NEJM: 阿利吉仑治疗2型糖尿病的临床试验：心肾终点

　　背景  这项研究旨在确定使用直接肾素抑制剂能否减少患有慢性肾病和（或）心血管疾病的2型糖尿病患者的心血管和肾脏事件。

　　方法  我们以双盲的方式将9561例患者随机分配，接受阿利吉仑（300 mg/d）或安慰剂作为血管紧张素转换酶抑制剂（ACEI）或血管紧张素受体拮抗剂（ARB）的辅助治疗。主要终点为以下事件的组合：至心血管死亡或首次发生心脏停搏伴复苏的时间；非致死性心肌梗死；非致死性卒中；因心衰计划外住院；终末期肾病、肾衰竭导致死亡，或需要肾脏替代治疗（透析或移植不可行或未开始）；或基线血清肌酐水平倍增。

　　结果  在第二次中期有效性分析后试验提前终止。中位随访32.9个月后，783例（18.3%）被分配至阿利吉仑组的患者出现主要终点，相比之下，732例（17.1%）被分配至安慰剂组的患者[风险比1.08，95%可信区间（CI）0.98~1.20；P = 0.12]出现主要终点。对次要肾脏终点的效应相似。阿利吉仑组收缩压和舒张压较低（组间差异分别为1.3 mmHg和0.6 mmHg），且尿白蛋白/肌酐比平均下降程度较大（组间差异为14%，95%CI 11%~17%）。阿利吉仑组有高钾血症（血清钾水平≥6 mmol/L）的患者比例显著高于安慰剂组（11.2%对7.2%），阿利吉仑组报告低血压的患者比例也较高（12.1%对8.3%）（两项比较P值均＜0.001）。

　　结论  在心血管和肾脏事件高危的2型糖尿病患者中，本研究的数据并不支持在肾素血管紧张素系统阻滞标准治疗的基础上加阿利吉仑，加阿利吉仑甚至还有可能有害。

Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes

BACKGROUND

This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both.

METHODS

In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting–enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level.

RESULTS

The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons).

CONCLUSIONS

The addition of aliskiren to standard therapy with renin–angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.)