型糖尿病患者严格血糖控制和心血管事件的预防

2型糖尿病患者严格血糖控制和 心血管事件的预防 中山大学附属第一医院内分泌科 肖 海 鹏 Challenge To have patients believe in your guidance for the management of their diabetes mellitus. National Geographics (2004) August Prevalence of obesity increased 61% between 1991 and 2000 More than 60% of US adults are overweight Only 43% of obese persons advised to lose weight during checkups BMI and weight gain major risk factors for diabetes Prevalence (%) Diabetes Mean body weight kg Year Mokdad et al. Diabetes Care. 2000;23:1278. Mokdad et al. JAMA. 1999;282:1519. Mokdad et al. JAMA. 2001;286:1195. Prevalence of Diabetes and Obesity Global prevalence of diabetes * 246 million people with diabetes worldwide = roughly 6% of the adult population In 2007, the five countries with the largest numbers of people with diabetes are: India, China, United States, Russia, Germany By 2025, the largest increases in diabetes prevalence will occur in low- and middle-income countries Each year an additional 7 million people worldwide develop diabetes * Diabetes Atlas, 3rd edition, International Diabetes Federation, 2006 中国的 2型糖尿病管理面临严峻的挑战 “中国的糖尿病患者可能居世 界之最 ” “经济的迅速发展，带来了传 统生活方式的根本性变革 ，导致了中国 2型糖尿病 患者的剧增。 ” 潘长玉 301医院 Diabetes complications Each year 3.8 million deaths worldwide are attributable to diabetes Diabetes is associated with complications such as: Diabetic neuropathy Renal failure Blindness Macrovascular disease Macrovascular complications are a major cause of death in people with diabetes 心血管疾病在糖尿病者中的比 率 新诊断的 2型糖尿病患者 25% 总糖尿病人群 50% 占糖尿病死亡原因 65-75% Am Heart J 1999;138:5330 欧洲心脏调查结果 n=2107 n=2854 The Euro Heart Survey on diabetes and the heart， European Heart Journal (2004) 25, 18801890 43,509 例高危人群中 9,125例合并心血管疾病 OGTT 结果 任一心血管事件 , n=9,125 NGT I-IFG IGT DM 相对比例 (%) Presentation of Novartis Satellite symposium during ESC 2004,Munich,Germany NAVIGATOR GAMI:急性 心梗患者中的糖代谢异 常 心肌梗死患者 Bartnik M, et al. J Intern Med. 2004 Oct;256(4):288-97. 中国心脏调查结果 -汇总 （ n=3513） 中华内分泌代谢杂志 2006, 22:7 Risk of cardiovascular disease (CVD) in relation to HbA1c The ARIC Study Relative risk of CVD n = 1626 (p 0.001) 5.2 5.2 5.7 5.7 6.5 6.5 8.2 8.2 HbA1c Ajusted for age, gender, race, smoking, BMI, visceral obesity, physical activity, BP and dyslipidemia. Adapted from: Selvin, E. et coll. Arch. Int. Med. 165: 1910-1916, 2005 GAMI :新诊断高血糖 是心肌梗死后 “无心血管事件存活 ”的预测 因素 Bartnik M, et al. Eur Heart J. 2004;25(22):1990-7. 中位数随访时间 :34月 Diabetes patients requiring glucose-lowering therapy and non-diabetics with a prior myocardial infarction carry the same cardiovascular risk: A population study of 3.3 million people Circulation 117:1945-54, 2008 All 3.3 mio Danes older than 30 years were followed from 1997 to 2002 by nation wide registers Medication treated diabetes patients and nondiabetics with and without a prior myocardial infarction were compared At baseline 71, 801 Danes had medication treated diabetes and 79, 575 had a prior myocardial infarction Relative risk for CVD mortality was 2.42 in men with diabetes mellitus without a prior myocardial infarction and 2.44 in nondiabetic men with a prior myocardial infarction (P=0.60) Hazard Ratio Diabetes, Glucose, and CV Disease DM is an established risk factor for CVD In DM, higher glucose levels/A1c predict higher CV risk Stratton IM, et al. BMJ 2000; 321:405412 12% rise per 1% rise in A1C P 10 Kg ) 过于严格的血糖控制目标 (HbA1c6.0%) VADT: 退伍军人 2型糖尿病血糖 控制 和血管并发症的研究 美国多中心研究 1791 退伍军人 (平均年龄 60.4 yrs); 97%为男性 强化治疗组 (A1c 下降 1.5%) v 标准治疗组 40% 有既往心血管病史 一级终点 : 主要心血管事件的发生时间 (复合终点 ) VADT: 结果和分析 平均随访 5.6 年 A1c 6.9% A1c 在 6个月内降低 2% 心血管终点和死亡率上没有显 著性差异 体重增加 9 Kg 严重低血糖发生率 21.2% ADVANCE 协作组研究 2型糖尿病强化降压 /降糖和血管事件结果 2型糖尿病患者严格血糖控制和血管结局 ADVANCE: 析因设计 强化降糖组 标准降糖组 以达美康缓释片（格列齐特 缓释片）为起始治疗 不限制其他药物的使用（磺 脲类除外） 目标： HbA1c 6.5% 除达美康缓释片以外的其他 磺脲类药物为起始治疗 不限制其他药物的使用（磺 脲类除外） 依照各地指南标准 ADVANCE: 血糖结果 ADVANCE: 终点结果 微血管和大血管复合终点结果 主要大血管事件 全因死亡 微血管事件 ADA 2008 Anual Meeting in SanFrancisco No positive trial effect of Intensive glucose lowering on macrovascular complications in type 2 diabetes, at least in the types of patients studied ACCORD ADVANCE VADT 比较 : ACCORD, ADVANCE 348:2294-303 DCCT EDIC：早期代谢控制的益处 颈动脉内膜厚度 DCCT/EDIC Study 累积的心血管事件数 欧洲糖尿病协会 减少 2型糖尿病心血管风险 英国前瞻性糖尿病研究 20年干预 研究结束后 10年随访结果 (1997-2007) UKPDS 结 果 Mean (95%CI) UKPDS 结束 10年后随访结果 ： HbA1c的变 化 磺脲类 /胰岛素 vs. 常规治疗 微血管疾病风险比 强化治疗 (磺脲类 /胰岛素 ) vs. 常规治疗 (肾衰竭，玻璃体积血，光凝固法 ) HR (95%CI) 心梗风险比 (致死性或非致死性心梗或猝死 ) 强化治疗 (磺脲类 /胰岛素 ) vs. 常规治疗 HR (95%CI) 全因死亡风险比 强化治疗 (磺脲类 /胰岛素 ) vs. 常规治疗 HR (95%CI) 早期血糖控制所带来的延续效应 (Legacy Effect ) 研究结束后随访 8.5年结果 综合终点 1997 2007 任何与糖尿病相关的终点 RRR: 12% 9% P: 0.029 0.040 微血管疾病 RRR: 25% 24% P: 0.0099 0.001 心梗 RRR: 16% 15% P: 0.052 0.014 全因死亡 RRR: 6% 13% P: 0.44 0.007 1 Rury R. Holman et al, N Engl J Med. 2008 ;359(15):1618-20 RRR = Relative Risk Reduction, P = Log Rank 强化治疗 (磺脲类 /胰岛素 ) vs. 常规治疗 2型糖尿病强化组长期随访结果 UKPDS: 延迟效应 实际意义 : 提示 “血糖记忆 ”效应 需要 尽早 及 严格血糖 控制 可能获得长期的心血 管获益 Steno-2 Post Trial aim 1 To examine whether an intensified multifactorial intervention similar to current guidelines has an impact on mortality in patients with type 2 diabetes and microalbuminuria2 To examine whether risk reductions already achieved for both macro- and microvascular disease with intensified multifactorial intervention were sustained in a clinical setting outside the structured framework of a clinical trialADA JUNE 2008 47 STENO-2 Percentage of Patients Who Reached the Intensive- Treatment Goals at a Mean of 7.8 Years Glycosylated Hemoglobin 6.5% Patients (%) 0 20 30 40 50 60 70 10 80 Cholesterol 175 mg/dl Triglycerides 150 mg/dl Systolic BP 130 mm Hg Diastolic BP 80 mm Hg P=0.06 P0.001 P=0.19 P=0.001 P=0.21 Intensive therapy Conventional therapy Gde P et al. NEJM. 2003;348: 383393. STENO-2 Composite End Point of Death from CV Causes, Nonfatal MI, CABG, PCI, Nonfatal Stroke, Amputation, or Surgery for Peripheral Atherosclerotic Artery Disease Gde P et al. NEJM. 2003;348: 383393. Primary Composite End Point (%) 0 0 3612 966048 847224 60 30 40 20 10 50 Intensive therapy Conventional Therapy Months of Follow-up P=0.007 Hazard ratio = 0.47 (95 percent c.i., 0.24 to 0.73; P=0.008) Steno-2 研究 : 2型糖尿病多因素干预对死亡率的 影响 Numbers at risk Conventional Intensive Steno-2 Post Trial: Mortality 80 80 80 78 77 75 69 72 63 65 51 62 43 57 HR=0.54 (0.32-0.89), P=0.015 30 39 Years of follow-up Percentage of patients dying (%) Gaede P et al. NEJM 358: 580-591, 2008 Implications of these findings for clinical care Treatment to A1C targets below or around 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular diasease. Until more evidence becomes available, the general goal of 7% appears reasonable. (ADA, B-level) Implications of these findings for clinical care For selected individuals, including those with short duration of DM, long life expectancy , and no significant cardiovascular disease. HbA1C less than 7% is reasonable if this can be achieved without significant hypoglycemia or