Dallas Diabetes Research Center at Medical City, Dallas, Texas.
University of Texas Southwestern Medical Center, Dallas.
JAMA. 2019 Jan 1;321(1):69-79. doi: 10.1001/jama.2018.18269.
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 A1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/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 outcome was time to first occurrence of the composite of CV death, nonfatal myocardial 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/1.73 m2; 80.1% with UACR >30 mg/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 < .001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis. CONCLUSIONS AND RELEVANCE: Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01897532.
重要性：2 型糖尿病与心血管（CV）风险增加相关。先前的试验已经证明了 3 种二肽基肽酶 4（DPP-4）抑制剂的 CV 安全性，但包括的高危 CV 和慢性肾脏病患者数量有限。
目的：评估选择性 DPP-4 抑制剂利格列汀在 27 个国家/地区的 605 个临床中心，对 2 型糖尿病、糖化血红蛋白 6.5%至 10.0%、高危 CV（血管疾病史和尿白蛋白肌酐比[UACR]＞200 mg/g）和高危肾脏风险（降低的 eGFR 和微量或大量白蛋白尿）的高危 CV 和肾脏事件的患者，CV 结局和肾脏结局的影响。
设计、地点和参与者：2013 年 8 月至 2016 年 8 月期间，在 27 个国家/地区的 605 个临床中心，对 2 型糖尿病、糖化血红蛋白 6.5%至 10.0%、高危 CV（血管疾病史和 UACR＞200 mg/g）和高危肾脏风险（降低的 eGFR 和微量或大量白蛋白尿）的成年人进行了一项随机、安慰剂对照、多中心非劣效性试验。排除了终末期肾病（ESRD）患者。最终随访时间为 2018 年 1 月 18 日。
干预措施：患者被随机分配接受利格列汀，5mg 每日一次（n=3494）或安慰剂，每日一次（n=3485），同时接受常规治疗。可根据临床需要和当地临床指南添加其他降糖药物或胰岛素。
主要结果和测量：主要结果是首次发生 CV 死亡、非致死性心肌梗死或非致死性卒中的复合事件的时间。利格列汀相对于安慰剂的非劣效性定义为，利格列汀相对于安慰剂的风险比（HR）的双侧 95%置信区间上限小于 1.3。次要结果是首次发生经裁决的因肾衰竭、ESRD 或 eGFR 持续下降 40%或更多而导致的死亡的时间。
结果：在 6991 名入组者中，6979 名（平均年龄 65.9 岁；eGFR 54.6 mL/min/1.73 m2；80.1%的 UACR＞30 mg/g）接受了至少 1 次研究药物治疗，98.7%的患者完成了研究。中位随访 2.2 年后，利格列汀组和安慰剂组分别有 3494 名（12.4%）和 3485 名（12.1%）患者发生主要结局（绝对发生率差异，0.13 [95%CI，-0.63 至 0.90]每 100 人年）（HR，1.02；95%CI，0.89-1.17；P＜0.001 用于非劣效性）。肾脏结局发生在利格列汀组和安慰剂组的 3494 名患者中分别为 327 名（9.4%）和 306 名（8.8%）（绝对发生率差异，0.22 [95%CI，-0.52 至 0.97]每 100 人年）（HR，1.04；95%CI，0.89-1.22；P=0.62）。利格列汀组和安慰剂组分别有 2697 名（77.2%）和 2723 名（78.1%）患者发生不良事件；1036 名（29.7%）和 1024 名（29.4%）发生 1 次或多次低血糖事件；有 9 名（0.3%）和 5 名（0.1%）患者发生经裁决确认的急性胰腺炎事件。
结论和相关性：在患有 2 型糖尿病和高危 CV 和肾脏风险的成年人中，与安慰剂相比，利格列汀添加到常规治疗中，在中位 2.2 年的时间内，CV 复合结局的风险非劣效。
试验注册：ClinicalTrials.gov 标识符：NCT01897532。
Front Endocrinol (Lausanne). 2025-7-30
Diabetes Metab Res Rev. 2025-7
Cochrane Database Syst Rev. 2018-9-24
Cochrane Database Syst Rev. 2017-6-8
Kidney Int. 2017-6-1
N Engl J Med. 2017-4-13
Diabetes Obes Metab. 2017-3
Diabetes Care. 2016-10-17
Zotero 插件