Linagliptin and cardiorenal outcomes in Asians with type 2 diabetes mellitus and established cardiovascular and/or kidney disease: subgroup analysis of the randomized CARMELINA® trial

Nobuya Inagaki; Wenying Yang; Hirotaka Watada; Linong Ji; Sven Schnaidt; Egon Pfarr; Tomoo Okamura; Odd Erik Johansen; Jyothis T George; Maximilian von Eynatten; Julio Rosenstock; Vlado Perkovic; Christoph Wanner; Mark E Cooper; John H Alexander; Issei Komuro; Masaomi Nangaku

doi:10.1007/s13340-019-00412-x

Linagliptin and cardiorenal outcomes in Asians with type 2 diabetes mellitus and established cardiovascular and/or kidney disease: subgroup analysis of the randomized CARMELINA^® trial

Diabetol Int. 2019 Oct 22;11(2):129-141. doi: 10.1007/s13340-019-00412-x. eCollection 2020 Apr.

Authors

Nobuya Inagaki¹, Wenying Yang², Hirotaka Watada³, Linong Ji⁴, Sven Schnaidt⁵, Egon Pfarr⁶, Tomoo Okamura⁷, Odd Erik Johansen⁸, Jyothis T George⁹, Maximilian von Eynatten⁹, Julio Rosenstock¹⁰, Vlado Perkovic¹¹, Christoph Wanner¹², Mark E Cooper¹³, John H Alexander¹⁴, Issei Komuro¹⁵, Masaomi Nangaku¹⁶

Affiliations

¹ 1Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507 Japan.
² 2Department of Endocrinology, China-Japan Friendship Hospital, Beijing, People's Republic of China.
³ 3Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁴ 4Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, People's Republic of China.
⁵ 5Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
⁶ 6Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.
⁷ 7Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan.
⁸ 8Boehringer Ingelheim Norway KS, Asker, Norway.
⁹ 9Boehringer Ingelheim International GmbH, Ingelheim, Germany.
¹⁰ 10Dallas Diabetes Research Center at Medical City, University of Texas Southwestern Medical Center, Dallas, TX USA.
¹¹ 11George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia.
¹² 12Division of Nephrology, Department of Medicine, Würzburg University Clinic, Würzburg, Germany.
¹³ 13Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia.
¹⁴ 14Duke Clinical Research Institute, Duke Health, Durham, NC USA.
¹⁵ 15Department of Cardiovascular Medicine, University of Tokyo Hospital, Tokyo, Japan.
¹⁶ 16Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Abstract

Objective: Linagliptin, a dipeptidyl peptidase-4 inhibitor, demonstrated cardiovascular and renal safety in type 2 diabetes mellitus (T2DM) patients with established cardiovascular disease (CVD) with albuminuria and/or kidney disease in the multinational CARMELINA^® trial. We investigated the effects of linagliptin in Asian patients in CARMELINA^®.

Methods: T2DM patients with HbA1c 6.5-10.0% and established CVD with urinary albumin-to-creatinine ratio (UACR) > 30 mg/g, and/or prevalent kidney disease (estimated glomerular filtration rate [eGFR] 15-< 45 ml/min/1.73 m² or ≥ 45-75 with UACR > 200 mg/g), were randomized to linagliptin or placebo added to usual care. The primary endpoint was time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3-point MACE).

Results: Of the 6979 patients, 555 (8.0%) were Asians living in Asia. During a median follow-up of 2.2 years, 3-point MACE occurred in 29/272 (10.7%) and 33/283 (11.7%) of linagliptin and placebo patients, respectively (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.55-1.48), consistent with the overall population (HR 1.02; 95% CI 0.89-1.17; P value for treatment-by-region interaction: 0.3349). Similar neutrality in Asian patients was seen for other cardiorenal events including the secondary kidney endpoint of death from renal failure, progression to end-stage kidney disease, or ≥ 40% eGFR decrease (HR 0.96; 95% CI 0.58-1.59). Linagliptin was associated with a nominal decrease in the risk of hospitalization for heart failure (HR 0.47; 95% CI 0.24-0.95). Overall in Asian patients, linagliptin had an adverse event rate similar to placebo, consistent with the overall population.

Conclusions: Linagliptin showed cardiovascular and renal safety in Asian patients with T2DM and established CVD with albuminuria and/or kidney disease.

Keywords: Cardiovascular diseases; Diabetes mellitus, type 2; Prescription drugs; Renal insufficiency, chronic.