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
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
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DOI：
10.1001/jama.2018.18269
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发表时间：
2019-01-01
影响因子：
120.7
通讯作者：
Coles, Adrian
中科院分区：
文献类型：
--
作者：
Rosenstock, Julio;Perkovic, Vlado;Coles, Adrian
2型糖尿病与心血管（CV）风险增加相关。先前的试验已经证实了3种二肽基肽酶4 （DPP-4）抑制剂的CV安全性，但只纳入了有限数量的CV高风险和慢性肾脏疾病患者。目的评价利格列汀（一种选择性DPP-4抑制剂）对CV和肾脏事件高危2型糖尿病患者CV结局和肾脏结局的影响。设计、环境和参与者：2013年8月至2016年8月，在27个国家的605个临床站点进行了随机、安慰剂对照、多中心非优效性试验，受试者为2型糖尿病成人，血红蛋白A（1c）为6.5%至10.0%，CV高风险（血管疾病史和尿白蛋白肌酐比值[UACR]低于200mg/g），肾脏高风险（eGFR降低和微量或大量蛋白尿）。排除患有终末期肾病（ESRD）的参与者。最终随访于2018年1月18日进行。干预措施患者随机接受利格列汀，5mg每日一次（n = 3494），或安慰剂每日一次（n = 3485），并加入常规护理。其他降糖药物或胰岛素可根据临床需要和当地临床指南添加。主要结局和测量主要结局为心血管死亡、非致死性心肌梗死或非致死性卒中复合的首次发生时间。利格列汀相对于安慰剂的非劣效性标准是利格列汀相对于安慰剂的危险比（HR）的双侧95% CI上限小于1.3。次要终点是首次因肾功能衰竭、ESRD或eGFR从基线持续下降40%或更高而确定死亡的时间。结果6991名入组者中，6979名（平均年龄65.9岁；eGFR 54.6 mL/min/1.73m2; 80.1% UACR bb0 30mg/g）接受了至少1剂研究药物，98.7%完成了研究。在中位随访2.2年期间，利格列汀组和安慰剂组的主要结局分别发生在3494人中有434人（12.4%）和3485人中有420人（12.1%），（绝对发病率差为0.13 [95% CI,-0.63至0.90]/ 100人年）(HR, 1.02; 95% CI, 0.89-1.17； P
IMPORTANCE Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease.OBJECTIVE To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events.DESIGN, SETTING, AND PARTICIPANTS Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A(1c) of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] > 200mg/g), and high renal risk (reduced eGFR and micro-or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018.INTERVENTIONS Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines.MAIN OUTCOMES AND MEASURES Primary outcomewas time to first occurrence of the composite of CV death, nonfatalmyocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline.RESULTS Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73m2; 80.1% with UACR > 30mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI,-0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P