UACR significantly declined by 3 months, and sitagliptin use was also associated with a reduction in HbA1c over the treatment period. (11)

Emerging Evidence- Dapagliflozin in Nerve Regeneration: A 2025 randomized controlled study was conducted at PGIMER, Chandigarh, India, involving 40 T2DM patients with diabetic peripheral neuropathy, assessed dapagliflozin's impact on nerve regeneration. After 6 months, intraepidermal nerve fibre density significantly increased in the dapagliflozin group (p = 0.01), along with corneal nerve fibre density (p = 0.002) and nerve branch density (p< 0.001). Oxidative stress markers improved, with glutathione peroxidase increasing (p=0.019) and malondialdehyde decreasing [p< 0.001]. (12)

Dapagliflozin Sitagliptin: Real-World Indian Evidence:

Dapagliflozin Sitagliptin Achieves Glycemic Control Across Age-Groups: A retrospective study, including 3,112 Indian T2D adult patients assessed the age-stratified efficacy of dapagliflozin + sitagliptin FDC. Age groups included patients aged 18–40, 41–60, and >60 years, as available. The primary endpoint analysis included 838 patients with baseline HbA1c ≥8%. HbA1c significantly reduced from 9.29% to 7.98% at 3 months (change from baseline −1.31%, p < 0.001). Across age groups, HbA1c reduction ranged from −1.17% to −1.41% (p < 0.001). FBG decreased by 30.64–38.4 mg/dL and PPBG by 42.89–52.76 mg/dL (p < 0.001) across all groups. These findings demonstrated the real-world effectiveness of dapagliflozin + sitagliptin FDC in improving glycemic control irrespective of age. (13)

Dapagliflozin Sitglitptin Leads to Significant Weight Reduction in T2D: In another Indian study involving 358 Indian patients with T2DM, 93.0% (n=333) experienced weight reduction while on the FDC of dapagliflozin and sitagliptin. Of these, 47.5% reported a weight loss of up to 2 kg, 37.4% lost between 2–4 kg, and 8.1% experienced a weight loss exceeding 4 kg. (14)

Adherence Benefits of Dapagliflozin + Sitagliptin FDC: The FDC of dapagliflozin and sitagliptin simplify the treatment regimen, reducing the pill burden and potentially enhancing patient adherence. An Indian real-world study noted that the use of FDC was associated with consistent glycemic control across all follow-up visits, suggesting improved compliance with the simplified dosing schedule. (14)

Dapagliflozin and Sitagliptin Combination- When to Use It? Expert Consensus Recommendations

The 2024 Indian expert consensus recommends the FDC of Dapagliflozin and Sitagliptin for T2DM patients with HbA1c ≥7.5%, cardiovascular risk, heart failure, ASCVD, CKD, or hypoglycemia risk. The combination improves fasting and postprandial glycemia, mitigates renal decline, and reduces genitourinary infections, with Sitagliptin providing weight neutrality and Dapagliflozin promoting weight reduction. The 24-hour coverage of dapagliflozin supports glycemic stability and comprehensive cardio-renal-metabolic protection. (3)

Take Home Messages

• Guidelines from RSSDI, ADA, AACE, and KDIGO endorse SGLT2i and DPP4i for cardio-renal-metabolic protection in T2DM, with specific recommendations for patients with HF, CKD, and ASCVD.(3)
• The FDC of dapagliflozin and sitagliptin effectively reduces HbA1c, body weight, and blood pressure in T2DM patients, with significant benefits in those with cardiovascular and renal comorbidities.
• Real-world evidence from Indian studies demonstrates consistent HbA1c reduction and weight loss with the FDC across age groups and BMI categories.
• The FDC simplifies treatment regimens, reducing pill burden and enhancing patient adherence while maintaining consistent glycemic control without increasing hypoglycemia risk.
• The 2024 published DiSi Study indicated that among SGLT2i/DPP4i FDCs, dapagliflozin–sitagliptin is the preferred FDC of choice among Indian clinicians.

References:

1. International Diabetes Federation. IDF Diabetes Atlas: 11th Edition, 2025. Brussels, Belgium: International Diabetes Federation, Apr. 2025. www.diabetesatlas.org (accessed May 2025).

2. Das, Ashok K et al. “Two-year trends from the LANDMARC study: A 3-year, pan-India, prospective, longitudinal study on the management and real-world outcome in patients with type 2 diabetes mellitus.” Endocrinology, diabetes & metabolism vol. 6,2 (2023): e404. doi:10.1002/edm2.404

3. Ray, Soumitra1; Ezhilan, J2; Karnik, Rajiv3; Prasad, Ashish4; Dhar, Rajashree4. Expert Opinion on Fixed Dose Combination of Dapagliflozin Plus Sitagliptin for Unmet Cardiovascular Benefits in Type 2 Diabetes Mellitus. Journal of Diabetology 15(2):p 131-141, April-June 2024. | DOI: 10.4103/jod.jod_19_24

4. Chadha, Manoj et al. “Expert Opinion: Optimum Clinical Approach to Combination-Use of SGLT2i + DPP4i in the Indian Diabetes Setting.” Diabetes therapy : research, treatment and education of diabetes and related disorders vol. 13,5 (2022): 1097-1114. doi:10.1007/s13300-022-01219-x

5. Chawla, Manoj et al. “Retrospective Observational Study on Assessing Sitagliptin and Dapagliflozin as a Fixed-Dose Combination in the Indian Population With Type 2 Diabetes Mellitus: The SIDAXA Study.” Cureus vol. 16,5 e60815. 21 May. 2024, doi:10.7759/cureus.60815

6. Furtado, Remo H M et al. “Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction.” Circulation vol. 139,22 (2019): 2516-2527. doi:10.1161/CIRCULATIONAHA.119.039996

7. Yang, Tsung-Yuan et al. “Association of Sitagliptin with cardiovascular outcome in diabetic patients: a nationwide cohort study.” Acta diabetologica vol. 53,3 (2016): 461-8. doi:10.1007/s00592-015-0817-x

8. Ali, Ahmed E et al. “Effect of Dapagliflozin in Patients with Heart Failure: A Systematic Review and Meta-Analysis.” Global heart vol. 18,1 45. 22 Aug. 2023, doi:10.5334/gh.1258

9. Chen, Dong-Yi et al. “Sitagliptin and cardiovascular outcomes in diabetic patients with chronic kidney disease and acute myocardial infarction: A nationwide cohort study.” International journal of cardiology vol. 181 (2015): 200-6. doi:10.1016/j.ijcard.2014.12.029

10. Fadini, Gian Paolo et al. “Long-term benefits of dapagliflozin on renal outcomes of type 2 diabetes under routine care: a comparative effectiveness study on propensity score matched cohorts at low renal risk.” The Lancet regional health. Europe vol. 38 100847. 1 Feb. 2024, doi:10.1016/j.lanepe.2024.100847

11. Shah, Parag et al. “Revisiting the Cardiorenal Safety of Sitagliptin in Type 2 Diabetes Mellitus: A Literature Review.” The Journal of the Association of Physicians of India vol. 73,4 (2025): e19-e25. doi:10.59556/japi.73.0924

12. Adhikari, Umanath, et al. "Dapagliflozin for Small Nerve Fibre Regeneration in Diabetic Peripheral Neuropathy: A Randomised Controlled Study (DINE)." Journal of the Peripheral Nervous System, vol. 30, no. 1, 2025, pp. e70011, https://doi.org/10.1111/jns.70011. Accessed 16 May 2025.

13. Bharathi, Prakadeesh, et al. "Study on Effectiveness in Real-world with Dapagliflozin and Sitagliptin Fixed Dose Combination in Patients with Type 2 Diabetes Mellitus in India: Retrospective Study from Electronic Medical Records." Endocrine Practice, vol. 30, no. 5, suppl., May 2024, pp. S23-S24.

14. Bhattacharjee, Rana et al. “The Real DAPSI: A Real-World Retrospective Study on Assessing the Efficacy and Safety of a Fixed-Dose Combination of Dapagliflozin and Sitagliptin in the Indian Population.” Cureus vol. 15,10 e46767. 9 Oct. 2023, doi:10.7759/cureus.46767

15. Saboo B, Prajapati C, Muralidharan P, et al. DiSi Survey: Use of Generic DPP4i–SGLT2i Fixed-dose Combinations in Indian Clinical Practice. J Assoc Physicians India 2024;72(12):22–24.

Abbreviations: T2DM: Type 2 Diabetes Mellitus, SGLT2i: Sodium-Glucose Cotransporter-2 Inhibitors, DPP4i: Dipeptidyl Peptidase-4 Inhibitors, FDC: Fixed Dose Combination, CVD: Cardiovascular Disease, ASCVD: Atherosclerotic Cardiovascular Disease, HF: Heart Failure, eGFR: Estimated Glomerular Filtration Rate, ESKD: End-Stage Kidney Disease, MACE: Major Adverse Cardiovascular Events, PPBG: Postprandial Blood Glucose, FBG: Fasting Blood Glucose, CFB: Change From Baseline, KDIGO: Kidney Disease Improving Global Outcomes, RSSDI: Research Society for the Study of Diabetes in India, AACE: American Association of Clinical Endocrinology, ADA: American Diabetes Association, PGIMER: Postgraduate Institute of Medical Education and Research, EMR: Electronic Medical Record.