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糖尿病患者发生心血管风险已经成为2型糖尿病管理中的重要问题。在降糖药物层出不穷的新时代，哪些能使CV获益？对于罹患CVD及其高风险的患者，降糖治疗如何用药？ 来源｜医学界内分泌频道 糖尿病患者发生心血管(CV)事件风险是无糖尿病人群的2-4倍[1]，包括心绞痛、非致死性心梗、缺血性卒中等。心血管疾病(CVD)是糖尿病患者首要死因[2]。3B研究显示，72%的中国2型糖尿病(T2DM)患者合并高血压、血脂紊乱等心血管危险因素[3]。CV风险已经成为T2DM管理中的重要问题。 大型临床研究显示，强化降糖组未能明显减少CV事件。相反，在 ACCORD研究中，强化治疗组有较高的总体和CV死亡率[4,5]。虽然严格降糖对CV的影响尚有争议，但降糖药物的额外效应日益受到重视。 美国食品药品监督管理局（FDA）要求对上市的新型降糖药物在CV高危人群中开展以CV事件为终点的临床研究，即心血管结局试验(CVOT)[6]。 在降糖药物层出不穷的新时代，哪些能使CV获益？对于罹患CVD及其高风险的患者，降糖治疗如何用药？ 盘点：四种降糖药具有CV保护效应 总的来说，对动脉粥样硬化性心血管疾病（ASCVD），二甲双胍和吡格列酮具有潜在的获益[2]，胰高血糖素样肽-1受体激动剂（GLP-1RA）利拉鲁肽、钠-葡萄糖协同转运蛋白-2抑制剂（SGLT-2i）恩格列净以及卡格列净在CVOT均表现出确切的CV保护效应。 UKPDS研究显示，与传统治疗（饮食控制为主）相比，二甲双胍可显著降低心肌梗死风险39％(Ｐ＝0.010)，CV事件复合终点风险下降30％(Ｐ＝0.020)，后续的10年随访研究仍发现二甲双胍治疗较传统治疗使心肌梗死风险下降33％(Ｐ＝0.005)[7,8]。 PROactive研究显示，与安慰剂相比，吡格列酮治疗组在次级终点（全因死亡、非致死性心肌梗死或卒中）相对风险下降16％（Ｐ=0.027）。但继续随访7.8年未发现统计学意义[9]。 EMPA-REG OUTCOME研究发现，恩格列净可显著降低伴有CVD的T2DM患者的主要不良心血管事件(包括心血管死亡、非致死性心肌梗死或卒中，3P- MACE)[10]。 而卡格列净进行的CANVAS研究同样提示卡格列净使3P-MACE复合终点及心衰住院风险显著下降[11]。 利拉鲁肽是第一个经CVOT证实具有CV获益的GLP-1RA。LEADER研究纳入9340例罹患CVD或CVD高风险的T2DM患者，其中 81.3%的患者既往有心血管病史(包括心肌梗死、卒中或短暂性脑缺血发作、曾行血运重建术、冠状动脉或颈动脉或下肢动脉狭窄≥50％)，中位随访时间3.8年，旨在评估利拉鲁肽与安慰剂对患者CV结局的影响[12]。 结果显示，与安慰剂相比，利拉鲁肽可使3P-MACE风险降低13％(Ｐ＜0.001)，CV死亡风险降低22％(Ｐ＝0.007)，扩展的心血管事件复合终点（心血管死亡、非致死性心肌梗死、非致死性卒中、血运重建、不稳定性心绞痛住院或心力衰竭住院）风险降低 12%(Ｐ＝0.005），且不增加心衰住院风险[12]。 两大途径，助力利拉鲁肽CV保护优势 利拉鲁肽的CV保护作用，推测其通过两大途径实现： ■ 对CV系统的直接作用。在心肌细胞、血管平滑肌与内皮细胞表面都分布有GLP-1受体，GLP-1RA可促进心肌细胞葡萄糖摄取，增加血管内一氧化氮产量而扩张血管、增加血流，改变自主神经系统平衡，还表现出修复受损血管内皮、抗炎作用从而延缓动脉粥样硬化进程[13,14,15,16,17]； ■ 对CV系统的间接作用，主要体现在对心血管危险因素的改善上。在一系列LEAD研究中观察到，利拉鲁肽可降低空腹血糖及餐后血糖,降低HbA1c 1.1-1.6%，低血糖风险小，且减轻体重的同时改善胰岛素抵抗，降低收缩压[18,19,20,21,22,23]，改善血脂谱[21,23]。更重要的是，利拉鲁肽主要减少内脏脂肪，而内脏脂肪在CVD的发病机制中占据着重要地位[24,25]。另外，利拉鲁肽每日仅需注射1次，依从性好。 目前尚无证据表明，GLP-1RA的CV获益具有类效应，这可能与不同GLP-1RA的结构有关（利拉鲁肽与天然GLP-1同源性高达97%）[26,27]。 降糖新时代的治疗策略：防控大血管病变 新时代背景下，糖尿病的治疗策略，已从单纯控糖逐渐转变为以控制多种代谢异常，预防和延缓糖尿病大血管病变的综合管理。 2017版《中国2型糖尿病防治指南》指出，对糖尿病大血管病变的预防，需要全面评估和控制心血管疾病风险因素，并将利拉鲁肽列为T2DM高血糖治疗的二联用药[1]；在2018年美国内分泌临床医师协会(AACE) / 美国内分泌学院(ACE)的糖尿病指南中，利拉鲁肽则在二联治疗中推荐程度最高。2018年美国糖尿病学会(ADA)指南也推荐利拉鲁肽作为T2DM合并ASCVD时联用二甲双胍的优选药物之一[2]。该药也在美国FDA获批为具有CVD获益的药物[2]，利拉鲁肽的心血管结局评估——可降低伴有CVD的T2DM患者的MACE风险也已写入中国新版说明书[28]。 小结 T2DM患者合并多重CV危险因素，CV风险管控已经成为T2DM管理中的重要问题。对于伴有CVD的T2DM患者，在降糖、降压、调脂、抗血小板治疗同时，可以考虑使用利拉鲁肽等具有CV保护效应的降糖药物，以降低风险，改善结局，尽量延长患者寿命。 参考文献 1. 贾伟平，陆菊明，纪立农，等. 中国2型糖尿病防治指南（2017版）. 中华糖尿病杂志, 2018, 10(1): 4-67. 2. American Diabetes Association. Standards of medical care in diabetes—2018. Diabetes Care,2018, 41(suppl 1):S1-S159. 3. Linong Ji, Dayi Hu, Changyu Pan, et al. Primacy of the 3B Approach to Control Risk Factors for Cardiovascular Disease in Type 2 Diabetes Patients. Am J Med, 2013, 126(10): 925.e11-22. 4. Patel A, MaeMbaon S, Chalmers J, et al. The ADVANCE collaboartive gorup. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med, 2008, 358: 2560-72. 5. Gerstein HC, Miller ME, Byington RP, et al. The action to control cardiovascular risk in diabetes study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med, 2008, 358: 2545-2559. 6. U.S. Food and Drug Administration. Guidance for industry diabetes mellitus: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD, 2008. Available from http://www./downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm071627.pdf). 7. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS33). UK Prospective Diabetes Study(UKPDS) Group. Lancet, 1998, 352: 837-853. 8. UKPDS Group. 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes (UKPDS 80). N Engl J Med, 2008, 359: 1577-89. 9. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet, 2005, 366(9493): 1279-89. 10. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med, 2015, 373(22): 2117-28. 11. Mahaffey KW, Neal B, Perkovic V, et al. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation,2018,137:323-334. 12. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med, 2016, 375(4): 311-2 13. Drucker DJ. The biology of incretin hormones. Cell Metab, 2006, 3: 153-165. 14. Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab, 2016, 24: 15-30. 15. Nathanson D, Frick M, Ullman B, Nystr¨om T. Exenatide infusion decreases atrial natriuretic peptide levels by reducing cardiac filling pressures in type 2 diabetes patients with decompensated congestive heart failure. Diabetol Metab Syndr, 2016, 8: 5. 16. Liu L, Liu J, Huang Y. Protective effects of glucagon-like peptide 1 on endothelial function in hypertension. J Cardiovasc Pharmacol, 2015, 65: 399-405. 17. Kumarathurai P, Anholm C, Larsen BS, et al. Effects of liraglutide on heart rate and heart rate variability: a randomized, double-blind, placebo controlled crossover study. Diabetes Care, 2017, 40: 117-124. 18. M. Marre, J. Shaw, M. Brändle, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabetic Medicine, 2009, 26, 268–278. 19. MICHAEL NAUCK, ANDERS FRID, KJELD HERMANSEN, et al. Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes: The LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care, 2009, 32: 84–90. 20. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet, 2009, 373(9662):473-81. 21. Bernard Zinman, John Gerich, John B. Buse, et al. Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 MetTZD). Diabetes Care, 2009, 32: 1224-1230. 22. D. Russell-Jones, A. Vaag, O. Schmitz, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia, 2009, 52: 2046–2055. 23. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet, 2009, 374(9683): 39-47. 24. Jendle J, Nauck MA, Matthews DR, et al. Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue. Diabetes Obes Metab, 2009, 11(12): 1163-72. 25. Ryotaro Bouchi, Yujiro Nakano, Tatsuya Fukuda, et al. Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: a randomized control trial. Endocrine Journal, 2017, 64(3): 269-281. 26. Muhammad Abdul-Ghani, Ralph A. DeFronzo, Stefano Del Prato, et al. Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived? Diabetes Care, 2017, 40: 813–820. 27. Knudsen LB, Nielsen PF, Huusfeldt PO, et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem, 2000, 43(9): 1664-9. 28. 利拉鲁肽 CFDA说明书. |
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