磺脲类药物治疗可能增加死亡风险

休斯顿——一项纳入约24,000例接受单药治疗的2型糖尿病患者的回顾性研究显示，接受格列吡嗪、格列本脲或格列美脲治疗的患者的死亡风险，较二甲双胍治疗者升高59%~68%。

俄亥俄州Summa Western Reserve医院的Kevin M. Pantalone博士在内分泌学会年会上指出：“目前，美国食品药品管理局(FDA)要求对所有糖尿病治疗药物进行心血管安全性研究。而磺脲类药物被美国糖尿病学会(ADA)视为经过了核心验证的传统治疗，似乎获得了关于心血管风险的特许通行证。”为了进一步评估磺脲类药物的心血管安全性，他与同事进行了这项回顾性研究。

Kevin M. Pantalone博士

研究者使用克利夫兰医院电子医疗记录系统中的数据，共纳入23,915例开始接受二甲双胍或3种磺脲类药物之一的单药治疗的2型糖尿病患者。对患者中位随访2.2年，在58,513患者-年的随访中共发生2,546例死亡。

一项校正16种变量的多因素Cox回归分析显示，格列吡嗪治疗与全因死亡相对风险较二甲双胍治疗增高64%独立相关。格列本脲治疗与死亡风险增高59%相关，格列美脲与死亡风险增高68%相关。2,721例基线时被证实患有冠心病(CAD)的糖尿病患者中，在5,980患者-年的随访中共发生419例死亡；在这一亚组中，格列吡嗪治疗者的总死亡风险较二甲双胍治疗者增高41%，格列本脲治疗者的总死亡风险较二甲双胍治疗者增高38%。

研究者指出，鉴于美国大约有2600万例糖尿病患者，并且多数患者同时患有CAD或CAD风险增高，二甲双胍和以上3种磺脲类药物是糖尿病患者最常使用的处方药物，因此这项研究结果的临床意义非常重大。

Pantalone医生的这项研究由阿斯利康公司提供的一项研究基金资助。

爱思唯尔  版权所有

By: BRUCE JANCIN, Cardiology News Digital Network

HOUSTON – Glipizide, glyburide, and glimepiride were independently associated with 59%-68% greater all-cause mortality risks than metformin in a retrospective study of nearly 24,000 type 2 diabetic patients on monotherapy for control of blood sugar.

Notably, among the 2,721 subjects with documented coronary artery disease (CAD), glipizide and glyburide carried an increased overall mortality risk compared with metformin, but glimepiride did not, according to Dr. Kevin M. Pantalone of Summa Western Reserve Hospital in Cuyahoga Falls, Ohio.

"Metformin, when not contraindicated, should be the first-line agent used to control blood sugar levels in patients with type 2 diabetes. Our results suggest that if a sulfonylurea is required to control blood sugar levels, glimepiride may be the preferred sulfonylurea in those with known coronary artery disease," he said at the annual meeting of the Endocrine Society.

Given that this was a retrospective study, it has to be viewed as hypothesis generating. A prospective study is warranted to establish the causal mechanism for the observed increase in mortality risk associated with these three widely prescribed sulfonylureas.

"The Food and Drug Administration now requires all drugs for the treatment of diabetes to have a cardiovascular safety study. These older drugs, which are considered tier 1, core-validated therapies by the American Diabetes Association, appear to have been given a free pass in terms of their cardiovascular risk," the endocrinologist observed.

He reported on 23,915 patients with type 2 diabetes who began monotherapy with metformin or one of the three sulfonylureas. The study was conducted using data from the Cleveland Clinic’s electronic health record system. Patients were followed for a median of 2.2 years, during which 2,546 deaths occurred in 58,513 person-years of follow-up.

In a multivariate Cox regression analysis adjusted for 16 variables, glipizide was independently associated with a 64% greater relative risk of all-cause mortality than was metformin. Glyburide was linked to a 59% increased risk, and glimepiride was associated with a 68% increased risk.

Among 2,721 diabetic patients with documented baseline CAD, there were 419 deaths during 5,980 person-years of follow-up. In this subgroup with CAD, glipizide had a 41% increased overall mortality risk, and glyburide had a 38% greater risk than metformin.

The clinical implications of these study findings are huge, Dr. Pantalone said. An estimated 26 million Americans have diabetes, and most of them either have known CAD or are at elevated risk for it. The four antidiabetic drugs examined in the study are among the most widely prescribed agents for blood glucose control, and all four are available in generic versions at bargain basement prices.

Dr. Alvin Powers commented that controversy surrounding the safety of sulfonylureas dates back several decades. As far as he’s concerned the issue remains unresolved, given the limitations of Dr. Pantalone’s retrospective study design.

"I think we really need a prospective comparison. I think metformin remains the primary drug, and when we add a second-line drug, the studies would show that glipizide and glimepiride are probably preferred over glyburide because of the length of time they’ve been studied. But I think that because glycemic control is important, the second-line drug still can be a sulfonylurea," said Dr. Powers, professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Vanderbilt Diabetes Center.

Dr. Pantalone’s study was supported by a research grant from AstraZeneca.