ORLANDO (EGMN) – Metformin use was associated with a significant decrease in the risk of all-cause death among diabetic patients at risk for cardiovascular events.

The subanalysis of the Reduction of Atherothrombosis for Continued Health (REACH) Registry found that subjects with type 2 diabetes who took metformin were 24% less likely to die from all-cause mortality over 2 years than were those who did not take the drug. The association remained significant even after researchers controlled for age and gender, and after factoring in a number of baseline characteristics that varied significantly between the groups.

“Given the diversity of the 44 countries and widely different practice settings involved in the registry, we think these data are highly relevant,” Dr. Ronan Roussel said at the annual meeting of the American Diabetes Association. While perhaps not sufficient to make practice recommendations, he did say the results are strong enough to prompt clinical trials, especially when viewed in the context of the growing body of evidence about metformin’s cardioprotective effects.

The REACH Registry was established to track outcomes in patients with atherothrombosis or atherothrombotic risk factors. Almost 70,000 patients were enrolled. They were either symptomatic, with documented cardiovascular, coronary artery or peripheral artery disease; or asymptomatic with at least three risk factors for atherothrombosis.

Of this group, 19,699 had type 2 diabetes and 2-year outcomes data. Dr. Roussel of the Groupe Hospitalier Bichat-Claude Bernard, Paris, and his colleagues compared those who were taking metformin at baseline with those who were not. Metformin was taken by 40% of the patients.

There were some significant baseline differences between the groups, Dr. Roussel noted. Patients taking metformin were significantly younger (67 vs. 69 years), had a higher average fasting blood glucose (138 mg/dL vs. 131 mg/dL), and higher systolic blood pressure (138mmHg vs. 136 mmHg).

Prior arterial disease was present in 80% of those taking metformin and 75% of those not. Metformin users were also taking significantly more cardiovascular drugs, including aspirin (74% vs. 69%), statins (75% vs. 67%), and angiotensin-converting enzyme inhibitors (54% vs. 49%).

Over the 2-year follow-up period, there were 1,270 deaths. After researchers adjusted for gender and age only, metformin was associated with a 33% reduction in the risk of all-cause death. A Kaplan-Meier analysis showed that the mortality trajectories began to separate early, with a significant difference appearing around 6 months.

After adjustment for the other factors, the mortality difference still remained significant in favor of metformin use, with a 24% risk reduction in all-cause death.

When the researchers examined the genders separately, they found no statistically significant differences. “But women did appear to have more of an advantage,” with a 34% risk reduction, compared with a 24% reduction in men, Dr. Roussel said.

In an age analysis, with subjects split into groups 40-65 years, 65-80 years, and older than 80 years, the risk reductions were significant for the youngest group (37%), and the middle group (23%). The oldest subjects did not have a survival advantage with the drug.

Metformin also improved the odds of survival in patients with existing congestive heart failure, conferring a significant 31% reduction in the risk of death.

While renal insufficiency is considered a contraindication to metformin use, Dr. Roussel noted that REACH subjects with moderately impaired renal function appeared to benefit from the drug. Those with a glomerular filtration rate of 30-60 mL/min had a significant 36% reduction in the risk of death; those with a GFR of less than 30 mL/min or greater than 60 mL/min did not gain a significant survival advantage.

Subjects who were taking insulin as well as metformin benefited more than did those who were taking metformin alone (hazard ratio 0.64 vs. 0.80).

The REACH Registry is sponsored by Sanofi-Aventis, Bristol-Myers Squibb, and the Waksman Foundation, Tokyo. Dr. Roussel disclosed that he has received research support or consulting fees from Sanofi-Aventis, Servier Laboratories, Roche, Eli Lilly & Co., Novo Nordisk Inc., Medtronic Inc., and LifeScan Inc.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

奥兰多(EGMN)——有心血管事件发生风险的糖尿病患者服用二甲双胍可显著减少全因死亡风险。

 

对减少动脉粥样硬化血栓形成实现持续健康(REACH)注册研究进行的亚组分析发现，服用二甲双胍的2型糖尿病患者2年的全因死亡风险相对于未服用者减少24%。在研究者们校正年龄和性别之后，以及对大量具有明显组间差异的基线特征进行析因分析后，此相关性仍具有统计学意义。

 

Ronan Roussel博士在美国糖尿病学会年会上说：“鉴于注册处中的44个国家具有多样性以及各医疗机构的诊治实践有较大差异，故我们认为这些数据具有高度相关性。”这可能尚不足以制定实践建议，但他确实表示这些结果足以推动临床试验的进行，特别是在考虑到有越来越多的证据证实二甲双胍具有心脏保护效应的情况下。

 

成立REACH注册处旨在追踪有粥样硬化血栓形成危险因素的患者转归。募集的患者例数接近70,000例。这些受试者是确诊为心血管、冠状动脉或外周动脉病变的有症状患者或是至少存在3个粥样硬化血栓形成危险因素的无症状患者。

 

在该组患者中，有19,699例患有2型糖尿病且有2年转归数据。巴黎Groupe Hospitalier Bichat-Claude Bernard医院的Roussel博士及其同事比较了基线时在服用二甲双胍的患者与未服用者，服用二甲双胍者占40%。

 

Roussel博士指出，一些基线特征存在显著的组间差异：服用二甲双胍的患者年龄明显偏小(67岁对69 岁)，平均空腹血糖水平较高(138 mg/dl对 131 mg/dl)，且收缩压较高(138 mmHg 对 136 mmHg)。

 

二甲双胍服用者中有80%既往有动脉病变，而未服用者中有75%。二甲双胍服用者服用的心血管药物亦明显偏多，其中包括阿司匹林(74% 对69%)、他汀类药物(75% 对67%)以及血管紧张素转化酶抑制剂(54%对49%)。

 

2年随访过程中发生了1,270例死亡。在研究者们仅对性别和年龄进行调整后，二甲双胍与全因死亡风险减少33%有关。Kaplan-Meier分析结果表明，死亡率曲线很早就开始分开，在大约6个月就出现显著差异。

 

在对其他因素进行调整后，两组患者之间在死亡率上仍存在显著差异，服用二甲双胍结局较优，其全因死亡风险减少24%。

 

研究者在分性别进行检验时未发现有统计学意义的性别差异。“但女性确实看起来更优一些”，其风险减少34%，而男性减少24%，Roussel博士说。

 

在一项年龄分析中，受试者被分成40~65岁年龄组、65~80岁年龄组及80岁以上年龄组。其分析结果显示最年轻组(37%)和中间年龄组(23%)风险减少最为明显，而最年长的受试者服用此药无生存收益。

 

合并充血性心力衰竭的患者服用二甲双胍后生存几率得到提高，死亡风险显著减少达31%。

 

尽管肾功能不全被视为二甲双胍用药的一个禁忌证，但Roussel博士指出，有中度肾功能损害的REACH研究受试者服用此药仍有收益。肾小球滤过率(GFR)介于30~60 ml/min的患者死亡风险显著减少达36%；GFR< 30 ml/min或>60 ml/min的受试者未获得明显的生存收益。

 

用胰岛素配伍二甲双胍的受试者收益大于仅服用二甲双胍者(危险比：0.64 对 0.80)。

 

REACH注册研究由赛诺菲安万特、百时美施贵宝以及东京Waksman基金会赞助。Roussel博士披露其本人已收到赛诺菲安万特、施维亚实验室、罗氏、礼来、诺和诺德、美敦力以及LifeScan公司的研究资助或顾问费。

 

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