非胰島素類降血糖藥物與心血管疾病之安全性

Non-insulin Anti-diabetic Drugs and Cardiovascular Safety

10.6314/JIMT.201904_30(2).07

曾國賓(Kuo-Bin Tseng)

第二型糖尿病（Type II diabetes mellitus） ； 糖尿病藥物（Anti-diabetic drugs） ； 心血管疾病（Cardiovascular disease） ； 心臟衰竭（Heart failure）

內科學誌

30卷2期（2019 / 04 / 01）

107 - 131

繁體中文

在本篇文獻回顧，我們主要在探討口服降血糖藥物（雙胍類（Metfornin）、磺醯尿素類（Sulfonylurea）、美格替耐類（Meglitinide）、噻唑烷二酮類衍生物（Thiazolidinedione）、甲型醣苷酶抑制劑（α-glucosidase inhibitors）、雙肽基肽酶-4抑制劑（Dipeptidyl Peptidase-IV inhibitors）和第二型鈉-葡萄糖轉運蛋白抑制劑（Sodium-Glucose Co-transporter 2 inhibitors））及注射劑型降血糖藥物（類升糖素肽-1受體促效劑（Glucagon-Like Peptide-1 Receptor Agonists））長遠在心血管安全之影響。現有的證據顯示雙胍類metformin在第二型糖尿病患並沒有產生心血管疾病負面的影響；因為它可以改善一些心血管危險因子及可能減少心血管疾病的發病率和死亡率。目前磺醯尿素類與心血管疾病增加與否的關係仍是眾說紛紜。許多研究其中大部分是大型資料庫的回溯性分析，但是有些是前瞻性研究，顯示使用磺醯尿素類來治療第二型糖尿病會增加心血管疾病的風險。但是包括UKPDS（United Kingdom Prospective Diabetes Study）、ADVANCE（Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation）和ACCORD（Action to Control Cardiovascular Risk in Diabetes）等大型臨床試驗，發現磺醯尿素類並沒有增加第二型糖尿病患心血管疾病的死亡率或者發病率。最近幾年的統合分析也呈現相互矛盾的結果，有些顯示磺醯尿素類有增加心血管死亡率，但另有結論認為沒有增加心血管疾病的風險。或許要等到目前進行中的CAROLINA（The Cardiovascular Outcome Study of Linagliptin vs. Glimepiride in Patients with Type 2 Diabetes）trial結果出爐，這些藥物對於心血管安全的釐清及定義也許有所幫助。研究顯示美格替耐類對於傳統心血管疾病危險因子貢獻度顯得比較弱，雖然有研究指出repaglinide可以減少脂蛋白（a）。單一藥物治療第二型糖尿病，研究發現相較於metformin，repaglinide不論病患過去是否有心肌梗塞病史，並沒有增加主要心血管事件、心因性死亡率或總死亡率。Rosiglitazone有顯著增加心肌梗塞風險及增加心血管死亡率風險。Pioglitazone對於一些心血管危險因子的改善是有幫助的，同時可以延緩動脈粥樣硬化與減少心血管事件。在IRIS（the Insulin Resistance Intervention after Stoke）試驗，對於有胰島素阻抗合併最近有缺血性腦中風或短暫性腦缺血發作非糖尿病患者，pioglitazone則有降低腦中風或心肌梗塞的風險。ACE（the Acarbose Cardiovascular Evaluation）trial結果顯示acarbose並沒有減少心血管疾病的風險。DPP-4抑制劑（saxagliptin，alogliptin和sitagliptin）對於有高風險心血管疾病的第二型糖尿病人既沒有增加也沒有顯著改善心血管事件。Saxagliptin意外地發現有高風險引起心臟衰竭住院。Lixisenatide在有急性冠心症的第二型糖尿病患身上並沒有得到心血管的益處。緩釋型exenatide對心血管的outcomes也沒有顯著有更好的結論。相較之下，長效型liraglutide與超長效型semaglutide則可以減少主要心血管事件和死亡的發生率。Empagliflozin和canagliflozin等兩種SGLT-2抑制劑顯示有明顯降低三重主要心血管事件、總死亡率與心臟衰竭住院的風險，另外empagliflozin則可以減低心血管的死亡率。CVD-REAL（Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors）研究，SGLT-2抑制劑是可以減少心臟衰竭住院及總死亡率的風險。更進一步的CVD-REAL次級分析顯示SGLT-2抑制劑具有一定程度減少心肌梗塞及中風的風險。CVD-REAL 2研究也顯示SGLT-2抑制劑有顯著減少心血管疾病之風險。總之，對於第二型糖尿病的治療，除了應個別化考量之外，也應該評估降糖尿病藥物是否會增加心血管事件的風險。

In this review, we examine the effect of oral (metformin, sulfonylureas, meglitinides, a-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and sodium-glucose co-transporter-2 inhibitors) and injectable (glucagon-like peptide-1 receptor agonists) glucose-lowering drugs on long-term studies of cardiovascular (CV) safety. Available evidence indicates that metformin does not exert adverse effects on cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM); because it improves some cardiovascular risk factors (CVRFs), metformin may reduce CVD morbidity and mortality. It remains unclear at the present time whether or not sulfonylureas are associated with an increased CVD risk. Many studies, mostly retrospective analyses of large databases but some prospective, have demonstrated an increased CVD risk in T2DM patients treated with sulfonylureas. However, UKPDS (United Kingdom Prospective Diabetes Study), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), and ACCORD (Action to Control Cardiovascular Risk in Diabetes) trials failed to demonstrate an increase in either CVD mortality or morbidity in sulfonylurea-treated T2DM patients. Recent meta-analyses also have generated conflicting results with some purporting to show an increase in cardiovascular mortality, while another concluded that there was no increase in CV disease. The ongoing CAROLINA (Cardiovascular Outcome Trial of Linagliptin Versus Glimepiride in Type 2 Diabetes) trial, might help to clarify and define the CV safety of these drugs. Meglitinides has no any effect on classic CVRFs, although a decrease in Lipoprotein(a) has been reported with repaglinide. Monotherapy with repaglinide in T2DM patients with and without previous myocardial infarction, seems to be associated without increased major cardiovascular events, cardiovascular mortality and all-cause mortality compared with metformin. Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular cause. Pioglitazone exerts beneficial effects on a number of CVRFs and may slow the progression of atherogenesis and reduces CV events. In IRIS (the Insulin Resistance Intervention after Stoke) trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or transient ischemic attack, pioglitazone was associated with a lower risk of stroke or myocardial infarction. The release of ACE (the Acarbose Cardiovascular Evaluation) trial showed that acarbose did not reduce the risk of major adverse cardiovascular events. Subsequent CV outcome trials with DPP-4 inhibitors (saxagliptin, alogliptin, and sitagliptin) showed noninferiority but failed to demonstrate any superiority in patients with T2DM and high CV risk. An unexpected higher risk of hospitalization for heart failure (HF) was reported with saxagliptin. Among glucagon-like peptide-1 receptor agonists (GLP-1 RA), Lixisenatide, did not show CV benefits in patients with T2DM and acute coronary syndrome. Extended-release exenatide was also not significantly better for CV outcomes. By contrast, long-acting GLP-1 RA (liraglutide) and longer-acting GLP-1 RA (semaglutide), both decreased the incidence of major adverse CV events and mortality. 2 Sodium-Glucose Cotransporter-2 (SGLT-2) inhibitors empagliflozin and canagliflozin showed a significant reduction in triple major cardiovascular events, all-cause mortality and hospitalization for HF (and also CV mortality for empagliflozin). In CVD-REAL study (Comparative Effectives of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransport-2 Inhibitors), SGLT-2 inhibitors were associated with a lower risk of hospitalization for HF and all-cause mortality. A further sub-analysis of CVD-REAL showed that SGLT-2 inhibitors were associated with a modestly lower risk of myocardial infarction and stoke. Confirmatory findings were reported in another similar study performed in other countries (CVD-REAL 2). In conclusion, treatment of T2DM is an individualized and complex challenge in which targeting cardiovascular risk factors is an important component in the decision making.