Effect of linagliptin versus placebo on cardiovascular and kidney outcomes in nephrotic-range proteinuria and type 2 diabetes: the CARMELINA randomized controlled trial

Christoph Wanner, Mark E. Cooper, Odd Erik Johansen, Robert Toto, Julio Rosenstock, Darren K. McGuire, Steven E. Kahn, Egon Pfarr, Sven Schnaidt, Maximilian von Eynatten, Jyothis T. George, Nicholas D. Gollop, Nikolaus Marx, John H. Alexander, Bernard Zinman, Vlado Perkovic, CARMELINA investigators

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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 5 mg 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/1.73 m2). 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 UACR ≥50% [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.

Original languageEnglish
Pages (from-to)226-236
Number of pages11
JournalClinical Kidney Journal
Issue number1
Early online date17 Jan 2021
Publication statusPublished - Jan 2021


  • albuminuria
  • DPP-4 inhibitor
  • HbA1c
  • kidney disease
  • linagliptin
  • renal impairment
  • Type 2 diabetes

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