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1、2 2型糖尿病患者严格血糖控制和型糖尿病患者严格血糖控制和心血管事件的预防心血管事件的预防 中山大学附属第一医院内分泌科 肖 海 鹏ChallengeTo have patients believe in your guidance for the management of their diabetes mellitus.National Geographics (2004) AugustPrevalence of obesity increased 61% between 1991 and 2000More than 60% of US adults are overweightOnly
2、43% of obese persons advised to lose weight during checkupsBMI and weight gain major risk factors for diabetesPrevalence (%)DiabetesMean body weightkgYearMokdad 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 ObesityGl
3、obal 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, GermanyBy 2025, the largest increases in diabetes prevalence will occur i
4、n low- and middle-income countriesEach 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 complicationsEach year 3.8 million
5、deaths worldwide are attributable to diabetesDiabetes is associated with complications such as: Diabetic neuropathy Renal failureBlindnessMacrovascular diseaseMacrovascular 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
6、1999;138:5330欧洲心脏调查结果欧洲心脏调查结果n=2107n=2854The Euro Heart Survey on diabetes and the heart，European Heart Journal (2004) 25, 1880189043,509 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=9,125NGT I-IFG IGT DM相相对对比比例例 (%)Presentation of Novartis Satellite symposium during ESC 2004,Munich,GermanyNAVIGATORGAMI:急性
7、心梗患者中的糖代谢异常急性心梗患者中的糖代谢异常心肌梗死患者心肌梗死患者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中华内分泌代谢杂志 2006, 22:7Risk of cardiovascular disease (CVD) in relation to HbA1c The ARIC StudyRelative risk of CVDRelative risk of CVDn n = 1626 ( = 1626 (p p 0.001) 0.001)HbAHbA1c1c
8、Ajusted for age, gender, race, smoking, BMI, visceral obesity, physical activity, BP and dyslipidemia.Ajusted for age, gender, race, smoking, BMI, visceral obesity, physical activity, BP and dyslipidemia.Adapted from: Selvin, E. Adapted from: Selvin, E. et collet coll. . Arch. Int. MedArch. Int. Med
9、. 165: 1910-1916, 2005. 165: 1910-1916, 2005GAMI :新诊断高血糖新诊断高血糖是心肌梗死后是心肌梗死后“无心血管事件存活无心血管事件存活”的预测因的预测因素素Bartnik M, et al. Eur Heart J. 2004;25(22):1990-7. 中位数随访时间:3_月Diabetes patients requiring glucose-lowering therapy and non-diabetics with a prior myocardial infarction carry the same cardiovascular
10、risk: A population study of 3.3 million peopleCirculation 117:1945-54, 2008All 3.3 mio Danes older than 30 years were followed from 1997 to 2002 by nation wide registersMedication treated diabetes patients and nondiabetics with and without a prior myocardial infarction were comparedAt baseline 71, 8
11、01 Danes had medication treated diabetes and 79, 575 had a prior myocardial infarctionRelative risk for CVD mortalityRelative risk for CVD mortality was 2.42 in men with diabetes mellitus without a prior myocardial infarctionand2.44 in nondiabetic men with a prior myocardial infarction (P=0.60) Haza
12、rd RatioDiabetes, Glucose, and CV DiseaseDM is an established risk factor for CVDIn DM, higher glucose levels/A1c predict higher CV riskStratton IM, et al. BMJ 2000; 321:40541212% rise per 1% rise in A1CP .035Fatal & Nonfatal StrokeHazard Ratio14% rise per 1% rise in A1CP .0001101 Fatal & Nonfatal M
13、I1043% rise per 1% rise in A1CP .0001101Amputation/Death from PVD6578916% rise per 1% rise in A1CP .021Heart Failure 6578910 0.88 (0.79,0.99) Any diabetes-related endpoint 0.84 (0.71,1.00) Myocardial infarction 1.11 (0.81,1.51) Stroke 0.75 (0.60,0.93) Microvascular diseaseRelative risk (95% CI)Relat
14、ive risk0.10.52.010Favors more intensiveFavors less intensiveUK Prospective Diabetes StudyBlood glucose and vascular risk in diabetes -UKPDS高血糖和心血管风险越来越多的越来越多的2型糖尿病患型糖尿病患者出现心血管并发症者出现心血管并发症UKPDS 表明高血糖和心表明高血糖和心血管疾病之间存在流行病血管疾病之间存在流行病学上的关联学上的关联但是严格的血糖控制能否但是严格的血糖控制能否降低该风险降低该风险? ACCORD, ADVANCE & VADT 等大型
15、研究就是针等大型研究就是针对上述问题而设计对上述问题而设计ACCORD: 2型糖尿病强化降糖的效应研究多中心研究 (77 研究中心) 美国/加拿大10,251 例患者 (平均年龄 62.2 岁)强化治疗组(目标A1c 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 年A1c 6.9%A1c 在
16、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 Meetin
17、g in SanFrancisco No positive trial effect of Intensive glucose lowering on macrovascular complications in type 2 diabetes, at least in the types of patients studiedACCORDADVANCEVADT比较: ACCORD, ADVANCE & VADT 研究特点特点ACCORD ADVANCE VADT基线基线: :年龄 (岁 ) 病程 (年) 心血管疾病 (%)62103566832601141干预干预: :目标HbA1c (%)
18、 研究时间 (yr) 胰岛素 (%)6.03.4776.55.0416.05.689结果结果: : HbA1c (%) 心血管死亡 (% 强化组 v 标准组 ) 严重低血糖 (%) 6.42.6 v 1.8 *16.26.54.5 v 5.22.76.94.5 v 3.721.2Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified SubgroupsHazard Ratios for the Primary Outcome and Death from Any Cause in Prespe
19、cified SubgroupsN Engl J Med,2003;348:2294-303DCCTDCCTEDICEDIC：早期代谢控制的益处：早期代谢控制的益处颈动脉内膜厚度颈动脉内膜厚度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的变化磺脲类磺脲类/ /胰岛素胰岛素 vs.vs. 常规治疗常规治疗微血管疾病风险比强化治疗强化治疗 ( (磺脲类磺脲类/ /胰岛素胰岛素) ) vs.v
20、s. 常规治疗常规治疗( (肾衰竭，玻璃体积血，光凝固法肾衰竭，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致死性或非致死性心梗或猝死) )强化治疗强化治疗 ( (磺脲类磺脲类/ /胰岛素胰岛素) ) vs.vs. 常规治疗常规治疗HR (95%CI)全因死亡风险比强化治疗强化治疗 ( (磺脲类磺脲类/ /胰岛素胰岛素) ) vs.vs. 常规治疗常规治疗HR (95%CI)早期血糖控制所带来的延续效应(Legacy Effect )研究结束后随访年结果综合终点综合终点 19972007任何与糖尿病相关的终点任何与糖尿病相关的终点RRR:12%9%
21、P: 0.029 0.040 微血管疾病微血管疾病RRR: 25%24% P: 0.00990.001心梗心梗RRR:16%15% P: 0.0520.014全因死亡全因死亡RRR:6%13% P: 0.440.007 1 Rury R. Holman et al, N Engl J Med. 2008 ;359(15):1618-20 RRR = Relative Risk Reduction, P = Log Rank强化治疗强化治疗 (磺脲类磺脲类/胰岛素胰岛素) vs. 常规治疗常规治疗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
22、制可能获得长期的心血管获益Steno-2 Post Trial aim1To examine whether an intensified multifactorial intervention similar to current guidelines has an impact on mortality in patients with type 2 diabetes and microalbuminuria2To examine whether risk reductions already achieved for both macro- and microvascular disea
23、se with intensified multifactorial intervention were sustained in a clinical setting outside the structured framework of a clinical trialSTENO-2Percentage of Patients Who Reached the Intensive-Treatment Goals at a Mean of 7.8 YearsGlycosylatedHemoglobin6.5%Patients (%)02030405060701080Cholesterol175
24、 mg/dlTriglycerides150 mg/dlSystolic BP130 mm HgDiastolic BP80 mm HgP=0.06P0.001P=0.19P=0.001P=0.21IntensivetherapyConventionaltherapyGde P et al. NEJM. 2003;348: 383393.STENO-2Composite End Point of Death from CV Causes, Nonfatal MI, CABG, PCI, Nonfatal Stroke, Amputation, or Surgery for Peripheral
25、 Atherosclerotic Artery DiseaseGde P et al. NEJM. 2003;348: 383393.Primary Composite End Point (%)003612 966048847224 603040201050Intensive therapyConventional TherapyMonths of Follow-upP=0.007Hazard 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 riskCon
26、ventionalIntensiveSteno-2 Post Trial: Mortality80808078777569726365516243573039Years of follow-upPercentage of patients dying (%)Gaede P et al. NEJM 358: 580-591, 2008Implications of these findings for clinical careTreatment to A1C targets below or around 7% in the years soon after the diagnosis of
27、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 careFor selected individuals, including those with short duration of DM, long
28、 life expectancy , and no significant cardiovascular disease. HbA1C less than 7% is reasonable if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Implications of these findings for clinical careConversely, less stringent A1C goals 7% may be appropriate fo
29、r patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, or extensive comorbid conditions or those with long-standing diabetes in whom the general goal is difficult to attain.Implications of these findings for clinical careFor
30、primary and secondary CVD risk reduction in patients with diabetes, providers should continue to follow the evidence-based recommendations for blood pressure treatment, lipid-lowering with statins, aspirin prophylaxis, smoking cessation, and healthy lifestyle behaviors.糖尿病: Getting the balance right 生活质量和长寿谢 谢！
