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作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　March 31, 2010 — 根據線上發表於3月9日糖尿病照護(Diabetes Care)期刊的一篇回溯世代研究結果，服用glipizide、glyburide或glimepiride單方治療的第2型糖尿病患者，其整體死亡率風險差不多。不過，該研究發現認為，對於已經有冠狀動脈疾病(CAD)的病患，glimepiride是比較適合的磺醯尿素類(sulfonylurea)藥物。
　　
　　俄亥俄州克里夫蘭診所的Kevin M. Pantalone醫師等人寫道，磺醯尿素類藥物傳統上被分析為一類藥物，但是，對於個別磺醯尿素類藥物的性質差異而言，可能是不適當的，例如低血糖風險、磺醯尿素類受體選擇性以及對心肌缺血前置處理的效果等。研究目的在於評估一個第2型糖尿病世代使用個別磺醯尿素類藥物和整體死亡風險之間的關聯。
　　
　　藉由一個學院的健康中心泛企業電子健康記錄系統，研究者檢視了服用磺醯尿素類藥物單方治療的11,141名年紀至少18歲的第2型糖尿病患，有些有CAD病史，且在研究開始時皆未使用胰島素或非胰島素針劑，這些病患中，4279 人一開始即使用glyburide單方、4325人使用glipizide、2537人使用glimepiride。根據電子健康紀錄以及社會安全局死亡索引確認死亡率，且將此世代與多變項模式進行比較。
　　
　　整個世代中，這些藥物之間，對於整體死亡率風險並沒有顯著差異。不過，對於有CAD的病患，使用glyburide和glipizide時，整體死亡率風險有比glimepiride增加的趨勢，glyburide相較於glimepiride之風險比[HR]為1.36(95%信心區間[CI])為0.96 -1.91)，glipizide 相較於glimepiride之風險比(HR)為1.39(95% CI，0.99 - 1.96)。
　　
　　根據這些發現，研究者結論表示，並未發現個別磺醯尿素類藥物的死亡率風險增加，不過，他們認為，對於已經有CAD的病患，glimepiride是比較適合的磺醯尿素類藥物。
　　
　　以色列耶路撒冷Hadassah醫學中心內科部內分泌與代謝服務小組Sameer A. Kassem博士受Medscape Diabetes Endocrinology之邀請發表評論時表示，此研究探討了尚無定論的一個問題，即某些磺醯尿素類藥物和心血管副作用之間的可能關聯，該研究留給我們一個開放式問題，而非確定的答案，部份因素歸諸研究設計與樣本大小，雖然它包括了超過11,000名參與者，但是有冠狀動脈疾病的人數相對偏低(341人使用glimepiride、548人使用 glipizide、580人使用 glyburide)。
　　
　　作者們承認有一些研究限制，包括回溯型設計；缺乏隨機化，可能有選樣偏差；缺乏關於處方藥物順從性的資料；不知道研究開始之後的藥物使用情況，此外，儘管有進行多變項分析校正開始時的變項和風險因素之相關差異，藥物組並未就開始時的變項和風險因素取得平衡。
　　
　　Kassem博士表示，顯然地，研究強度不足以證明增加的死亡率有統計上的顯著意義，另一方面，這可能是因為低血糖這個性質導致(低血糖與glyburide明顯有關)心血管死亡率，而非藥物對心臟之缺血前置處理的直接效果。
　　
　　因此，Kassem博士建議，後續研究採前瞻、大型控制試驗，比較不同的磺醯尿素類藥物，以便有足夠的強度探討心血管死亡率等心血管副作用。
　　
　　Kassem博士結論指出，雖然不具統計上的顯著意義，現在這些資料和之前的研究都強調，不同的磺醯尿素類藥物可能有不同的心血管副作用，當開方glyburide給CAD病患時須謹慎。
　　
　　AstraZeneca藥廠支持本研究，部分研究作者宣告與AstraZeneca、Daiichi Sankyo、Merck、Pfizer、Novo Nordisk和/或GlaxoSmithKline等藥廠有各種財務關係，Kassem博士宣告沒有相關資金上的往來。
　　
　　Diabetes Care. 線上發表於2010年3月9日。


Overall Mortality in Patients With Type 2 Diabetes May Be Similar With Different Sulfonylureas

By Laurie Barclay, MD
Medscape Medical News

March 31, 2010 — The risk for overall mortality is similar in patients with type 2 diabetes receiving glipizide, glyburide, or glimepiride monotherapy, according to the results of a retrospective cohort study, reported online March 9 in Diabetes Care. However, the findings suggest that glimepiride may be the preferred sulfonylurea in patients with underlying coronary artery disease (CAD).

"Sulfonylureas have historically been analyzed as a medication class, which may be inappropriate given the differences in properties inherent to the individual sulfonylureas: hypoglycemic risk, sulfonylurea receptor selectivity and effects on myocardial ischemic preconditioning," write Kevin M. Pantalone, DO, from Cleveland Clinic in Cleveland, Ohio, and colleagues. "The purpose of this study was to assess the relationship of individual sulfonylureas and the risk of overall mortality in a large cohort of patients with type 2 diabetes."

Using an academic health center enterprise-wide electronic health record system, the investigators identified 11,141 patients with type 2 diabetes receiving sulfonylurea monotherapy who were at least 18 years old, with and without a history of CAD, and not taking insulin or a noninsulin injectable at baseline. Of these patients, 4279 had started monotherapy with glyburide, 4325 with glipizide, and 2537 with glimepiride. Mortality rate was determined from the electronic health record and Social Security Death Index, and cohorts were compared with multivariable Cox models.

In the entire cohort, these agents did not differ significantly in the risk for overall mortality. In patients with documented CAD, however, there was a trend towards increased overall mortality risk with glyburide vs glimepiride (hazard ratio [HR], 1.36; 95% confidence interval [CI], 0.96 - 1.91) and glipizide vs glimepiride (HR, 1.39; 95% CI, 0.99 - 1.96).

On the basis of these findings, the investigators concluded that no increased mortality risk among the individual sulfonylureas was identified. However, they did suggest that glimepiride may be the preferred sulfonylurea in patients with underlying CAD.

"This study deals with unsettled issues concerning the possible association between certain types of sulfonylureas and cardiovascular adverse events," Sameer A. Kassem, MD, PhD, from Endocrinology Metabolism Service, Department of Internal Medicine at Hadassah Medical Center in Jerusalem, Israel, told Medscape Diabetes & Endocrinology when asked for independent comment. "The study leaves us with open questions rather than firm answers, partly due to study design and sample size. Although it included more than 11,000 participants, the [number of] patients with coronary artery disease [was] relatively small (341 glimepiride, 548 glipizide, and 580 glyburide)."

The authors acknowledge limitations of this study, including retrospective design; lack of randomization, causing possible selection bias; lack of documentation of compliance with the prescribed medication; and unknown medication exposure times after baseline. In addition, the medication groups were not balanced regarding baseline variables and risk factors, although the multivariable analysis adjusted for differences in relevant baseline variables and risk factors.

"Obviously, the study is not powered to show increased mortality with statistical significance," Dr. Kassem said. "Another aspect of this issue is the possible contribution of hypoglycemia per se (clearly associated with glyburide) to cardiovascular mortality rather than a direct effect of the drug on ischemia preconditioning in the heart."

Therefore, in future research, Dr. Kassem recommends a prospective, large, controlled trial comparing different classes of sulfonylureas, with sufficient power to show cardiovascular adverse events including cardiovascular mortality.

"Although not statistically significant, the data shown here and in previous studies emphasize the possible differences in cardiovascular adverse events between different sulfonylureas," Dr. Kassem concluded. "Precautions should be taken when prescribing glyburide to patients with CAD."

AstraZeneca supported this study. Some of the study authors have disclosed various financial relationships with AstraZeneca, Daiichi Sankyo, Merck, Pfizer, Novo Nordisk, and/or GlaxoSmithKline. Dr. Kassem has disclosed no relevant financial relationships.

Diabetes Care. Published online March 9, 2010.