類升糖素胜肽-1受體促效劑能預防缺血性中風嗎？

有鑑於心血管疾病(Cardiovascular disease, CVD)併發症對第二型糖尿病(type 2 diabetes, T2DM) 患者的健康負擔，人們越來越關注 T2DM 和 CVD間的共同管理。控制血糖仍然是管理 T2DM 的主要基礎，儘管強化血糖控制對第一型糖尿病患者預防微血管併發症和心血管疾病的重要性已得到充分證實 [ 1 , 2 ]，但其在 T2DM 患者中降低心血管風險的作用尚未明確[ 3 , 4 , 5 ]。因此，預防大血管併發症最有效的方法似乎是減少多重危險因子（戒菸、戒酒、健康飲食、維持運動、積極的血糖及血壓控制、血脂異常的治療等）。

為此，現今糖尿病治療方針已更新，以提供有關如何預防和管理 CVD [ 6 ] 的建議，再加上來自健康法規機構的壓力遽增，即抗糖尿病治療顯示出心血管安全性和益處，特別是對於心血管死亡率、非致命性心肌梗塞和中風等主要心血管事件 [ 7 , 8 ]。根據這些法規機構要求，已經完成了幾項心血管事件評估試驗(CVOT)，試驗結果顯示出某些抗糖尿病治療的 CVD 風險較低[ 9 , 10 , 11 , 12 ]。

在接受類升糖素胜肽-1受體促效劑 ( glucagon-like peptide 1 receptor agonists, 簡稱GLP-1RA ) 治療的T2DM患者中觀察到主要心血管事件 ( major cardiovascular event, MACE )的發生率顯著降低，這顯示某些類別的藥物可能對患者具有心臟保護作用[ 13 , 14 ]。然而，與僅具有 CV 危險因素的患者相比，GLP-1RA 對心血管事件的改善似乎在患有 T2DM合併曾罹患CVD的患者中更為顯著 [ 15 , 16 , 17 , 18]。特別是使用 GLP-1RA，包括lixisenatide, exenatide, liraglutide, semaglutide, albiglutide and dulaglutide，可顯著降低曾有CVD病史的T2DM患者的 MACE 風險達14%，而未有 CVD病史患者的風險則僅下降6%[ 17]。

在GLP-1RA的CVOT之統合分析中[19]，在T2DM 患者中使用 GLP-1RA與降低非致死性中風、所有中風和 MACE 的發生率相關，這些藥物與降低心血管和全因死亡率有關。此外，使用 GLP-1RA進行次級預防僅與減少MACE 相關，不影響中風的復發。

在接受 GLP-1 RA治療的 T2DM 患者中，上述結果針對所有中風和致死性事件都是一致的。在大多數隨機對照試驗（randomized controlled trial，RCT）中，與其他心血管事件相比，中風事件的獲益都是更大的。除了降低MACE外，GLP-1RA 耐受性良好，依從性也很好，且少有主要不良事件或低血糖事件。中風初級預防的這些益處可歸因於 HbA1c、體重、低密度脂蛋白膽固醇值和收縮壓的降低。GLP-1RA還可以改善內皮細胞和血小板的功能，提供神經保護益處並減輕動脈粥樣硬化、血管收縮和血管發炎反應 [ 17 ]。

根據美國中風協會 (American Stroke Association, ASA) 的最新治療指引[20]，只要確定中風或短暫性腦缺血發作 (transient ischaemic attack, TIA) 的原因，即可以訂定具體的預防策略來降低額外中風的風險。因為中風或 TIA 會增加未來發生其他中風的風險。根據美國心臟協會的新聞稿，隨著預防策略的改進，研究指出，中風復發率從 1960 年代的 8.7% 降低到 2000 年代的 5.0%，但在中風倖存者中，第二次中風的許多危險因素仍然管理不善。

此指引中提起最近的臨床試驗顯示，在 3 類降糖藥物中，至少有 1 種藥物可以降低患有 T2DM和已罹患的動脈粥樣硬化性血管疾病(established atherosclerotic vascular disease, ASCVD)（包括缺血性中風ischemic stroke或高風險）患者的 MACE 風險：thiazolidinediones, GLP-1 RA, 及sodium-glucose cotransporter 2 inhibitor ( SGL-2i )。與thiazolidinediones和一些 GLP-1RA的數據不同，SGLT-2i的心血管事件評估試驗並未顯示對中風有作用，而是對心血管死亡、心肌梗塞和心臟衰竭有作用。在包括缺血性中風在內的已確診 ASCVD 患者中，應優先考慮預防進一步的血管事件時，應在metformin中加入 GLP-1 RA治療，無需考慮當時的HbA1c 值。

目前雖無法證實代謝症候群的良好控制可以降低中風的風險，但一些具有血管益處的抗糖尿病藥物，如GLP-1RA已被證明在添加到常規治療中時可以減少這些影響，無論是在T2DM患者的初級預防還是高血管風險或已罹患ASCVD的病患。

Reference:

1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.
   
   
2. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–53.
   
   
3. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.
   
   
4. UK Prospective Diabetes Study. (UKPDS) Group: intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK prospective diabetes study (UKPDS) group. Lancet. 1998;352:837–53.
   
   
5. Action to Control Cardiovascular Risk in Diabetes Study. Group: effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.
   
   
6. Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes H-P, Huikuri H. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD-summary. Diab Vasc Dis Res. 2014;11:133–73.
   
   
7. Schnell O, Rydén L, Standl E, Ceriello A. Updates on cardiovascular outcome trials in diabetes. Cardiovasc Diabetol. 2017;16:128.
   
   
8. Food and Drug Administration: Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. US Department of Health and Human Services. 2008.
   
   
9. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.
   
   
10. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;2016:311–22.
    
    
11. Sanon VP, Patel S, Sanon S, Rodriguez R, Pham SV, Chilton R. Differential cardiovascular profiles of sodium-glucose cotransporter 2 inhibitors: critical evaluation of empagliflozin. Ther Clin Risk Manag. 2017;13:603.
    
    
12. Trujillo JM, Nuffer WA. Impact of sodium–glucose cotransporter 2 inhibitors on nonglycemic outcomes in patients with type 2 diabetes. Pharmacotherapy. 2017;37:481–91.
    
    
13. Giugliano D, Maiorino MI, Longo M, Bellastella G, Chiodini P, Esposito K. Type 2 diabetes and risk of heart failure: a systematic review and meta-analysis from cardiovascular outcome trials. Endocrine. 2019;65:15–24.
    
    
14. Giugliano D, Meier JJ, Esposito K. Heart failure and type 2 diabetes: From cardiovascular outcome trials, with hope. Diabetes Obes Metab. 2019;21:1081–7.
    
    
15. Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus—systematic review and meta-analysis of cardiovascular outcomes trials. Circulation. 2019;139:2022–31.
    
    
16. Giugliano D, Maiorino MI, Bellastella G, Chiodini P, Esposito G. Glycemic control, pre-existing cardiovascular disease and risk of major cardiovascular events in patients with type 2 diabetes mellitus: a systematic review with meta-analysis of cardiovascular outcome trials vs intensive glucose control trials. J Am Heart Assoc. 2019;8:e012356.
    
    
17. Giugliano D, Maiorino MI, Bellastella G, Longo M, Chiodini P, Esposito K. GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: an updated meta-analysis including the REWIND and PIONEER 6 trials. Diabetes Obes Metab. 2019;21:2576–80.
    
    
18. Bellastella G, Maiorino MI, Longo M, et al. Glucagon-like peptide-1 receptor agonists and prevention of stroke. Systematic review of cardiovascular outcome trials with meta-analysis. Stroke. 2020;51:666–9.
    
    
19. Malhotra K, Katsanos AH, Lambadiari V, Goyal N, Palaiodimou L, Kosmidou M, Krogias C, Alexandrov AV, Tsivgoulis G, GLP-1 receptor agonists in diabetes for stroke prevention: a systematic review and meta-analysis. J Neurol. 2020 Jul;267(7):2117-2122.
    
    
20. Dawn O. Kleindorfer, Amytis Towfighi, Seemant Chaturvedi, Kevin M. Cockroft, Jose Gutierrez, Debbie Lombardi-Hill, Hooman Kamel, Walter N. Kernan, Steven J. Kittner, Enrique C. Leira, Olive Lennon, James F. Meschia, Thanh N. Nguyen, Peter M. Pollak, Pasquale Santangeli, Anjail Z. Sharrief, Sidney C. Smith Jr, Tanya N. Turan, and Linda S. Williams, 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2021;52:e364–e467