Wanner Christoph, Cooper Mark E, Johansen Odd Erik, Toto Robert, Rosenstock Julio, McGuire Darren K, Kahn Steven E, Pfarr Egon, Schnaidt Sven, von Eynatten Maximilian, George Jyothis T, Gollop Nicholas D, Marx Nikolaus, Alexander John H, Zinman Bernard, Perkovic Vlado
Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg, Germany.
Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia.
Clin Kidney J. 2021 Jan 17;14(1):226-236. doi: 10.1093/ckj/sfaa225. eCollection 2021 Jan.
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.
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.
NRP was present in 646/6979 [9.3% (LINA/PBO = 317/ = 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 m). 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).
Individuals with T2D and NRP have a high disease burden. LINA reduces their albuminuria burden and HbA1c, without affecting CV or kidney risk.
肾病范围蛋白尿（NRP）与肾功能快速丧失及心血管（CV）疾病风险增加相关。我们评估了利格列汀（LINA）对伴有或不伴有NRP的2型糖尿病（T2D）患者心血管和肾脏结局的影响。
利格列汀心血管和肾脏微血管结局研究将患有T2D和CV疾病及/或肾脏疾病的参与者随机分为LINA 5毫克组或安慰剂（PBO）组。主要终点[首次发生3点主要不良心脏事件（3P-MACE）的时间]和肾脏结局，在接受一剂或多剂研究药物治疗的参与者中，根据基线（BL）时的NRP状态[尿白蛋白：肌酐比值（UACR）≥2200毫克/克]进行评估。
646/6979名[9.3%（LINA/PBO = 317/ = 329）]参与者存在NRP，与无NRP者相比，他们更年轻（62.3/66.1岁）且估算肾小球滤过率（eGFR）更低（39.9/56.1毫升/分钟/1.73平方米）。在中位2.2年期间，NRP组发生3P-MACE的发生率比无NRP组（PBO组）高2.0倍，LINA的作用呈中性，与NRP无关。肾脏死亡、终末期肾病（ESKD）或eGFR降低≥40%或≥50%的复合终点，NRP组（PBO组）的发生率高12.3倍和13.6倍；对于前者观察到LINA作用存在异质性[NRP是/否：风险比0.80（0.63 - 1.01）/1.25（1.02 - 1.54）；P交互作用0.005]，但后者未观察到[0.83（0.64 - 1.09）/1.17（0.91 - 1.51），P交互作用0.07]。肾脏死亡或ESKD未观察到异质性[0.88（0.64 - 1.21）/0.94（0.67 - 1.31），P交互作用0.79]。无论是否存在NRP，糖化血红蛋白A1c（HbA1c）均显著降低，且未增加低血糖风险。与基线相比，回归至正常白蛋白尿[1.20（1.07 - 1.34）]和UACR降低≥50%[1.15（1.07 - 1.25）]，LINA组更常见，与NRP状态无关（P交互作用>0.05）。
患有T2D和NRP的个体疾病负担较高。LINA可减轻他们蛋白尿负担和HbA1c，而不影响心血管或肾脏风险。
