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
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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®.
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).
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.
Linagliptin showed cardiovascular and renal safety in Asian patients with T2DM and established CVD with albuminuria and/or kidney disease.
KeywordsDiabetes mellitus, type 2 Cardiovascular diseases Renal insufficiency, chronic Prescription drugs
The CARMELINA® trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Giles Brooke, PhD, CMPP, of Elevate Scientific Solutions during the preparation of this manuscript.
Compliance with ethical standards
Conflicts of interest
N.I. has received honoraria from Kowa company; research funding from Mitsubishi Tanabe, Daiichi Sankyo and AstraZeneca; and subsidies/donations from Takeda, MSD, Ono, Sanofi, Japan Tobacco Inc., Mitsubishi Tanabe, Novartis, Boehringer Ingelheim, Kyowa Kirin, Astellas, Daiichi Sankyo, Kissei Pharmaceutical, Dainippon Pharma, Sanwa kagaku, Eli Lilly, Novo Nordisk, Teijin Pharma, and Taisho-Toyama Pharma. W.Y. has attended advisory boards for Novo Nordisk; received investigator-initiated trial research funds from AstraZeneca; been a speaker for Novo Nordisk, Bayer, Sanofi Aventis, Merck Sharp & Dohme China, AstraZeneca, Eli Lilly, Boehringer Ingelheim, and Servier; and received honorarium and travel support as an advisory board member from Merck & Co., Inc. H.W. has received honoraria from Eli Lilly, Mitsubishi Tanabe Pharma, Sanofi, Takeda Pharmaceutical Company, Novartis Pharma, Nippon Boehringer Ingelheim, Daiichi Sankyo, Ono Pharmaceutical, Astellas Pharma, FUJIFILM Pharma, Terumo Corporation, MSD; research funding from Eli Lilly, Novartis Pharma, Sanwa kagaku; subsidies/donations from Mitsubishi Tanabe Pharma, Kissei Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, Sumitomo Dainippon Pharma, Sanofi, MSD, Pfizer Japan, Astellas Pharma, Takeda Pharmaceutical Company, Novo Nordisk, Teijin Pharma; and departmental endowments from Takeda Pharmaceutical Company, MSD, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Kowa company, and Sanwa kagaku. L.J. has received consulting and lecture fees from Eli Lilly and Company, Bristol-Myers Squibb, Novartis, Novo Nordisk, Merck, Bayer, MSD, Takeda, Sanofi, Roche, Boehringer Ingelheim, and AstraZeneca; and research support from Roche, Sanofi, MSD, AstraZeneca, Novartis, and Bristol-Myers Squibb. S.S., E.P., T.O., O.E.J., J.T.G., and M.v.E are employees of Boehringer Ingelheim. J.R. has served on scientific advisory boards and received honoraria or consulting fees from Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Boehringer Ingelheim, and Intarcia; he has also received grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Genentech, Janssen, Lexicon, Boehringer Ingelheim, and Intarcia. V.P. has received research support from the Australian National Health and Medical Research Council (Project and Program Grant); served on steering committees for trials supported by AbbVie, Boehringer Ingelheim, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk, Pfizer, Retrophin, and Tricida; and served on advisory boards, spoken at scientific meetings, or both for AbbVie, Astellas Pharma, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect Corporation, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Roche, Sanofi, Servier, and Vitae. He has a policy of having honoraria paid to his employer. C.W. has received fees for advisory services to Boehringer Ingelheim and MSD as well as honoraria for lecturing from AstraZeneca, Eli Lilly and Sanofi. M.E.C. has received fees for advisory services and honoraria from Boehringer Ingelheim, Sanofi, Servier, Bayer, Astra Zeneca, Reata, MundiPharma and MSD and a grant from NovoNordisk. J.H.A. has received personal fees from Abbvie, Bristol-Myers Squibb, CSL Behring, Janssen Pharmaceutics, Novo Nordisk, Pfizer, Portola, and Teikoku; and institutional research support from Boehringer Ingelheim, Bristol-Myers Squibb, Cryolife, CSL Behring, Tenax Therapeutics, and VoluMetrix. I.K. has received honororia from Astellas Pharma Inc., MSD K.K., Edwards Laboratories Corporation, Otsuka Pharmaceutical Co. Ltd, Kowa Company, Ltd., Daiichi Sankyo Company, Limited, Taisho Pharma Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd, Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Limited, Toa Eiyo Ltd, Bayer Yakuhin, Ltd, Terumo Corporation, Nipro Corporation; research funding from Ono Pharmaceutical Co., Ltd; and subsidies/donations from Actelion Pharmaceuticals Japan Ltd. Astellas Pharma Inc., Amgen Astellas BioPharma K.K., AstraZeneca K.K., MSD K.K., Shionogi & Co., Ltd, Daiichi Sankyo Company, Limited, Takeda Pharmacentical Company Limited, Toa Eiyo Ltd, Nippon Boehringer Ingelheim Co., Ltd, Bayer Yakuhin, Ltd, and Pfizer Japan Inc. M.N. is an advisor for KHK, Astellas, GSK, Daiichi-Sankyo, Mitsubishi-Tanabe, JT, Boehringer-Ingelheim; has received honoraria from KHK, Astellas, AstraZeneca, GSK, Daiichi-Sankyo, Mitubishi-Tanabe, Chugai, Torii, JT; manuscript fees from KHK; research funding from JT, KHK; and subsidies/donations from KHK, Astellas, Ono, Daiichi-Sankyo, Takeda, Mitsubishi-Tanabe, Chugai, Torii, MSD, Otsuka, Dainippon-Sumitomo, JT, and Boehringer Ingelheim.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and/or with the Helsinki Declaration of 1964 and later versions.
Human rights statement
This research involves human participants. This report was limited to the Asian population from the CARMELINA® trial (ClinicalTrials.gov Identifier, NCT01897532). The study protocol was approved by the institutional review board or independent ethics committee from each site (approval numbers: not applicable) and all patients provided written informed consent before entering the trial. Full details of the approval process are provided in previous publications [20, 22].
Informed consent or substitute for it was obtained from all patients for being included in the study.
- 7.International Diabetes Federation. IDF Diabetes Atlas. 8th ed. Brussels: International Diabetes Federation; 2017.Google Scholar
- 12.Chen Y, Ning G, Wang C, Gong Y, Patel S, Zhang C, Izumoto T, Woerle HJ, Wang W. Efficacy and safety of linagliptin monotherapy in Asian patients with inadequately controlled type 2 diabetes mellitus: a multinational, 24-week, randomized, clinical trial. J Diabetes Investig. 2015;6(6):692–8.CrossRefGoogle Scholar
- 14.Kawamori R, Inagaki N, Araki E, Watada H, Hayashi N, Horie Y, Sarashina A, Gong Y, von Eynatten M, Woerle HJ, Dugi KA. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes Metab. 2012;14(4):348–57.CrossRefGoogle Scholar
- 15.Ma RC, Del Prato S, Gallwitz B, Shivane VK, Lewis-D’Agostino D, Bailes Z, Patel S, Lee J, von Eynatten M, Di Domenico M, Ross SA. Oral glucose lowering with linagliptin and metformin compared with linagliptin alone as initial treatment in Asian patients with newly diagnosed type 2 diabetes and marked hyperglycemia: subgroup analysis of a randomized clinical trial. J Diabetes Investig. 2018;9(3):579–86.CrossRefGoogle Scholar
- 20.Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, Alexander JH, Pencina M, Toto RD, Wanner C, Zinman B, Woerle HJ, Baanstra D, Pfarr E, Schnaidt S, Meinicke T, George JT, von Eynatten M, McGuire DK. CARMELINA investigators. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019;321(1):69–79.CrossRefGoogle Scholar
- 21.McGuire DK, Alexander JH, Johansen OE, Perkovic V, Rosenstock J, Cooper ME, Wanner C, Kahn SE, Toto RD, Zinman B, Baanstra D, Pfarr E, Schnaidt S, Meinicke T, George JT, von Eynatten M, Marx N. CARMELINA investigators. Linagliptin effects on heart failure and related outcomes in individuals with type 2 diabetes mellitus at high cardiovascular and renal risk in CARMELINA. Circulation. 2019;139(3):351–61.CrossRefGoogle Scholar
- 22.Rosenstock J, Perkovic V, Alexander JH, Cooper ME, Marx N, Pencina MJ, Toto RD, Wanner C, Zinman B, Baanstra D, Pfarr E, Mattheus M, Broedl UC, Woerle HJ, George JT, von Eynatten M, McGuire DK. CARMELINA investigators. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovasc Diabetol. 2018;17(1):39.CrossRefGoogle Scholar
- 24.Marx N, McGuire DK, Perkovic V, Woerle HJ, Broedl UC, von Eynatten M, George JT, Rosenstock J. Composite primary end points in cardiovascular outcomes trials involving type 2 diabetes patients: should unstable angina be included in the primary end point? Diabetes Care. 2017;40(9):1144–51.CrossRefGoogle Scholar
- 25.Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I. SAVOR-TIMI steering committee investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.CrossRefGoogle Scholar
- 27.Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR. TECOS study group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42.CrossRefGoogle Scholar
- 28.Gantz I, Chen M, Suryawanshi S, Ntabadde C, Shah S, O’Neill EA, Engel SS, Kaufman KD, Lai E. A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2017;16(1):112.CrossRefGoogle Scholar
- 31.Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669–701CrossRefGoogle Scholar
- 38.Groop PH, Cooper ME, Perkovic V, Hocher B, Kanasaki K, Haneda M, Schernthaner G, Sharma K, Stanton RC, Toto R, Cescutti J, Gordat M, Meinicke T, Koitka-Weber A, Thiemann S, von Eynatten M. Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial. Diabetes Obes Metab. 2017;19(11):1610–9.CrossRefGoogle Scholar
- 40.Cornel JH, Bakris GL, Stevens SR, Alvarsson M, Bax WA, Chuang LM, Engel SS, Lopes RD, McGuire DK, Riefflin A, Rodbard HW, Sinay I, Tankova T, Wainstein J, Peterson ED, Holman RR. TECOS study group. Effect of sitagliptin on kidney function and respective cardiovascular outcomes in type 2 diabetes: outcomes from TECOS. Diabetes Care. 2016;39(12):2304–10.CrossRefGoogle Scholar