Efficacy and safety of teneligliptin added to metformin in Chinese patients with type 2 diabetes mellitus inadequately controlled with metformin: A phase 3, randomized, double‐blind, placebo‐controlled study

Abstract Introduction We evaluated the efficacy and safety of teneligliptin compared with placebo when added to metformin therapy in Chinese patients with type 2 diabetes inadequately controlled with metformin monotherapy. Methods This multicentre, randomized, double‐blind, placebo‐controlled, parallel‐group study enrolled type 2 diabetes patients with glycosylated haemoglobin (HbA1c) 7.0%−<10.0% and fasting plasma glucose (FPG) <270 mg/dl, receiving a stable metformin dose ≥1000 mg/day. Teneligliptin 20 mg or placebo was administered orally once daily (qd) before breakfast for 24 weeks. The primary efficacy end‐point was change in HbA1c from baseline to Week 24. Safety end‐points included the incidence of adverse events (AEs). Results The least square mean (LSM) change from baseline (standard error [SE]) was −0.72 (0.07) (95% confidence intervals [CI], −0.87, −0.58) for teneligliptin and −0.01 (0.07) (95% CI, −0.16, 0.13) for placebo. The differences (LSM ± SE) between the placebo and teneligliptin groups in HbA1c and FPG were −0.71% ± 0.11% (p < .0001) and −16.5 ± 4.7 mg/dl (p = .0005), respectively. Teneligliptin yielded significant changes in HbA1c (−0.81%; p < .0001) and FPG (−22.2 mg/dl; p < .0001) at Week 12. At Week 24, more patients achieved HbA1c <7.0% with teneligliptin (41.7%) compared with placebo (16.1%; p < .0001). Treatment‐emergent AE incidence was similar with teneligliptin (58.9%) and placebo (68.3%); upper respiratory tract infection, hyperuricaemia and hyperlipidaemia were the most common AEs. Conclusions Teneligliptin 20 mg qd for 24 weeks added to ongoing metformin treatment significantly decreased HbA1c and FPG levels compared with placebo in Chinese type 2 diabetes patients. The combination was safe and tolerable.


| INTRODUC TI ON
China is the most populous country in the world and has the largest population of diabetes patients. 1 It is estimated that over 100 million Chinese individuals have diabetes. 1 The sharp increase in diabetes prevalence in China in the past 30 years 1 has raised many concerns and emphasizes the need for more stringent prevention and treatment strategies.
Aside from traditional lifestyle changes and initial first-line treatment with metformin for patients inadequately controlled with lifestyle changes alone, current management guidelines recommend intensification of treatment with other antihyperglycaemic agents. 2,3 With prolonged use and disease progression, metformin monotherapy may be less effective for disease control. 4 The burden of type 2 diabetes is growing, with long-term microvascular (ie, nephropathy, neuropathy and retinopathy), macrovascular (eg, atherosclerosis and peripheral vascular diseases) and other complications. 5,6 Additionally, current standard treatments have several limitations, such as poor medication adherence, 7 10,11 which has an insulinotropic effect and glucagonostatic actions that can augment postprandial insulin secretion, resulting in a glucose-lowering effect. [12][13][14] Teneligliptin is a potent third-generation DPP-4 inhibitor with long action duration that results in stable glucose levels during the day 15,16 and inhibitory effects lasting 24 h. 17 Teneligliptin requires no dose adjustment because of hepatic and renal excretion, 16 even in patients with severe renal impairment or end-stage renal disease. 18 Furthermore, it has pleiotropic effects, including improvements in lipid profile, left ventricular function, adiponectin levels and a natriuretic effect. 17 Previous studies of DPP-4 inhibitors in combination with metformin [19][20][21] as well as studies of teneligliptin added to metformin therapy 22,23 conducted elsewhere showed that the combination was generally tolerable and resulted in improved glucose control, without increased hypoglycaemic risk. However, no clinical trials of teneligliptin added to metformin therapy in type 2 diabetes patients inadequately controlled with metformin monotherapy have been conducted in China. This study evaluated the efficacy and safety of teneligliptin compared with placebo when added to metformin therapy in Chinese patients with type 2 diabetes inadequately controlled with metformin monotherapy, diet and exercise.

| Study design, setting, randomization and blinding
This was a multicentre, randomized, double-blind, placebo-con- Patients with 75% or higher treatment compliance during the placebo run-in period were randomly assigned to teneligliptin 20 mg once daily or placebo in a 1:1 ratio by a computer-generated randomization code. The Interactive Web Randomization System was used for static block randomization. Patients, investigators, laboratory personnel and sponsors were blinded to treatment.
Patients were free to discontinue their participation in the study by withdrawing consent or could be withdrawn from the study at any time if they presented with lack of glycaemic control during the double-blind treatment period, onset of health-endangering AEs, deterioration of their medical condition and requiring therapy/treatment, or by investigator's decision.

| Participants
Patients with a documented diagnosis of type 2 diabetes; age ≥18 years; with an HbA1c value ranging from ≥7.0% to <10.0% and fasting plasma glucose (FPG) <270 mg/dl (15 mmol/L) at the screening visit (Day −28) and on Day −14; and undergoing a stable regimen (ie, used during the 8 weeks prior to study start) of metformin monotherapy ≥1000 mg/day plus diet and exercise therapy, which remained unchanged for at least eight consecutive weeks at the screening visit (Day −28), were enrolled in this study.
Patients were excluded from the study if they had a history of type 1 diabetes or a secondary form of diabetes; previous insulin treatment within 1 year prior to the screening visit; treatment with any prohibited concomitant medication within 8 weeks prior to the K E Y W O R D S diabetes mellitus, dipeptidyl peptidase-IV inhibitors, metformin, type 2 screening; and comorbidities. Further exclusion criteria are provided in Appendix S1.

| Interventions
The treatment intervention in this study consisted of the administration of teneligliptin (Mitsubishi Tanabe Pharma Corporation) at a dose of 20 mg or placebo (formulated and packaged identically to the active drug), both administered orally once daily before breakfast for 24 weeks in patients already receiving monotherapy with a stable dose of metformin ≥1000 mg/day. The prohibited concomitant medications were insulin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, glinides, DPP-4 inhibitors, GLP-1 receptor agonists, herbal medicines that lower blood glucose levels, new drugs intended for diabetes, or fixed-dose combination tablets including the above-mentioned active ingredients, and adrenocorticosteroids (excluding for external use). Medications not mentioned here could be used concomitantly for the treatment of complications and AEs.
In principle, medications already in use at the screening visit were used until 2 weeks after the final dose of the study drug without any change in prescription. No dose adjustments were planned.

| Outcomes
The primary efficacy end-point was change in HbA1c from baseline to Week 24.
The secondary efficacy end-point was change in FPG from baseline to Week 24.
Other end-points were as follows: proportion of patients who achieved HbA1c <7.0% at Week 24; change in fasting insulin, C-peptide and glucagon from baseline to Week 24; change in homeostatic model assessment-insulin resistance and homeostatic model assessment-beta-cell function (HOMA-IR and HOMA-β) from baseline to Week 24; change in body weight from baseline to Week 24; and change in HbA1c and FPG from baseline to Week 12.
The safety end-points were AEs, classified using the Medical Dictionary for Regulatory Activities version 21.0; adverse drug reactions (ADRs); treatment-emergent AEs (TEAEs); hypoglycaemic episodes; cardiovascular events (adjudicated by an independent event adjudication committee); vital sign measurements (blood pressure, pulse rate and body temperature); laboratory measurements; and 12-lead electrocardiogram (ECG).

| Measures
Data on baseline demographic and disease characteristics of patients were collected. Blood samples to measure HbA1c, FPG, insulin, C-peptide and glucagon were collected in a fasted state at study sites and were measured at a central laboratory. Documented symptomatic hypoglycaemia is defined in Appendix S1. Cardiovascular events (ie, death, myocardial infarction, hospitalization for unstable angina or heart failure, stroke or transient ischaemic attack, or urgent revascularization procedures) were evaluated by an event adjudication committee.

| Sample size
The planned sample size was 240 patients, with 120 patients to be randomly assigned to each treatment group. Further details are provided in Appendix S1.

| Statistical analysis
The analysis sets are defined in Appendix S1. Efficacy and safety analyses were performed using the full analysis set (FAS) and safety analysis set, respectively.
All statistical tests were 2-sided with a significance level of 5%; 95% confidence intervals (CI) were calculated for the treatment effects and differences between groups. Descriptive statistics (number of non-missing values [n], mean, standard deviation [SD], median, minimum and maximum) were used for continuous variables and frequency counts and percentages for discrete variables.
Analysis of covariance (ANCOVA) was used for the analysis of the primary, secondary and other efficacy end-points, with treatment as a fixed effect and baseline as a covariate; that is, ANCOVA was used to adjust for differences in the baseline HbA1c value be- HbA1c value as a covariate. Subgroup analyses were conducted for change in HbA1c from baseline to Week 24 by baseline characteristics. Multiplicity due to multiple testing was not adjusted within or between the primary, secondary and other efficacy end-points. SAS Version 9.2 or higher (SAS Institute) was used for the analyses.

| Ethical considerations
The protocol and other related documents were approved by an Independent Ethics Committee. The study was conducted accord- Harmonisation guidelines, and all applicable regional and local legislation.

| Participants
Of the total of 429 patients who provided informed consent, 247 patients were randomly assigned to treatment (123 patients to the teneligliptin group and 124 to the placebo group); 182 patients were not eligible for randomization, the majority of whom did not

| Baseline data
Baseline characteristics of both groups were generally comparable (Table 1). In the teneligliptin and placebo groups (FAS), respectively, 66.4% and 54.0% of patients were male, with a mean ± SD age of 56.0 ± 9.8 and 54.7 ± 10.1 years, and a mean ± SD body mass index (BMI) of 26.00 ± 3.15 and 26.19 ± 3.22 kg/m 2 . The mean ± SD duration of diabetes was 5.05 ± 3.90 and 5.41 ± 4.22 years, the mean ± SD of HbA1c at baseline was 7.90 ± 0.68% and 7.87 ± 0.72%, and the mean ± SD of metformin total daily dose was 1368.9 ± 341.4 and 1392.9 ± 353.1 mg, respectively. The treatment compliance was greater than 75% in 98.4% of patients in the teneligliptin group and in 99.2% of patients in the placebo group.

| Primary efficacy end-point
The mean ± SD of HbA1c at Week 24 was 7.18 ± 1.02% and 7.85 ± 1.04% in the teneligliptin and placebo groups, respectively. 152.1 ± 42.9 and 172.7 ± 43.2 mg/dl, respectively. Figure 3 shows the mean changes in FPG from baseline to Week 24 in both groups.

| Safety
The safety analysis set consisted of 247 patients (124 patients in the teneligliptin group and 123 patients in the placebo group). TEAEs were observed in 73 patients (58.9%) in the teneligliptin group and 84 patients (68.3%) in the placebo group. The most frequent AEs by preferred term with an incidence ≥2% in any group were upper respiratory tract infection (11.3% and 17.9% in the teneligliptin and placebo groups, respectively), hyperuricaemia (8.9% and 10.6%, respectively) and hyperlipidaemia (6.5% and 5.7%, respectively;

| DISCUSS ION
Diabetes is estimated to affect >100 million Chinese individuals, 1 and while metformin is the recommended first-line pharmacologic therapy, 3 monotherapy may become less effective at maintaining disease control over time. 4 The combination of the DPP-4 inhibitor teneligliptin plus metformin has been reported previously to be tolerable and to improve glucose control. 22,23 However, data relating to the use of this combination in Chinese patients are lacking. This is TA B L E 2 Summary of adverse events, treatment-emergent adverse events, and adverse drug reactions (safety analysis set) and treatment-emergent adverse events by system organ class and preferred term with an incidence of ≥2% Notes: Percentages are based on the number of patients in each treatment group. Each patient is counted only once within each system organ class and within each preferred term.
a The severity of an AE was graded by Investigator as 1 = mild, 2 = moderate and 3 = severe. If any AE occurred more than once, the highest severity was summarized. For AEs with missing severity, the most severe assessment was imputed. b ADRs were defined as AEs where the causal relationship to study drug was classified as a reasonable possibility. Any missing relationship of an AE to study drug was considered a reasonable possibility. c All AEs as described by the investigators (verbatim) were coded using MedDRA version 21.0.

| Limitations
The main limitations of this study were the lack of an active comparator, the short treatment period (24 weeks) and limited generalizability to populations of other ethnicities. Further, safety and efficacy outcomes of teneligliptin in combination with other drugs for diabetes, or for comorbidities (eg, hypertension) need to be clarified. Finally, statistically significant results of non-primary efficacy end-points should be considered only as signals of possible treatment effects because alpha levels were not adjusted for multiple testing.

| CON CLUS IONS
Teneligliptin once daily at a dose of 20 mg for 24 weeks, concomitantly administered with metformin, significantly decreased HbA1c and FPG levels compared with placebo in Chinese type 2 diabetes patients inadequately controlled with metformin therapy.
The combination was well tolerated, and no new safety concerns were raised.

ACK N OWLED G EM ENTS
The authors would like to thank Keyra Martinez Dunn, MD, of Edanz Evidence Generation for providing medical writing assistance, which was funded by Mitsubishi Tanabe Pharma, Tokyo, Japan.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author, upon reasonable request.