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Journal of Diabetes 8 (2016) 229– 237

O R I G I N A L A RT I C L E

Efficacy and safety of linagliptin in Asian patients with type 2 diabetes mellitus inadequately controlled by metformin: A multinational 24-week, randomized clinical trial*† Weiqing WANG,1 Jinkui YANG,2 Gangyi YANG,3 Yan GONG,4 Sanjay PATEL,5 Candice ZHANG,6 Toshiyasu IZUMOTO7 and Guang NING1 1 Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 6Boehringer Ingelheim International Trading, Shanghai, 2Beijing Tongren Hospital, Capital Medical University, Beijing, 3The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China, 4Boehringer Ingelheim Pharma, Ingelheim, Germany, 5Boehringer Ingelheim, Bracknell, UK, and 7Nippon Boehringer Ingelheim, Tokyo, Japan

Correspondence Weiqing Wang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No.197 Ruijin 2nd Road, Shanghai 200025, China. Tel: +86 138 1783 6184 Fax: 86 21 64373514 Email: [email protected] *This trial has been registered with ClinicalTrials.gov (ID NCT01215097). † All decisions regarding this paper, coauthored by the Editor-in-Chief, were made by Professor Zachary Bloomgarden. Received 22 April 2014; revised 12 January 2015; accepted 20 February 2015. doi: 10.1111/1753-0407.12284

Abstract Background: Despite the increasing prevalence of type 2 diabetes mellitus (T2DM) in Asia, clinical trials for glucose-lowering therapies are often dominated by Caucasian and/or Western populations. The present Phase III randomized placebo-controlled double-blind, 24-week study evaluated the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin added to metformin in Asian T2DM patients. Methods: In all, 306 patients (n = 265 Chinese; n = 24 Malaysian; n = 17 Filipino), aged 18–80 years with HbA1c between ≥7.0 and ≤10.0% and on metformin therapy were randomized (2:1) to either linagliptin 5 mg daily or placebo added to metformin. Antidiabetes drugs other than metformin were washed out prior to randomization. The primary endpoint was change in mean HbA1c from baseline after 24 weeks. Results: Baseline characteristics were well-matched between the groups (overall mean [±SD] HbA1c 8.0 ± 0.8%). Adjusted mean (±SE) HbA1c decreased in the linagliptin and placebo groups by −0.66 ± 0.05 and −0.14 ± 0.07%, respectively (placebo-corrected difference −0.52 ± 0.09%; 95% confidence interval [CI] −0.70, −0.34; P < 0.0001). In patients with baseline HbA1c ≥8.5%, the placebo-corrected decrease in HbA1c was −0.89 ± 0.17% (P < 0.0001). Adverse events occurred in similar proportions in the linagliptin and placebo patients (27.3% and 28.0%, respectively) and few were considered drug-related (2.4% and 0.0%, respectively). Hypoglycemia occurred in 1.0% of patients in both groups. Linagliptin therapy was weight neutral. Conclusions: Linagliptin 5 mg was efficacious and well tolerated over 24 weeks in Asian patients with T2DM inadequately controlled by metformin. Keywords: Asian patients, dipeptidyl peptidase-4 inhibitor, linagliptin.

Significant findings of the study: Treatment with the dipeptidyl peptidase-4 inhibitor linagliptin added to metformin reduced HbA1c by a significant and clinically meaningful −0.52%. What this study adds: The present randomized clinical trial provides evidence for the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin added to metformin therapy in a dedicated population of Asian patients with T2DM. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd

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Linagliptin added to metformin in Asians

W. WANG et al.

Introduction Among Asian individuals, type 2 diabetes mellitus (T2DM) is commonly characterized by early pancreatic β-cell dysfunction and diminishing insulin secretion.1,2 In East Asians in particular, T2DM occurs in people who are younger and who are less obese compared with Caucasian patients of European descent.3 Risk for T2DM begins to appear in this population at a body mass index (BMI) of approximately 23 kg/m2.4 For most patients with T2DM, international guidelines recommend the biguanide metformin as first-line therapy.5,6 As the disease progresses, combination therapy with an additional oral antidiabetes drug (OAD) or basal insulin may be needed to achieve or maintain an HbA1c target.5,6 The paradigm of treatment endorsed jointly by the European Association for the Study of Diabetes and the American Diabetes Association includes five potential two-drug treatment strategies, namely supplementing metformin with either a sulfonylurea, a thiazolidinedione (TZD), a dipeptidyl peptidase (DPP)-4 inhibitor, a glucagon-like peptide (GLP)-1 receptor agonist, or basal insulin, depending on individual patient needs and risk factors.6 In addition, α-glucosidase inhibitors are widely used in Asia despite their association with gastrointestinal side effects. A DPP-4 inhibitor has certain advantages that make it a rational treatment option: unlike GLP-1 agonists and insulin, they are orally administered; unlike sulfonylureas and insulin, they are associated with a low risk for hypoglycemia; and, unlike TZDs and insulin, they are not associated with weight gain.6 Linagliptin is a potent and selective DPP-4 inhibitor that prolongs the half-life of the incretin hormone GLP-1, thereby promoting insulin secretion in a glucose-dependent manner.7 Because linagliptin is eliminated primarily via the bile and gut, it can be used without dose adjustment in patients with chronic kidney disease.8 No dose adjustment is required for patients with impaired liver function. In multinational Phase III clinical trials that included Asian patients, linagliptin as monotherapy or in combination with other glucose-lowering drugs reduced hyperglycemia with a low risk of hypoglycemia and did not cause weight gain.9–12 A pooled analysis of data for South and East Asian patients from these studies suggested that linagliptin was an efficacious and well-tolerated treatment option for Asian patients with inadequately controlled T2DM.13 In a global Phase III trial, linagliptin added to metformin reduced HbA1c by a placeboadjusted mean of −0.64 ± 0.07% (95% confidence interval [CI] −0.78, −0.50; P < 0.0001) over 24 weeks.11 Linagliptin has also been evaluated in combination 230

with metformin plus a sulfonylurea.12 A subgroup analysis of that trial has provided evidence for the efficacy and tolerability of linagliptin and metformin plus sulfonylurea in Chinese patients.14 The present dedicated study was undertaken to evaluate the efficacy and safety of linagliptin 5 mg added to metformin in Asian patients with T2DM.

Methods Study overview The present study was a randomized double-blind placebo-controlled parallel-group multicenter Phase III trial (ClinicalTrials.gov ID: NCT01215097). Prior to randomization, patients on metformin and one other OAD discontinued the other OAD treatment only and underwent a wash-out period of 4 weeks. This patient group was then subjected to a 2-week placebo run-in period. Patients pretreated with metformin alone directly entered the 2-week placebo run-in period. The trial was performed in compliance with the principles laid down in the Declaration of Helsinki, in accordance with the International Conference of Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice, and in accordance with applicable regulatory requirements. All participants provided informed written consent.

Patients The patient population in this study originated from 19 centers in three countries (China, The Philippines, and Malaysia). Eligible patients were men and women aged 18–80 years with inadequately controlled T2DM who had been treated with metformin (stable dose ≥1500 mg/ day or maximum tolerated dose) alone or with one other OAD. Additional inclusion criteria were HbA1c 7.0%– 10.0% at the start of the placebo run-in and BMI ≤45 kg/m2 at screening. Patients were ineligible to participate if they had experienced myocardial infarction, stroke, or transient ischemic attack ≤6 months prior to informed consent; had unstable or acute congestive heart failure; had impaired hepatic function at screening; or confirmed hyperglycemia (glucose ≥240 mg/dL) after overnight fasting during the wash-out or run-in periods. Other key exclusion criteria were treatment with a TZD, insulin, GLP-1 agonist, DPP-4 inhibitor, or anti-obesity drugs; recent alcohol and/or drug abuse; current treatment with systemic steroids; renal failure or impairment at screening; and participation in another trial ≤2 months prior to informed consent.

© 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd

W. WANG et al.

Treatments Patients who met the entry criteria at the end of the run-in period were randomized to linagliptin 5 mg or matching placebo in a 2:1 ratio. The randomization was stratified by HbA1c (240 mg/dL during the first 12 weeks and >200 mg/dL during the last 12 weeks of treatment, or a glucose level >400 mg/dL at a randomly performed measurement. A patient was to be discontinued from the study if his or her FPG remained uncontrolled despite rescue therapy initiated as described above. Endpoints The primary endpoint of the study was change from baseline in HbA1c after 24 weeks. Secondary endpoints were change from baseline in HbA1c in Chinese patients, occurrence of target HbA1c efficacy responses (

Efficacy and safety of linagliptin in Asian patients with type 2 diabetes mellitus inadequately controlled by metformin: A multinational 24-week, randomized clinical trial.

Despite the increasing prevalence of type 2 diabetes mellitus (T2DM) in Asia, clinical trials for glucose-lowering therapies are often dominated by Ca...
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