Introduction

The prevalence of type 2 diabetes mellitus (T2DM) is increasing globally, including India, with an estimated 1 in 7 adults (aged 20-79 years) living with diabetes as per the International Diabetes Federation Diabetes Atlas 2021. [1] Being a progressive disease, diabetic patients eventually require a multi-drug regimen to maintain glycemic control. [2] Dipeptidyl peptidase‐4 inhibitor (DPP4i), an antidiabetic agent available since 2006, is useful in lowering glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) and post-prandial plasma glucose (PPG) with low risk of hypoglycemia. [3] Furthermore, this drug class has an established evidence of not increasing cardiovascular (CV) risk in patients with T2DM. [4] Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a recently developed anti-hyperglycemic agent, and their usage is increasing due to their cardio-renal benefit. [5] SGLT2i helps in reducing body weight and lowers blood pressure, which in turn reduces cardiac afterload with subsequent improvement in ventricular arterial coupling and cardiac efficacy. [6] With these established clinical benefits, there exists a strong rationale for combining a DPP4i and a SGLT2i in patients with T2DM due to their different yet complementary glucose-lowering effects. [7] As a pharmacologic treatment for patients with T2DM, the American Diabetes Association (ADA) 2022 standard of care guidelines recommend other oral antidiabetic (OAD) agents with or without metformin therapy based on glycemic needs. [8] Moreover, the guidelines suggest dual combination therapies especially when HbA1c is ≥1.5% above glycemic target to achieve patients’ target HbA1c. [9] Though the guidelines are applicable universally, there is a need to improvise the HbA1c management approach further in patients with T2DM in India uncontrolled on metformin monotherapy due to diverse population and management practices. One potential approach is utilizing fixeddose combination (FDC) therapies to achieve better glycemic control and treatment compliance.

Expert opinion from International panel of clinicians on clinical approach to FDCs in the management of T2DM recommended a rational use of FDCs (double or triple) in managing such patients in India. [10] The panel aligned that adding a lowdose antidiabetic medication to monotherapy can enhance drug efficiency by 80%. Likewise, with the complementary mode of action, both DPP4i and SGLT2i have proven to be an adequate dual combination therapy to achieve target HbA1c levels in patients with inadequately controlled diabetes on high-dose metformin therapy. [7] In India, teneligliptin is one of the widely used DPP4i since 2015, [11] and is available as 20 mg once-daily dosage for the treatment of T2D as add-on therapy to metformin. Remogliflozin etabonate is a recently approved SGLT2i, [12] and is available as 100 mg twice-daily dosage regimen. In previous studies, teneligliptin combined with SGLT2i was shown to be welltolerated and effective in improving glycemic control. [12,13] Also, due to its multiple elimination pathways, teneligliptin requires no dosage adjustment in patients with hepatic or renal impairment and have a low probability for drug-drug interactions. [14] FDC of teneligliptin and remogliflozin etabonate needs to be further evaluated in the Indian population with T2DM uncontrolled on metformin therapy.

In this study, we evaluated the FDC of remogliflozin etabonate (100 mg) and teneligliptin (10 mg) administered twicedaily in comparison to teneligliptin 20 mg administered once-daily in patients with inadequately controlled T2DM on a stable dose of metformin (≥1500 mg per day). Bioequivalence and comparable DPP4 inhibition of teneligliptin 10 mg twice-daily and 20 mg once-daily dosage regimen is already established. [15]

Materials And Methods

Study design and participants

This was a randomized, double-blind, double-dummy, active-controlled, two-arm, parallel-group, multicenter, phase III study conducted at 21 sites in India. Patients aged ≥18 and ≤65 years, diagnosed with T2DM, who had received a stable dose of metformin ≥1500 mg/day as monotherapy for at least 10 weeks before screening and had inadequate glycemic control at screening defined as HbA1c levels of ≥8% to ≤11%, and provided informed consent were enrolled in the study. Patients were excluded if they were diagnosed with Type 1 diabetes mellitus and diabetes insipidus, had a history of metabolic acidosis or diabetic ketoacidosis, had a body mass index of ≥45 kg/m² at screening and estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73

m², with presence or history of congestive heart failure defined as New York Heart Association (NYHA) class III/IV, and presented with unstable or acute congestive heart failure. The detailed list of inclusion and exclusion criteria is provided in Supplementary Table 1.

Supplementary Table 1: Inclusion and Exclusion criteria.

Treatment and interventions

Eligible patients were randomized (1:1) to receive one of the following treatments:

FDC of remogliflozin etabonate 100mg/teneligliptin 10 mg (RE+TE10) twice-daily or teneligliptin 20 mg (TE20) once-daily for 16 weeks as an add-on to the existing treatment with metformin. Metformin 1500 mg tablet was administered twice-daily along with the FDC of RE+TE10 twice-daily or TE20 once-daily at investigator discretion.

All the patients were screened at study entry and the screening period lasted for 3 weeks with a 2-week run-in period followed by treatment randomization (Figure 1). All patients received two tablets in the morning and one tablet in the evening, with food, preferably at the same time, including a double-blind matching placebo. Randomization was performed using a third-party interactive voice and web response system, and patients were stratified according to their HbA1c levels at screening (8%–8.9%, 9%–9.9%, and 10%–11%). Study visits were scheduled at Weeks 6, 12, and 16 after initiating treatment(s). A follow-up visit occurred two weeks post-last treatment dose for patients who completed the study. At screening, run-in and all treatment visits, standard dietary consultation and exercise modification information was provided to patients as per the applicable national/international guidelines.

Figure 1: Study design.

Concomitant medications such as lipid-lowering agents/oral hypertensives were allowed, provided the drug/dose remained stable one month before and throughout the study period. Also, topical, inhaled, and intranasal corticosteroids were permitted. Oral corticosteroids were permitted if the daily dose was ≤20 mg of prednisone and it remained stable for at least three months before screening and throughout the treatment. Concomitant medications for weight loss, other antidiabetic agents, oral contraceptive pills, immunosuppressants, any medication that can interfere with blood glucose, and potent inducers of cytochrome P450 3A4 (CYP3A4) were prohibited.

Patients were eligible for an open-label rescue medication from Week 6 up to Week 16 if they had an FPG ˃240 mg/dL at Week 6 and FPG ˃200 mg/dL or HbA1c ˃9% at Week 12. The choice and dosage of rescue medication were at the investigator’s discretion, but the use of DPP4i, Glucagon like receptor-1 analog, and SGLT2i was not permitted.

Endpoints and assessments

The primary efficacy endpoint was mean change in HbA1c from baseline to Week 16. The secondary efficacy endpoints were mean change from baseline to Week 12 in HbA1c levels; mean change from baseline in FPG, PPG, and body weight, the proportion of patients achieving a therapeutic glycemic response (HbA1c ˂7%) at Week 16, proportion of patients requiring rescue medication for hyperglycemia from Week 6 to Week 16, and safety and tolerability of the FDC throughout the study.

Safety was assessed by reporting treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), AEs of special interest (hypoglycemia, urinary tract infections, and genital fungal infections), lipid profile and other laboratory tests (hematology, blood chemistry, and urine parameters), vital signs, electrocardiogram (ECG), estimated glomerular filtration rate (eGFR) and physical examination.

Statistical analysis and sample size

A sample size of 123 patients per group was estimated to provide a power of 90% to detect a 0.5% treatment difference in HbA1c between RE+TE10 and TE20 groups, assuming a standard deviation (SD) of 1.2% and using a two-sided significance level of 5%.

The primary efficacy analysis was performed on the modified intent-to-treat (mITT) population. The mITT population included all randomized patients who received at least one study medication dose, who had a non-missing baseline measurement and at least one post-baseline efficacy measurement for primary efficacy variable. The differences between the FDC and TE groups were compared based on the Mixed Model Repeated Measure (MMRM) method, which included data from all visits until Week 16 and the following covariates: treatment, visit, HbA1c at baseline, baseline eGFR, center, and treatment by visit interaction. An unstructured covariance matrix was used, allowing adjustment for correlations between the time points within patients.

All secondary efficacy parameters were summarized by treatment groups and presented for mITT and per protocol (PP) populations. The PP population included all patients who were randomized, received at least one study medication dose, completed the study and did not have any major protocol deviations. The mean change from baseline in HbA1c levels at Week 12, the mean change from baseline in FPG, PPG and body weight at Week 16 were summarized and analyzed using the same model as for the primary endpoint, i.e., MMRM model to establish superiority of RE+TE10 vs. TE20. The proportion of patients achieving HbA1c ˂7% at Week 16 and the proportion of patients requiring rescue medication for hyperglycemia were summarized by treatment group and compared for RE+TE10 vs. TE20 using chi-square test.

All safety and tolerability analyses were performed on the safety population which included all patients who were randomized and received at least one dose of study medication. Safety findings were summarized descriptively. The severity of TEAEs were classified as mild, moderate, severe and life threatening.

All analyses were performed using SAS® software 9.4.

Ethics: The study was conducted following the Declaration of Helsinki, 2013 and in accordance with the International Council for Harmonization guidelines for Good Clinical Practice and New Drugs and Clinical Trials Rules, 2019 of Drugs and Cosmetics Act, 1940. The study was reviewed and approved by the Institutional Ethics Committee at each investigator site, and all participants provided written informed consent.

Results

Patient disposition, demographic and baseline characteristics

A total of 308 patients were randomized, of which 278 patients (90.3%; 143 in RE+TE10 and 135 in TE20 groups) completed the study. Thirty patients (9.7%) discontinued the study and the most common reason for discontinuation being patient unwilling to continue (4.9%), lost to follow-up (2.6%), and noncompliance with study procedures (1.6%). In total, 294 (95.5%) patients were included in the mITT population and 277 (89.9%) were included in the PP population. Patient disposition details is shown in Figure 2. The demographic and baseline characteristics were comparable between the treatment groups. (Table 1) The mean ± SD age of patients was 50.72 ± 9.33 years in the RE+TE10 and 51.63 ± 8.15 years in the TE20 groups. The mean HbA1c level at screening was 9.24% ± 0.79% in the RE+TE10 and 9.25% ± 0.78% in the TE group.

Table 1: Patient demographic and baseline characteristics.

Figure 2: Patient disposition.

Efficacy

Primary endpoints (mITT population)

The mean baseline HbA1c levels were comparable between groups in the mITT population and was 8.77% ± 1.01 and 8.86% ± 1.10 in the RE+TE10 and TE20 groups, respectively. The mean change from baseline in HbA1c at Week 16 was significantly higher in the RE+TE10 (-1.23% ± 0.13) when compared with TE (-0.79% ± 0.13) with a least-square (LS) mean difference of -0.44% (95% confidence interval [CI]: -0.75; -0.13; p=0.006) (Figure 3A and Table 2). The RE+TE10 group was superior compared to the TE20 group with respect to the mean change in HbA1c from baseline to Week 16 (p=0.006).

The mean change in HbA1c values at Week 16 in the HbA1c 8-8.9% subgroup and HbA1c 10-11% subgroups did not show a significant difference between RE+TE10 and TE20 (p=0.475 and 0.311, respectively). However, a significant difference between RE+TE10 and TE20 was observed for the mean change HbA1c at Week 16 for the HbA1c 9-9.9% subgroup (p=0.003). (Table 2) Secondary endpoints (mITT population)

Mean change from baseline in HbA1c levels at Week 6 and 12 The RE+TE10 group was superior compared to the TE20 group with respect to mean change in HbA1c from baseline to Week 12. The LS mean (± standard error [SE]) change from baseline in HbA1c levels to Week 12 in the RE+TE10 and TE20 groups was -1.04% ± 0.11 and -0.69% ± 0.11 (both p<0.001), respectively. The mean reduction in HbA1c from baseline at Week 12 was significantly higher in the RE+TE10 than in the TE20 with a LS mean difference of -0.35% ± 0.12) (95% CI: -0.59, -0.11; p=0.004; Table 2).

Similarly, at Week 6, the LS mean reduction in HbA1c from baseline in the RE+TE10 group was statistically significant compared to the TE20 group (p=0.009).

Mean change from baseline in FPG and PPG levels at Week 16

At Week 16, a statistically significant reduction was observed in the FPG levels from baseline in the RE+TE10 and TE groups (p<0.001), respectively. (Figure 3B, Table 3). The LS mean change from baseline was -18.5 ± 4.32 mg/dL in RE+TE10 and -19.7 ± 4.46 mg/dLin TE20. However, the LS mean difference of 1.2 mg/dL (95% CI: -8.8, 11.2) was not statistically significant between the two groups (p=0.818).

Similarly, a statistically significant reduction from baseline was observed for PPG at Week 16 (Figure 3C, Table 3). The LS mean change from baseline in PPG levels was -38.3 ± 6.13 mg/dL (p <0.001) and -24.5 ± 6.32 mg/dL in the RE+TE10 and TE groups, respectively. The mean reduction in PPG levels was numerically higher in the RE+TE10 than the TE group by 13.8 ± 7.09 mg/dL (95% CI: -27.8, 0.2; p=0.053) (Table 3).

Mean change in body weight from baseline at Week 16. At Week 16, a statistically significant reduction in body weight was observed in the RE+TE10 group whereas statistically significant increase in body weight was observed in TE20 group. The LS mean change from baseline in total body weight was -0.97 ± 0.14 kg in the RE+TE10 group and 0.76 ± 0.14 kg in the TE20 group, respectively (both p<0.001) (Table 3).

Proportion of patients achieving HbA1c <7%, at Week 16

At Week 16, numerically greater proportion of patients achieved a therapeutic glycemic response of HbA1c ˂7% in the RE+TE10 (53 [35.6%]) compared to the TE20 (39 [26.9%]) group. However, the difference between the two groups was not statistically significant (p=0.109).

Proportion of patients requiring rescue medication for hyperglycemia during treatment by Week 16 Overall, by Week 16, significantly lesser proportion (p=0.039) of patients required rescue medication for hyperglycemia in the RE+TE10 group (6%; 9 patients) compared to the TE20 group (13.1%; 19 patients).

Figure 3: Mean change from baseline at Week 16 (mITT Population).

Table 2: Mean change from baseline in HbA1c%, stratified for screening HbA1c% (mITT Population).

Table 3: Mean change from baseline FPG, PPG and body weight (mITT Population).

Safety and tolerability

Overall, TEAEs were reported in 40 patients (13%), the incidence was comparable between the two treatment groups (14.2% [n=22] in the RE+TE10 group and 11.8% [n=18] in the TE group). Only one patient (0.6%) in the RE+TE10 group with TEAEs (vomiting, diarrhea) discontinued from the study, and the event was considered related to the treatment by the investigator (Table 4). The TEAEs reported in >1% of patients included diarrhea (n=3;1.9%), urinary tract infection (n=3; 1.9%), dyslipidemia (n=2; 1.3%), hyperglycemia (n=2; 1.3%) and hypoglycemia (n=3; 1.9%), in the RE+TE10 group, while in the TE20 group, the reported TEAEs were urinary tract infection (n=2; 1.3%), hyperglycemia (n=4; 2.6%), and hypoglycemia (n=2; 1.3%).

 All the TEAEs reported were mild-to-moderate in intensity. TEAEs of moderate intensity (gastritis, hyperglycemia, nocturia, vomiting, diarrhea, dyslipidemia) were reported in 1.3% (n=2) of patients in the RE+TE10 group and 3.9% (n=6) of patients in the TE20 group. The TEAEs of special interest of hypoglycemia and urinary tract infections were reported by 5 patients each; 3 (1.9%) in the RE+TE10 group and 2 (1.3%) in the TE20 group, respectively. There was only 1 (0.7%) patient in the TE20 group with symptomatic hypoglycemia and there were none in the RE+TE10 group. There were no reports of SAEs or deaths, or severe TEAEs throughout the study. (Table 5)

Clinical laboratory, vital signs and physical examination findings There was no clinically relevant difference from baseline to Week 16 for the clinical biochemistry, 12-lead ECG, hematology, urine analysis, and vital signs in the RE+TE10 group compared to the TE20 group.

Treatment compliance

Patients who received ≥80% of prescribed treatment were considered drug compliant. Overall, the mean treament compliance was 98.7% ± 3.52 and 98.55% ± 2.99 in the RE+TE10 and TE20 groups, respectively. The mean metformin compliance was similar between the two groups (99.27% ± 1.98 in the RE+TE10 group and 99.05% ± 2.67 in the TE20 group).

Table 4: Patients with treatment-emergent adverse events related to treatment (Safety population).

Table 5: Patients with treatment-emergent adverse events (Safety population).

Discussion

T2D is a complex and multifactorial disorder which generally requires a combination of several antidiabetic drugs to achieve optimal glycemic control. [7] Using FDC drug is a beneficial strategy that helps to achieve optimal therapeutic benefits and improves medication adherence in patients by minimizing pill burden. FDC drugs combine multiple active ingredients in a single dose product providing synergistic effects, better clinical outcomes, tolerability, and cost-effectiveness, which increases compliance and treatment adherence in patients. [10,16] Combining SGLT2i with DPP4i have shown to simplify the anti-diabetic therapy and improve the drug compliance. [7]

In the present study, we assessed the efficacy and safety of remogliflozin etabonate (100 mg) and teneligliptin (10 mg) twice-daily FDC therapy versus teneligliptin (20 mg) in patients with uncontrolled T2D on background therapy of metformin. The improvement in HbA1c in the RE+TE10 compared to TE20 was observed as early as Week 6 and was sustained over Week 12 and Week 16 confirming the superior efficacy of RE+TE10 compared to TE20 in terms of glycemic control. Also, the reduction observed in HbA1c from baseline to Week 16 in this study with RE+TE10 was similar to that reported in a clinical study with a combination of SGLT2i and DPP4i. [17] This proves that this RE+TE10 FDC has similar efficacy to other available SGLT2i and DPP4i combination.

Additionally, with rising HbA1c levels (HbA1c >8%), patients experience reduced functional independence. [18] The subgroup analysis based on baseline HbA1c levels between RE+TE10 and TE20 demonstrated a significant difference between two groups in HbA1c 9-9.9% subgroup (p=0.003), achieving HbA1c <7.5% with RE+TE10 at Week 16 from baseline, suggesting better outcomes for patients in this subgroup while for the other two subgroups (HbA1c 8-8.9% and 10-11%) difference was not statistically significant (Table 2). The reason of this findings could be the small no of patients in these subgroups. The results for FPG and PPG at Week 16 were not statistically significant between the two groups, however numerically higher reduction in the mean PPG levels were observed in the RE+TE10 than the TE20 group.

In our study, we found that addition of remogliflozin 100 mg and teneligliptin 10 mg to metformin resulted in numerically greater reduction in body weight than addition of teneligliptin 20 mg to metformin. Similar change in body weight was seen with teneligliptin and metformin. [19] Reduction in body weight and blood pressure with the use of SGLT2i in turn prevents the risk of CV death in patients with T2D. [6,20] In the TE20, patients who needed rescue medication were higher (13.1%) compared to the RE+TE10 (6%). Moreover, a significant proportion of patients in the RE+TE10 (35.6%) achieved HbA1c ˂7% compared to the TE20 (26.9%). As compared to TE20 statistically significant reductions in blood glucose and body weight in patients receiving RE+TE10 were observed from baseline to Week 16. Similar efficacy in providing glycemic and weight benefits was shown by other combinations of SGLT2is and DPP4is. [21-24] The greater percentage of patients attaining HbA1c ˂7% in RE+TE10 established the efficacy of FDC over TE20 in regulating blood glucose in patients with uncontrolled T2D. These findings support the overall clinical benefit of the FDC of remogliflozin/ teneligliptin versus reducing hyperglycemia as an adjunct to metformin compared to the use of teneligliptin alone.

Both teneligliptin 10 mg and 20 mg dosages have shown efficacy in providing similar glycemic control and are well tolerated, with a low incidence of hypoglycemia. [26] Similar safety and tolerability of remogliflozin administered concomitantly with other OADs was observed in a real-world clinical study. [27,28] Of note, no ketoacidosis was reported in the RE+TE10 in the present study. SGLT2is, directly and indirectly, stimulates glucagon secretion, promoting the beta-oxidation of fatty acids and the formation of ketone bodies. [28] DPP4i suppresses SGLT2iinduced glucagon secretion by inactivating two incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, increasing insulin and reducing glucagon. [29] This combined mechanism of action of the combination therapy could explain the absence of ketoacidosis in this study. These findings further reinforce the benefits of combining anti-hyperglycemic therapies with different action mechanisms.

With improvement in multiple underlying pathophysiological defects associated with T2D, the FDC also needs to provide convenience to patients such as oral dosing and minimizing pill burden, which will ultimately translate to improved adherence.[30] FDC of SGLT2i and DPP4i appears to be promising in meeting these criteria for improved medication adherence and treatment compliance among T2D patients. The overall drug compliance in our study was comparable between RE+TE10 and TE20 group and was >98% in both groups demonstrating good treatment adherence.

The strength of our study was the potential advantage of this FDC in increasing patient compliance and convenience. Our study was conducted at multiple centers spread across India thereby representing a wide range of patients from diverse bacgrounds which could be representative of larger population. Doubleblind randomized treatment allocation eliminated the likely bias in the study, and the risk of confounding was well-controlled. A limitation of this study is that it reports 16-week results, thus not allowing the evaluation of long-term benefits of the FDC when compared to teneligliptin as an add-on to metformin. Overall, the FDC of remogliflozin etabonate 100 mg and teneligliptin 10 mg was effective and was shown to significantly reduce the HbA1c levels in this population and was well-tolerated. No SAE, death or cardiovascular events were reported in the study.

Conclusion

Remogliflozin 100 mg and teneligliptin 10 mg FDC achieved significantly greater improvements in glycemic control than with teneligliptin 20 mg as an add-on to metformin, with the benefit of body weight reduction and was also well tolerated. The findings from this study support initiating FDC of remogliflozin 100 mg and teneligliptin 10 mg as an effective treatment option in patients with uncontrolled T2D reducing pill burden resulting in improved improving patient’s treatment compliance and medication adherence.

Clinical trial registration.: CTRI/2020/04/024841

Acknowledgements: The authors would like to thank Md. Najeeb Ashraf and Dr. Priya Singh from SciVoc Healthcare Consulting Pvt. Ltd. for the writing, editing, and submission support towards developing this manuscript.

Conflict of Interests: Rahul Kodgule, Monika Tandon, Rajesh Gaikwad, Amol Pendse, Kiran Khaladkar, Manoj Kumar, Sumit Bhushan, Sachin Suryawanshi, and Hanmant Barkate are employees of Glenmark Pharmaceuticals Limited. 

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