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Randomized Controlled Trial
. 2025 Feb;42(2):801-812.
doi: 10.1007/s12325-024-03037-y. Epub 2024 Dec 5.

Efficacy of Dapagliflozin + Sitagliptin + Metformin Versus Sitagliptin + Metformin in T2DM Inadequately Controlled on Metformin Monotherapy: A Multicentric Randomized Trial

Awadhesh Kumar Singh  1 , Ashok Kumar Das  2 , L Sreenivasa Murthy  3 , Samit Ghosal  4 , Rakesh Sahay  5 , K V S Harikumar  6 , Ganesh Hosahithlu Keshava  7 , Mayur Agarwal  8 , G Vijayakumar  9 , Pramila Kalra  10 , Piyush Lodha  11 , Sambit Das  12 , Shehla Shaikh  13 , Soumik Goswami  14 , T P Ajish  15 , Prashant Kumthekar  16 , Mihir Upadhyay  16 , Anthuvan Thamburaj  17 , Aushili Mahule  17 , Ashish Prasad  17 , Abhijit Pednekar  17
Affiliations
Randomized Controlled Trial

Efficacy of Dapagliflozin + Sitagliptin + Metformin Versus Sitagliptin + Metformin in T2DM Inadequately Controlled on Metformin Monotherapy: A Multicentric Randomized Trial

Awadhesh Kumar Singh et al. Adv Ther. 2025 Feb.

Abstract

Introduction: A slower adoption rate of fixed dose combinations (FDC) in diabetes management is partly due to insufficient data. This study evaluates the safety and efficacy of an FDC of dapagliflozin + sitagliptin + metformin hydrochloride extended release (XR), compared to a dual FDC of sitagliptin + metformin hydrochloride XR among patients with type 2 diabetes mellitus (T2DM) with poor glycemic control when treated with metformin monotherapy.

Methods: A total of 274 patients with T2DM were randomized (1:1) to either arm X, receiving FDC of dapagliflozin (10 mg) + sitagliptin (100 mg) + metformin hydrochloride XR (1000 mg) (Dapa + Sita + Met) tablets, or arm Y, receiving sitagliptin phosphate (100 mg) + metformin hydrochloride XR (1000 mg) (Sita + Met) tablets, and treated for 16 weeks. The outcome measures included changes in hemoglobin A1c (HbA1c)(%), fasting plasma glucose (FPG), 2-h post-prandial glucose (PPG), weight, and the proportion of patients achieving target HbA1c levels of < 7.0% by week 16 of the study period.

Results: The reduction in HbA1c at week 16 was significantly higher in arm X than in arm Y [estimated treatment difference (ETD), - 0.65% (95% CI - 0.76 to - 0.53; P < 0.0001)]. Arm X showed a marked decrease in FPG [ETD - 15.42 mg/dl; 95% CI (17.63, 13.22; P < 0.0001)], PPG [ETD - 30.39 mg/dl; 95% CI (35.59, 25.19; P < 0.0001)], and weight [ETD - 1.47 kg; 95% CI (1.59, 1.28; P < 0.0001)] after 16 weeks. In arm X, 54% of patients reached HbA1c < 7.0% compared to 29.9% in arm Y. The incidence of adverse events was comparable [13.14% (arm X) vs 12.4% (arm Y)]. There was no severe hypoglycemia-led treatment discontinuation.

Conclusion: Among patients with T2DM who have poor glycemic control with metformin monotherapy, triple FDC (Dapa + Sita + Met) effectively helped achieve better glycemic response compared to dual FDC (Sita + Met), with a comparable safety and tolerability profile.

Trial registration: CTRI/2022/01/039857.

Keywords: Dapagliflozin; Metformin; Sitagliptin; Triple fixed dose combination; Type 2 diabetes.

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Conflict of interest statement

Declarations. Conflict of Interest: Dr Aushili Mahule, Dr Ashish Prasad, Dr Abhijit Pednekar & Dr Anthuvan Thamburaj are the employees of USV Private Limited. Awadhesh Kumar Singh, Ashok Kumar Das, L Sreenivas Murthy, Samit Ghosal, Rakesh Sahay, KVS Hari Kumar, Ganesh Hosahithlu Keshava, Mayur Agarwal, G Vijayakumar, Pramila Kalra, Piyush Lodha, Sambit Das, Shehla Shaikh, Soumik Goswami, T.P Ajish, Prashant Kumthekar, Mihir Upadhyay have no nothing to disclose. The sponsors of the project were the manufacturers of the marketed product of drugs used in this study. Ethical Approval: The study was conducted, monitored, evaluated, and audited to comply with the International Conference on Harmonization Good Clinical Practice guidelines. The study was conducted in accordance with the ethical guidelines for biomedical research on human patients by the Indian Council of Medical Research, ethical principles of the Declaration of Helsinki, and New Drugs and Clinical Trials Rules 2019. The study also received the institutional ethics committee approval at each of the 12 study sites (Supplementary material; Table S1). The master ethics approval was obtained from Institutional Ethics Committee, Maharaja Agrasen Superspecialty Hospital (IEC/APV/JAN/2022/07). Informed written consent was obtained from all the study participants.

Figures

Fig. 1
Fig. 1
Patient disposition chart. ER extended release, SR sustained release, Arm X FDC of dapagliflozin 10 mg + sitagliptin 100 mg + metformin hydrochloride XR 1000 mg tablets, Arm Y sitagliptin phosphate tablets 100 mg and metformin hydrochloride tablets 1000 mg combipack
Fig. 2
Fig. 2
Primary endpoint: LSM (± SE) changes in the HbA1c level from baseline to week 16. ETD estimated treatment difference, LSM least square mean, SE standard error, Arm X FDC of dapagliflozin 10 mg + sitagliptin 100 mg + metformin hydrochloride ER 1000 mg tablets, Arm Y sitagliptin phosphate tablets 100 mg and metformin hydrochloride SR tablets 1000 mg combipack
Fig. 3
Fig. 3
Secondary endpoints: LSM (± SE) changes in the i FPG levels, ii 2-h PPG, iii body weight. ETD estimated treatment difference, FPG fasting plasma glucose, LSM least square mean, PPG postprandial glucose, SE standard error, Arm X FDC of dapagliflozin 10 mg + sitagliptin 100 mg + metformin hydrochloride ER 1000 mg tablets, Arm Y sitagliptin phosphate tablets 100 mg and metformin hydrochloride SR tablets 1000 mg combipack
Fig. 4
Fig. 4
Proportion of patients achieving a therapeutic glycemic response, defined as HbA1c < 7.0% at week 16. The p value is obtained using the chi-square test. Arm X FDC of dapagliflozin 10 mg + sitagliptin 100 mg + metformin hydrochloride ER 1000 mg tablets, Arm Y sitagliptin phosphate tablets 100 mg and metformin hydrochloride SR tablets 1000 mg combipack
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