@article{26a01c824a0c48f09d33cbc206031f3b,
title = "Effect of linagliptin versus placebo on cardiovascular and kidney outcomes in nephrotic-range proteinuria and type 2 diabetes: The CARMELINA randomized controlled trial",
abstract = "Background. Nephrotic-range proteinuria (NRP) is associated with rapid kidney function loss and increased cardiovascular (CV) disease risk. We assessed the effects of linagliptin (LINA) on CV and kidney outcomes in people with Type 2 diabetes (T2D) with or without NRP. Methods. Cardiovascular and renal microvascular outcome study with LINA randomized participants with T2D and CV disease and/or kidney disease to LINA 5mg or placebo (PBO). The primary endpoint [time to first occurrence of 3-point major adverse cardiac events (3P-MACE)], and kidney outcomes, were evaluated by NRP status [urinary albumin:creatinine ratio (UACR)2200 mg/g] at baseline (BL) in participants treated with one or more dose of study medication. Results. NRP was present in 646/6979 [9.3% (LINA/PBO n=317/n=329); median UACR 3486 (Q1: 2746/Q3: 4941) mg/g] participants, who compared with no-NRP were younger (62.3/66.1 years) and had lower estimated glomerular filtration rate (eGFR) (39.9/56.1 mL/min/1.73m2). Over a median of 2.2 years, 3P-MACE occurred with a 2.0-fold higher rate in NRP versus no-NRP (PBO group), with a neutral LINA effect, regardless of NRP. The composite of time to renal death, end-stage kidney disease (ESKD) or decrease of 40 or 50% in eGFR, occurred with 12.3-and 13.6-fold higher rate with NRP (PBO group); evidence of heterogeneity of effects with LINA was observed for the former [NRP yes/no: hazard ratio 0.80 (0.63-1.01)/1.25 (1.02-1.54); P-interaction 0.005], but not the latter [0.83 (0.64-1.09)/1.17 (0.91-1.51), P-interaction 0.07]. No heterogeneity was observed for renal death or ESKD [0.88 (0.64-1.21)/0.94 (0.67-1.31), P-interaction 0.79]. Glycated haemoglobin A1c (HbA1c) was significantly reduced regardless of NRP, without increasing hypoglycaemia risk. Regression to normoalbuminuria [1.20 (1.07-1.34)] and reduction of UACR50% [1.15 (1.07-1.25)] from BL, occurred more frequently with LINA, regardless of NRP status (P-interactions >0.05). Conclusions. Individuals with T2D and NRP have a high disease burden. LINA reduces their albuminuria burden and HbA1c, without affecting CV or kidney risk. ",
keywords = "albuminuria, DPP-4 inhibitor, HbA1c, kidney disease, linagliptin, renal impairment, Type 2 diabetes",
author = "Christoph Wanner and Cooper, {Mark E.} and Johansen, {Odd Erik} and Robert Toto and Julio Rosenstock and McGuire, {Darren K.} and Kahn, {Steven E.} and Egon Pfarr and Sven Schnaidt and {Von Eynatten}, Maximilian and George, {Jyothis T.} and Gollop, {Nicholas D.} and Nikolaus Marx and Alexander, {John H.} and Bernard Zinman and Vlado Perkovic and {on behalf of the CARMELINA investigators}",
note = "Funding Information: C.W. has received grant support, fees for advisory services and lecturing from Boehringer Ingelheim. Advisory services fees came from Bayer, MSD and MundiPharma, as well as fees for lecturing from Eli Lilly and AstraZeneca. M.E.C. has received research support from the Australian National Health and Medical Research Council (Project and Investigator Grants), and advisory boards or speaking at scientific meetings (or both) for Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, MSD, MundiPharma, Novartis, Novo Nordisk, Reata, Sanofi and Servier. O.E.J. was an employee of Boehringer Ingelheim at the time of writing of this manuscript, but is now an employee of Nestl{\'e} Health Science. R.T. is a consultant to Amgen, Boehringer Ingelheim, ZS Pharma, Relypsa, Novo Nordisk, Reata, AstraZeneca, Bayer and receives grant support from the NIH. J.R. has served on scientific advisory boards and received honoraria or consulting fees from Eli Lilly, Sanofi, Novo Nordisk, Janssen, Oramed, Boehringer Ingelheim and Intarcia; he has also received grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmithKline, Genentech, Janssen, Lexicon, Boehringer Ingelheim, Oramed and Intarcia. D.K.M. has received personal fees from Afimmune, Boehringer-Ingelheim, Janssen Research and Development LLC, Sanofi-Aventis Group, Merck Sharp and Dohme, Merck & Co., Lilly USA, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon, Eisai Inc., Pfizer, Metavant, Applied Therapeutics, Esperion. S.E.K. has received personal fees from Boehringer Ingelheim, Eli Lilly, Intarcia, Merck, Novo Nordisk and Pfizer. N.M. has given lectures for Amgen, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, NovoNordisk; has received unrestricted research grants from Boehringer Ingelheim; and has served as an advisor for Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca and NovoNordisk. In addition, he has served in trial leadership for Boehringer Ingelheim and Novo Nordisk. All personal compensation from pharma or device companies are declined. J.H.A. has received personal fees from Abbvie, Bayer, Bristol-Myers Squibb, CryoLife, CSL Behring, Novo Nordisk, Pfizer, Portola, Quantum Genomics, XaTek and Zafgen, and institutional research support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cryolife, CSL Behring, Ferring, Glaxosmithkline and XaTek. B.Z. has received consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi Aventis. E.P., S.S., J.T.G. and N.D.G. are employed by Boehringer Ingelheim. M.v.E. was employed by Boehringer Ingelheim at the time of conduct of the study, but is now an employee of Nestl{\'e} Health Science. V.P. has received research support from the Australian National Health and Medical Research Council (Project and Programme Grant); steering committees for trials supported by AbbVie, Boehringer Ingelheim, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk, Pfizer, Retrophin and Tricida; advisory boards or speaking at scientific meetings (or both) for AbbVie, Astellas Pharma, Astra Zeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect Corporation, Eli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen, Merck & Co, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Roche, Sanofi, Servier and Vitae. He has a policy of having honoraria paid to his employer. Parts of these data were presented during a late-breaking oral presentation at ERA-EDTA 14 June 2019, Budapest, Hungary. Funding Information: This study was sponsored by Boehringer Ingelheim. Publisher Copyright: {\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.",
year = "2021",
month = jan,
doi = "10.1093/ckj/sfaa225",
language = "English",
volume = "14",
pages = "226--236",
journal = "Clinical Kidney Journal",
issn = "2048-8505",
publisher = "Oxford University Press",
number = "1",
}
