Introduction

Two recent studies (VERIFY [NCT01528254] and GRADE [NCT01794143] having nearly similar (mean 5-year) follow-ups have now clearly suggested that the conventional approach of sequential addition of drugs in the treatment of type 2 diabetes (T2D) is an inferior strategy [1, 2]. Additionally, the VERIFY study showed initial combination therapy is superior to sequential addition therapy [1]. Intuitively, combination therapies that have different mechanisms of action and a. address various metabolic defects concerning the pathophysiology of T2D, b. having complementary and or synergistic actions, c. having the potential for a larger reduction of glycated hemoglobin (HbA1c) without potentiating hypoglycemia, d. can counter the undesirable effects produced by the individual agent, e. possessing cardio-renal protection, f. having good tolerability without any additional adverse effects, g. can reduce pill burden as a fixed-dose combinations (FDCs) allowing better compliance and h. administered through the oral route – are more likely to be a preferred modality for treating T2D [3]. To this end, triple-drug FDCs of metformin, dipeptidyl peptidase-4 inhibitors (DPP4i), and sodium-glucose co-transporter-2 inhibitors (SGLT2i) appear most promising. Indeed, combination therapy of metformin, DPP4i, and SGLT2i has the potential to correct seven pathophysiological defects of well-defined Ominous Octet, without provoking significant hypoglycemia [4,5,6]. A recent meta-analysis showed cardiovascular and renal benefits exerted by SGLT2i remain intact in association with DPP4i combination therapy with an expected additional HbA1c lowering [7]. Concerning international guidelines, the 2023 American Diabetes Association and European Association of Studies in Diabetes (ADA-EASD) have recommended using two drugs in T2D at diagnosis when HbA1c is ≥ 9% without osmotic symptoms and ≥ 8.5% in young adults with < 40 years of age [8], the 2022 American Association of Clinical Endocrinologists (AACE) guidelines [9] suggest using dual drug therapy when HbA1c > 1.5% above the desired target. The 2022 AACE guidelines recommend triple drug therapy as a first approach for treating asymptomatic patients with HbA1c levels > 9% (75 mmol/mol), while in patients with HbA1c levels ≤ 9% (75 mmol/mol), triple therapy is recommended if the patient has an inadequate response to monotherapy or dual therapy [9].

Several studies that have been conducted with FDCs of SGLT2i and DPP4i have shown superior HbA1c lowering compared with either agent, with or without background metformin therapy, without any notable increase in hypoglycemia or any other adverse events [10,11,12,13,14,15,16,17]. Indeed, the use of SGLT2i and DPP4i in the treatment of T2D has gained momentum, in light of the recent patent expiry of sitagliptin and dapagliflozin in some countries and the availability of several cheaper generic FDCs of these two drug combinations, especially in India. An expert consensus has recently highlighted the significant role of SGT2i and DPP4i FDCs in people with T2D in the Indian setting [18]. These findings supported studying the safety and efficacy of triple-drug FDC of metformin, sitagliptin, and dapagliflozin in the management of T2D in Indian settings.

Materials and methods

Study design

This study was a multicenter, randomized, double-blind, active-controlled, intention-to-treat, parallel-group, phase 3 trial (CTRI/2021/10/037461) that evaluated the efficacy and safety of triple-drug FDC in the treatment of T2D in Indian patients. This study was conducted following the ethical principles of the Helsinki Declaration, ICH-GCP (International Council for Harmonisation) E6 (R2) guidelines, local regulatory requirements for good clinical practice (GCP) for clinical research in India, and the national ethical guidelines of the Indian Council of Medical Research (ICMR) for biomedical and health research involving human participants [19,20,21,22]. The study enrolled 457 Indian patients with T2D who were inadequately controlled on metformin monotherapy (1000–1500 mg/day) for at least 6 weeks. The patients underwent a 2-week screening period before randomization. The eligibility criteria were as follows:

  • Willing to provide voluntary written informed consent

  • Male or female patients aged 18 to 65 years (both inclusive)

  • Patients with HbA1c value between 8.0% and 10.0%

Patients with known hypersensitivity to metformin, sitagliptin, dapagliflozin, or the study product excipients, a body mass index (BMI) exceeding 40 kg/m2, abnormal laboratory results (including eGFR < 60 mL/min by the CKD-EPI, hemoglobin < 10 g/dL, neutrophils < 2000/mm3, platelets < 100,000/mm3, total bilirubin > 1.5 X ULN (upper limit of normal), ALT/AST > 2.5 X ULN, serum amylase and/or lipase > 3 X ULN), type 1 diabetes, fasting plasma glucose (FPG) levels > 270 mg/dL, hypothyroidism, hyperthyroidism, hypotension, positive testing for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), genital mycotic or urinary tract infections, history of cardiovascular or respiratory diseases, and corticosteroid use for one week or more within 3 months before screening were excluded from the study.

Treatment regimen

A total of 274 eligible patients with T2D, recruited from 20 sites across India and meeting the study selection criteria, were randomized in a 1:1 ratio to either a fixed-dose combination (FDC) of three drugs (n = 137)—dapagliflozin propanediol 10 mg, sitagliptin phosphate 100 mg, and metformin hydrochloride 1000 mg extended-release (DSM), or an FDC of two drugs (n = 137)—sitagliptin phosphate 100 mg (SM) and metformin hydrochloride 1000 mg sustained-release. Out of the 274 patients, 253 completed the trial and were followed up at the end of 16 weeks having 126 patients in the DSM group and 127 patients in the SM group. The subject disposition of this trial is summarized in Fig. 1.

Fig. 1
figure 1

Subject Disposition. Abbreviations: FDC: Fixed Dose Combination; SM: Sitagliptin phosphate 100 mg + Metformin hydrochloride 1000 mg sustained release; DSM: Dapagliflozin propanediol 10 mg + Sitagliptin phosphate 100 mg + Metformin hydrochloride 1000 mg extended release

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Study assessment and endpoints

The primary endpoint was to evaluate the change in HbA1c from baseline to week 16, analyzed using an analysis of covariance (ANCOVA) model with treatment as a factor and baseline as a covariate. Secondary endpoints were changes in FPG, postprandial glucose (PPG), and body weight from baseline to Week 16. A two-sample t-test was conducted to examine the mean difference between treatment groups. Additionally, the safety and tolerability of DSM were assessed.

Results

HbA1c change at week 16

Table 1 displays patient demographic and baseline characteristics for the two treatment groups, comparable in all the parameters. In all, 253 patients completed the trial (126 patients in the DSM group and 127 in the SM group). At the end of Week 16, the DSM group showed a significant decrease in HbA1c levels to 7.42 ± 0.973 (∆ -1.45%; p = 0.0005). In contrast, the SM group only reduced HbA1c levels to 7.87 ± 1.073 (∆ -1%) (Table 2). The difference between the two groups from baseline and Week 16 was statistically significant (-0.45% (-0.70, -0.20; p = 0.0005)) (Fig. 2).

Table 1 Demographic and Clinical Characteristics
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Table 2 HbA1c, FPG, PPG, and Body Weight (kg) change at Week 16 from baseline
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Fig. 2
figure 2

HbA1c change at Week 16 from baseline. Abbreviations: HbA1c: haemoglobin A1c; SM: Sitagliptin phosphate 100 mg + Metformin hydrochloride 1000 mg sustained release; DSM: Dapagliflozin propanediol 10 mg + Sitagliptin phosphate 100 mg + Metformin hydrochloride 1000 mg extended release

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FPG (Fasting Plasma Glucose) change at week 16

After week 16, a notable difference emerged in the mean change of FPG levels from baseline between the DSM group [from 153.79 mg/dL to 132.7 mg/dL (∆ -21.09)] and the SM group [from 162.70 mg/dL to 154.01 mg/dL (∆ -8.69)] (Table 2). The difference between the DSM and SM groups was ∆ -12.4 mg/dL, with a statistical significance of P = 0.003 (Fig. 3).

Fig. 3
figure 3

FPG change at Week 16 from baseline. Abbreviations: FPG: Fasting Plasma Glucose; SM: Sitagliptin phosphate 100 mg + Metformin hydrochloride 1000 mg sustained release; DSM: Dapagliflozin propanediol 10 mg + Sitagliptin phosphate 100 mg + Metformin hydrochloride 1000 mg extended release; mg/dL: milligrams per deciliter

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PPG (Post-Prandial Glucose) change at week 16

By week 16, a substantial reduction in mean PPG levels from baseline was observed in the DSM group [from 228.90 mg/dL to 191.24 mg/dL] (∆ -37.66 mg/dL)], whereas the SM group demonstrated a lesser reduction [from 238.94 mg/dL to 219.73 (∆ -19.21 mg/dL)] (Table 2). This difference in PPG reduction was statistically significant, with the DSM group experiencing a more pronounced decrease (∆ -18.45 mg/dL; p = 0.01) as compared to the SM group (Fig. 4).

Fig. 4
figure 4

PPG change at Week 16 from baseline. Abbreviations: PPG: Post-prandial Glucose; SM: Sitagliptin phosphate 100 mg + Metformin hydrochloride 1000 mg sustained release; DSM: Dapagliflozin propanediol 10 mg + Sitagliptin phosphate 100 mg + Metformin hydrochloride 1000 mg extended release; mg/dL: milligrams per deciliter

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Body weight change at week 16

After 16 weeks, both groups experienced a significant reduction in body weight from baseline, with mean changes of -0.9 kg and -0.8 kg in the DSM and SM groups, respectively (p < 0.0001) (Table 2). However, there was no significant difference in body weight reduction between the DSM and SM groups (Table 2).

Safety and tolerability

Out of all 274 participants, 43 Treatment-Emergent Adverse Events (TEAEs) were reported in 33 subjects, with 16 subjects (11.7%) in the DSM group and 17 subjects (12.4%) in the SM group. None of these events were classified as serious treatment-emergent adverse events (SAEs). All reported events were categorized as mild (Grade 1), and no instances of moderate or severe events were observed. Eighteen of the reported events were considered related to the investigational product, 10 events in the DSM group and 8 in the SM group respectively (Table 3). In the DSM group, Gastritis (3 events), Dizziness (2 events), and Vomiting (1 event) were the most commonly reported related events. In the SM group, Headache (2 events), Cough (1 event), and Nasopharyngitis (1 event) were the most frequently reported related events (Table 3). All reported events resulted in complete recovery, with no unresolved events documented. These findings indicate that the investigational product was well-tolerated in both the DSM and SM groups, with no significant differences in the occurrence of TEAEs (Table 4).

Table 3 Adverse Event-Overview
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Table 4 TEAEs Related to Investigational and reference drug
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Discussion

As β-cell activity gradually declines, oral antidiabetics may become less effective when used for extended periods. In such cases, switching from monotherapy to combination (dual or triple) treatments may be required [10]. Nearly half of the newly diagnosed T2D patients in the United Kingdom Prospective Diabetes Study (UKPDS) conducted half a century ago were found to have poor glycemic control with monotherapy after three years [23]. Surprisingly these findings were replicated in recent studies including VERIFY and GRADE studies [1, 2]. While poor treatment adherence may be linked to insufficient glycemic control, it can additionally be caused by other factors including polypharmacy, complicated treatment regimens, advanced age, obesity or hypoglycemia, lack of education, and occupation [24]. To this end, a triple-drug regimen that combines DPP4i, metformin, and SGLT2i can effectively treat different aspects of T2D, such as insulin resistance, β-cell dysfunction, and glucose reabsorption. This combination is also likely to have a lesser risk of hypoglycemia and weight gain, which are common side effects of other antidiabetic drugs like sulfonylureas and insulin [12].

The only published Indian study that has shown the benefit of using a triple-drug combination of SGLT2i and DPP4i with metformin to control blood sugar levels is by Sahay et al. (2023). In phase 3 randomized 16-week study, that compared the safety and effectiveness of a triple-drug combination of dapagliflozin plus sitagliptin and metformin extended release (ER) and compared to both sitagliptin plus metformin sustained release (SR), and dapagliflozin plus metformin ER, showed a significant drop in HbA1c from baseline (-1.73%, -1.28%, and -1.33%, respectively; all p < 0.001). The triple drug combination of dapagliflozin, sitagliptin and metformin ER lowered HbA1c significantly better compared with dual therapy of sitagliptin plus metformin SR (∆ -0.46%; P < 0.001) and dapagliflozin plus metformin ER (∆ -0.4%; p < 0.001) [25]. These findings are concordant with our study that also finds superior HbA1c lowering of the triple drug combination of sitagliptin, dapagliflozin, and metformin ER compared with sitagliptin plus metformin SR (∆ -0.45%; p = 0.0005). Concerning global studies, in a 24-week, multicenter, randomized, double-blind study, involving 432 patients with T2D, Jabbour SA et al. (2014) showed adding dapagliflozin (10 mg/day) to sitagliptin (100 mg/day) with or without background metformin (≥ 1,500 mg/day) therapy led to more reductions in HbA1c levels (-0.5%), body weight (-2.1 kg), and FPG levels (-24.1 mg/dL) than placebo after 24 weeks, and these benefits were sustained until week 48 [10]. Mathieu et al. (2015) found dapagliflozin addition to saxagliptin plus metformin lowered HbA1c levels more than placebo (− 0.82% vs. − 0.10% respectively; p < 0.0001) at 24 weeks [13]. Similarly, Matthaei et al. (2015) showed saxagliptin along with dapagliflozin and metformin led to a greater reduction in mean A1C compared to placebo (− 0.51% vs. − 0.16%) at week 24 [12]. Moreover, in a 52-week study of 461 patients with T2D, Handelsman et al. (2019) found that the dapagliflozin and saxagliptin combination had a better HbA1c reduction than the sitagliptin and metformin combination at both 26 and 52 weeks, with similar safety and tolerability [26]. DeFronzo et al. (2015) assessed the safety and effectiveness of empagliflozin and linagliptin combinations as a second-line treatment for individuals with T2D who were not effectively managed on metformin. This study showed a sustained and superior HbA1c lowering with empagliflozin and linagliptin combination compared to either drug alone (linagliptin or empagliflozin) in a background metformin therapy, at 52 weeks. [15].

We acknowledge the strengths and weaknesses of our study. This is only a second randomized double-blind active comparator trial conducted in Indian people with T2D that compares the triple drug FDC of sitagliptin, dapagliflozin, and metformin combination therapy to dual therapy of sitagliptin and metformin combination. However, our study has some limitations. This study lasted only for 16 weeks, which may not be enough to see the long-term effects of the triple drug combination on glucose control. Also, the study had a small number of participants, which may limit the applicability of the results to other people with T2D in India. Notwithstanding these drawbacks, this study further strengthens our knowledge about the triple drug combination of SGLT2i, DPP4i, and metformin to be an effective agent in lowering HbA1c in Indian patients with T2D with an acceptable tolerability.

Conclusion

The triple combination (Dapagliflozin 10 mg, Sitagliptin 100 mg, and Metformin 1000 mg ER tablets) was superior to the combination of Metformin SR 1000 mg and Sitagliptin 100 mg in terms of HbA1c reduction, good control of FPG and PPG with favorable safety profile. This FDC may offer a promising treatment option to achieve optimal glucose for patients with T2D who are not controlled by mono or dual therapy.