阿利吉仑对糖尿病患者无心肾保护作用

根据一项纳入8,000余例患者的多国研究的结果，在合并肾脏或心血管疾病的2型糖尿病患者中，标准降压治疗基础上追加肾素抑制剂阿利吉仑未能减少严重心血管或肾脏事件。这一结果来自ALTITUDE(在2型糖尿病患者中使用心脏和肾脏终点的阿利吉仑试验)研究，该研究结果在2012年肾脏周上公布，并同时在线发表于11月3日的《新英格兰医学杂志》。

Hans-Henrik Parving博士

之前的研究数据提示，在糖尿病肾病患者中，直接肾素抑制剂阿利吉仑与一种血管紧张素受体阻滞剂(ARB)联合使用，较单纯ARB治疗可进一步减少白蛋白尿，哥本哈根大学的Hans-Henrik Parving博士及其同事说。但阿利吉仑与一种ARB或血管紧张素转化酶(ACE)抑制剂联用对肾脏和心血管预后的影响尚不明确。

为了确定肾素-血管紧张素-醛固酮系统(RAAS)双重阻滞的安全性，研究者随机给予36个国家、838个中心的8,606例成人患者标准治疗加阿利吉仑或安慰剂治疗。对于2007年10月~2010年6月募集的8,561例患者，可获取完整数据。符合入选标准的受试者患有2型糖尿病，并接受一种ARB或ACE抑制剂治疗(N. Engl. J. Med. 2012, Nov. 3 [doi:10.1056/NEJMoa1208799])。患者平均年龄为65岁，大约1/3为女性。两组患者的基线人口统计学特征相似。2个月后，接受阿利吉仑治疗的患者中有84%使用了最大剂量300 mg。主要复合终点包括心血管源性死亡、心脏停搏复苏、心肌梗死(致死或非致死)、卒中(致死或非致死)、计划外因心力衰竭住院、终末期肾病(因肾衰竭或肾功能不全而致的死亡)以及基线血清肌酐加倍。一例患者“可能发生多种不同类型的心血管或肾脏事件”。

结果显示，经过中位时间大约2.5年的随访，阿利吉仑组的783例患者(18%)和安慰剂组的732例患者(17%)达到主要终点，但差异无统计学意义(P=0.12)。6个月后，阿利吉仑组收缩压和舒张压较安慰剂组显著降低，且尿白蛋白/肌酐比值的平均降幅显著大于安慰剂组。但阿利吉仑组发生高钾血症(39% vs. 29%)和低血压(12% vs. 8%)的患者比例显著高于安慰剂组。阿利吉仑组和安慰剂组的全因死亡数无显著差异(119 vs. 102)。阿利吉仑组因不良事件退出试验的患者比例显著高于安慰剂组(13% vs. 10%)。最常见的不良事件为高钾血症、其次为肾功能受损和低血压。“在所有预先设定的亚组中，均可看到总体上缺乏关于主要复合心血管和肾脏终点的益处。”研究者称，另外有两项关于阿利吉仑联合其他肾素-血管紧张素系统阻滞剂治疗心力衰竭患者的试验正在进行中。

该研究由诺华公司资助。Parving博士接受了诺华公司提供的研究经费，并任职于诺华和赛诺菲公司的讲师团，此外还担任雅培、Reata和武田公司的顾问。

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By: HEIDI SPLETE, Cardiology News Digital Network

Adding the renin inhibitor aliskiren to standard hypertension treatment in type 2 diabetes patients with comorbid kidney or cardiovascular disease did not reduce serious cardiovascular or renal events, according to a multinational study of more than 8,000 patients.

The findings from ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) were presented at Kidney Week 2012 and simultaneously published online Nov. 3 in the New England Journal of Medicine.
 
Data from previous studies suggest that the direct renin inhibitor aliskiren, when combined with an angiotensin-receptor blocker (ARB), was associated with a greater decrease in albuminuria than ARB treatment alone in patients with diabetic renal disease, said Dr. Hans-Henrik Parving of the University of Copenhagen and his colleagues. However, the effect on renal and cardiovascular outcomes of combining aliskiren with an ARB or an angiotensin-converting–enzyme (ACE) inhibitor is unknown, they said.

To determine the safety of a dual renin–angiotensin–aldosterone system (RAAS) blockade, the researchers randomized 8,606 adults at 838 centers in 36 countries to receive standard treatment plus aliskiren or a placebo. Complete data were available for 8,561 patients enrolled between October 2007 and June 2010. Eligible patients had type 2 diabetes and were taking either an ARB or ACE inhibitor (N. Engl. J. Med. 2012, Nov. 3 [doi:10.1056/NEJMoa1208799]).

The average age of the patients was 65 years, and approximately one-third were female. Baseline demographics were similar between the two groups. After 2 months, 84% of the aliskiren patients were taking the maximum dose of 300 mg.

The primary composite outcome included death from cardiovascular causes, cardiac arrest with resuscitation, myocardial infarction (fatal or nonfatal), stroke (fatal or nonfatal), unplanned hospitalization for heart failure, end-stage renal disease (death attributable to kidney failure or loss of kidney function), and doubling of baseline serum creatinine. Any one patient "may have had multiple cardiovascular or renal events of different types," the researchers noted.

After a median follow-up of approximately 2.5 years, 783 patients in the aliskiren group (18%) and 732 in the placebo group (17%) met the primary end point, though the difference was not statistically significant (P = .12)

Aliskiren patients showed significantly lower systolic and diastolic blood pressures and higher mean reductions in urinary albumin-to-creatinine ratios after 6 months than placebo patients. However, significantly more aliskiren patients than placebo patients had hyperkalemia (39% vs. 29%, respectively) and hypotension (12% vs. 8%, respectively).

The number of deaths from any cause was not significantly different between the aliskiren and placebo groups (119 and 102, respectively).

Significantly more aliskiren patients than placebo patients discontinued the study drug due to an adverse event (13% vs. 10%). The most common adverse event was hyperkalemia, followed by renal impairment and hypotension.

"The overall lack of benefit with regard to the primary composite cardiovascular and renal outcome was observed across all the predefined subgroups," the researchers said.

Two trials of aliskiren in combination with another renin-angiotensin system blocker in heart failure patients are ongoing, the researchers said.

However, "the present study documented more adverse events in the aliskiren group than in the placebo group without clinical benefits to offset them, which underscores the need to go beyond surrogate biomarkers and obtain risk-benefit data from clinical end-point trials to better inform clinical decisions," they said.

Novartis supported the study. Dr. Parving has received funding from Novartis, served on the speakers bureau for Novartis and Sanofi, and has served as a consultant for Abbott, Reata, and Takeda.