Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
George Institute for Global Health, University of Sydney, New South Wales, Australia.
Am J Kidney Dis. 2015 Sep;66(3):441-9. doi: 10.1053/j.ajkd.2015.03.024. Epub 2015 May 7.
Although assessment of cardiovascular safety is mandated by regulatory agencies for the development of new drugs to treat type 2 diabetes, evaluation of their renal safety has been relatively neglected.
Individual patient-level data pooled analysis of 13 phase 2 or 3 randomized, double-blind, placebo-controlled, clinical trials of the dipeptidyl peptidase 4 inhibitor linagliptin.
SETTING & PARTICIPANTS: Participants who participated in any of 13 randomized clinical trials and fulfilled predefined inclusion/exclusion criteria, such as being drug-naive (hemoglobin A1c, 7.0%-11.0% [53-97 mmol/mol]) or being on background glucose-lowering therapy (hemoglobin A1c, 6.5%-10.5% [48-91 mmol/mol]).
Of 5,466 consenting individuals with inadequately controlled type 2 diabetes, 3,505 received linagliptin, 5mg/d, and 1,961 received placebo.
The primary kidney disease outcome was defined as first occurrence during the study of 6 predefined safety end points: new onset of moderate elevation of albuminuria (urinary albumin-creatinine ratio [ACR] >30 mg/g with baseline values ≤ 30 mg/g), new onset of severe elevation of albuminuria (ACR > 300 mg/g with baseline values ≤ 300 mg/g), reduction in kidney function (serum creatinine increase to ≥250 μmol/L from a baseline value <250 μmol/L), halving of estimated glomerular filtration rate (loss of baseline eGFR >50%), acute renal failure (ascertained from diagnostic codes), or death from any cause.
Albuminuria was assessed using ACR. GFR was estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.
Cumulative exposure (person-years) was 1,751 for linagliptin and 1,055 for placebo. The primary composite outcome occurred in 448 (12.8%) and 306 (15.6%) participants in the linagliptin and placebo groups, respectively. Linagliptin treatment significantly reduced the hazard of kidney disease events by 16% compared with placebo (HR, 0.84; 95% CI, 0.72-0.97; P=0.02).
Retrospective and hypothesis-generating study involving short- to midterm clinical trials.
Linagliptin was not associated with increased kidney disease risk in patients with type 2 diabetes. The potential of this drug to improve kidney disease outcomes warrants further investigation.
尽管监管机构要求对治疗 2 型糖尿病的新药进行心血管安全性评估，但对其肾脏安全性的评估相对忽视。
对二肽基肽酶 4 抑制剂利拉利汀的 13 项 2 期或 3 期随机、双盲、安慰剂对照临床试验的个体患者水平数据进行汇总分析。
参加任何 13 项随机临床试验且符合预定义纳入/排除标准的参与者，如药物初治（糖化血红蛋白 7.0%-11.0%[53-97mmol/mol]）或正在接受背景降糖治疗（糖化血红蛋白 6.5%-10.5%[48-91mmol/mol]）。
在 5466 名未能充分控制 2 型糖尿病的同意参与者中，3505 名接受利拉利汀 5mg/d，1961 名接受安慰剂。
主要肾脏疾病结局定义为研究期间首次出现 6 个预先定义的安全性终点之一：新出现中度白蛋白尿升高（尿白蛋白/肌酐比值[ACR]＞30mg/g，且基线值≤30mg/g）、新出现严重白蛋白尿升高（ACR＞300mg/g，且基线值≤300mg/g）、肾功能下降（血清肌酐从基线值＜250μmol/L升高至≥250μmol/L）、估计肾小球滤过率降低＞50%（eGFR 基线丢失）、急性肾衰竭（根据诊断代码确定）或任何原因导致的死亡。
白蛋白尿采用 ACR 评估。GFR 采用 CKD-EPI（慢性肾脏病流行病学合作）方程估算。
利拉利汀的累积暴露（人年）为 1751，安慰剂为 1055。利拉利汀组和安慰剂组分别有 448（12.8%）和 306（15.6%）名参与者发生主要复合结局。与安慰剂相比，利拉利汀治疗显著降低 16%的肾脏疾病事件风险（HR，0.84；95%CI，0.72-0.97；P=0.02）。
回顾性和生成假说的研究，涉及短期至中期临床试验。
在 2 型糖尿病患者中，利拉利汀与肾脏疾病风险增加无关。该药物改善肾脏疾病结局的潜力值得进一步研究。
