—糖尿病患者心血管并发症的危害及防治策略 全面干预，终点受益 —糖尿病患者心血管并发症的危害及防治策略

主要内容 糖尿病患者心血管疾病危害 糖尿病心血管并发症的发病机制 全面干预，终点受益

2007年全球有2.46亿糖尿病患者，预计2025年将有3.80亿糖尿病患者 糖尿病：日益严重的全球危机 2007年全球有2.46亿糖尿病患者，预计2025年将有3.80亿糖尿病患者 40.5 32.7 18.7 80.3 99.4 2025 43％ 67.0 28.3 46.5 48％ 大家知道，糖尿病在世界范围内有增长的趋势。据国际糖尿病联盟（IDF）报告，2007年全球糖尿病患者人数为2.46亿。到2025年，这个数字将会增长到3.8亿。糖尿病严重威胁着人类的健康，我们可以说：糖尿病是一个增长中的全球危机。 其中，我国的糖尿病患者已超过4000万，成为世界上糖尿病患者人数仅次于印度的第二大国。 2007 10.4 73％ 16.2 80％ 102％ Sicree, Shaw, Zimmet. Diabetes Atlas. IDF www.idf.org.2006

糖尿病患者心脑血管事件发生率增加 East-West研究:7年随访 50 40 30 20 10 非糖尿病 2型糖尿病 10 20 30 40 50 非糖尿病 2型糖尿病 心脑血管事件发生率 (%) 1059例2型糖尿病患者 基线特征 年龄： 45-64岁 性别：男性581例 女性478例 来源：东部510例(Kupio) 西部549例(Turku) 根据1985年WHO标准进行诊断 均排除1型糖尿病（根据C肽水平和是否发生酮症）； 既往心梗病史： 有：169例 无：890例 样本来自社会保险数据库，均接受药物治疗 基线时仅有9例患者接受降脂治疗（7男2女） 基线时，接受降压治疗 男性250例(43.7%) 女性271例(56.7%) + 有心肌梗死病史 - 无心肌梗死病史 - + - + - + - + - + - + 心肌梗死 卒中 心血管事件 Haffner SM,et al. NEJM 1998, 229-234

糖尿病患者心血管死亡危险增加 总死亡率 心血管死亡率 133例新诊断2型DM vs. 144例对照,15年前瞻性研究 D－糖尿病组 10年 5年 15年 D－糖尿病组 C－对照组 总死亡率 心血管死亡率 50 男性 P<0.001 女性P<0.001 50 男性 P<0.001 女性P<0.001 40 40 30 30 % % 20 20 10 目的：我们对新诊断的糖尿病患者和非糖尿病患者进行了15年的研究，已评估糖尿病患者的心血管事件死亡率。 试验设计和方法：研究对133名中年的新诊断的糖尿病患者和144名作为对照组的非糖尿病患者进行了15年的观察，并且对两组人群的5年和十年后的心血管风险进行了评估！ 结果：2型糖尿病患者的总死亡率显著增高（总死亡率：与对照组相比,男性 44.3%vs 12.9% 年龄校正【OR】5.0,P =0.001;女性 44.4%vs 11.0% [OR]5.2 P=0.001）。 主要是由于心血管事件死亡率的增加（对于男性和女性OR分别为6.2和11.2,两组的P＝0.001）。对于致死性和非致死性的心肌梗死和脑卒中，糖尿病患者组也明显增加。 通过单变量分析和多种多边量回归分析，显示不论是在诊断初始阶段或5年、10年时，高血糖都可以为糖尿病患者的心血管死亡率的评估因素。此外，通过分析糖尿病患者的血脂水平异常，也是心血管死亡的一个原因。 总结：这个观察时间长，入组均为新诊断的糖尿病患者，对于中年糖尿病患者，高血糖和血脂异常均可以提示存在较高的心血管死亡率。 O B J E C T I V E— We studied the 15-year cardiovascular mortality and morbidity of newly diagnosed patients with type 2 diabetes and of nondiabetic control subjects and the predictors of cardiovascular mortality in diabetic patients. RESEARCH DESIGN AND METHODS— We performed a 15-year prospective study of 133 middle-aged patients with newly diagnosed type 2 diabetes and 144 control subjects. Cardiovascular risk factors were assessed in both groups at baseline and after 5 and 10 years. R E S U LT S— Total mortality was markedly higher in patients with type 2 diabetes (total: 44.3 vs. 12.9% for men, age-adjusted odds ratio [OR] 5.0, P 0.001; 44.4 vs. 11.0% for women, OR 5.2, P 0.001), which was due to increased cardiovascular mortality (ORs for men and women: 6.2 and 11.2, respectively, P 0.001 for both). The incidences of fatal and nonfatal m y o c a rdial infarction and stroke were likewise higher in diabetic patients. In univariate analyses and various multiple logistic regression analyses, hyperglycemia was a constant predict r of cardiovascular mortality assessed at the time of diagnosis or at 5- or 10-year examinations. Moreover, lipoprotein abnormalities characteristic of type 2 diabetes (low HDL cholesterol , high LDL triglycerides or apolipoprotein B levels, and low LDL cholesterol / a p o l i p o p rotein B ratio as a marker for LDL size) were predictive of cardiovascular death in these analyses. C O N C L U S I O N S— This long-term study of a well-characterized group of newly diagnosed patients strengthens the view that the prognosis in middle-aged subjects is markedly impaired and that both hyperglycemia and compositional lipoprotein abnormalities repredictors of cardiovascular mortality in patients with type 2 diabetes. 10 C D C D C D C D 133例新诊断2型DM vs. 144例对照,15年前瞻性研究 Niskanen et al Diabetes Care 1998;21:1861-1869

糖尿病患者心肌梗死发病率增高 341例连续收治的心梗患者,81例DM vs.260例非DM 60 无糖尿病 53% 糖尿病 50 40 患者比例 (%) 30% 30 28% 25% 20 16% 14% 对连续的心肌梗塞（MI）住院患者的糖尿病及其合并症的发生和预后情况进行观察研究。81/341例（24％）患者伴有糖尿病。 对伴或不伴糖尿病的患者进行分组对照比较。合并糖尿病的患者中，相当一部分（51％）正接受洋地黄治疗，而未合并糖尿病的患者中占20％。 两组间需要治疗的室性快速型心律失常情况无差异。与未合并糖尿病患者相比（7％），高度A-V传导阻滞在合并糖尿病患者中更常见（19％，P＜0.001）。住院期间（25%, vs. 16% P < 0-2)）及1年随访期内（53% vs. 28% P < 0.001），合并糖尿病组患者的死亡率均高于未合并糖尿病组患者。糖尿病是独立的死亡预后风险因子（P< 0–01）。 与未合并糖尿病组患者相比（14％），合并糖尿病组患者中致命性再梗更为常见（30％，P<0.05）。总之，尽管冠心病治疗已有所改善，但合并糖尿病的MI仍预后不良。晚期死亡率高在相当大程度上与致命性再梗的高发生率有关。 Abstract The occurrence of diabetes mellitus and its complications and prognosis in an unselected consecutive series of patients with myocardial infarction (MI) was studied. Out of 341 patients 81 (24%) haddiabetes. Comparisons were made between patients with and without diabetes. Age was higher and female sex more common among patients with diabetes. A considerable proportion of patients with diabetes were on digitalis when admitted (51%) compared to 20% of those without. Ventricular tachy arrhythmias requiring treatment did not differ between the two groups. High-degree A V-block was considerably more common among patients with diabetes (19%) than those without (7% P<0.001). Mortality was higher in diabetic than in non-diabetic patients both during the hospital phase (25%, vs. 16% P < 0–02) and during one year of follow-up (53% vs. 28% P < 0.001). Diabetes was an independent prognostic risk factor for death (P< 0–01). Fatal reinfarction was more common among diabetic patients (30%) than those without (14%; P<0.05). In conclusion diabetics with MI have a poor prognosis despite improvements in coronary care. The high late mortality is to a large extent related to a high proportion of fatal reinfarctions. 10 住院期间死亡率 1年死亡率 致死性再梗 341例连续收治的心梗患者,81例DM vs.260例非DM Malmberg K, et al. Eur Heart J 1988;9:259–64.

入选30693例人群，其中970例糖尿病患者,随访时间为4年 糖尿病人群高血压流行病学研究 英国80%糖尿病患者 合并高血压 80％ 高血压 高血压标准：140/90 英格兰进行的一项全国范围内的流行病学调查。 按照地理学位置、种族和社会状况的分布特点，入选了具有代表性的人群。 随访时间为4年，入选患者30693例，其中970例糖尿病患者。 采用严格的高血压定义，即血压≥140/90mmHg，则有近80%的糖尿病患者为高血压。调整年龄后，糖尿病患者高血压发生率是非糖尿病患者 的2倍。调整了肥胖（体重指数）后，糖尿病患者发生高血压的风险仍增加2倍。 入选30693例人群，其中970例糖尿病患者,随访时间为4年 Tarnow L. et al. Diabetes Care (1994) 17:1247–1251.

糖尿病增加高血压患者心血管死亡风险 多种危险因子干预试验（MRFIT）： 比较两组中男性收缩压（SBP）及其它CV风险因子与CV死亡的关系。 非糖尿病（342815） 糖尿病（5163） 心血管死亡(/10,000 人年) 高血压可进一步加大已有的2型糖尿病相关心血管疾病高危程度。收缩压越高，糖尿病患者的绝对高危程度更大，这表明控制高血压后更有可能进一步预防糖尿病患者的CV死亡。 合并高血压可使糖尿病患者的CV发病风险大增加近2倍 vs 血压正常的糖尿病患者；同样，合并糖尿病的患者的CV发病风险是无糖尿病合并患者的2倍。糖尿病并高血压患者的CV发病风险较血压正常的非糖尿病患者群体增加近4倍。 多种危险因子干预试验（Multiple Risk Factor Intervention Trial，MRFIT）对大样本男性群体进行了筛查，比较糖尿病（n = 5,163）和非糖尿病（n = 342,815）男性中收缩压（SBP）及其它CV风险因子与CV死亡的关系。经年龄、种族、收入、血清胆固醇、SBP及吸烟史校正后，糖尿病男性的绝对死亡风险是非糖尿病男性的3倍（p < 0.0001）。SBP 与CV死亡风险积极相关，这一趋势在非糖尿病和糖尿病受试者中均有统计学意义（p < 0.001）。在各SBP水平，糖尿病男性的CV死亡均多于非糖尿病男性。此外，与非糖尿病男性相比，糖尿病男性中C V死亡率随着SBP水平的升高出现更为急剧的上升。因此，SBP越高，糖尿病患者的绝对高危程度越大，这表明控制高血压后更有可能进一步预防糖尿病患者的CV死亡。 The presence of hypertension further increases the already high risk of cardiovascular disease associated with type 2 diabetes. The higher the systolic blood pressure, the greater the absolute excess risk for diabetic patients, indicating a greater potential for prevention of CV death among patients with diabetes by control of elevated blood pressure. The presence of hypertension further increases the already high risk of cardiovascular (CV) disease associated with type 2 diabetes. There is an approximate 2-fold increased risk of CV disease in hypertensive vs. normotensive patients with diabetes; similarly, patients with diabetes have a 2-fold increased risk for CV disease than patients without diabetes. The combination of diabetes and hypertension gives an approximate 4-fold increase in CV risk over the nondiabetic, normotensive population.1,2 In the large cohort of men screened for Multiple Risk Factor Intervention Trial (MRFIT), the relationships of systolic blood pressure (SBP) and other CV risk factors to CV mortality were compared in men with diabetes (n = 5,163) and without diabetes (n = 342,815). The absolute risk of CV death was 3 times higher for men with diabetes than for those without diabetes, after adjustment for age, race, income, serum cholesterol, SBP, and cigarette smoking (p < 0.0001). SBP was positively related to the risk of CV death, with a significant trend in both nondiabetic and diabetic subjects (p < 0.001). At every level of SBP, CV death was much greater for men with diabetes than for men without diabetes. Moreover, with higher SBP levels, the CV mortality rate increased more steeply among those with diabetes than among those without diabetes. Thus, the higher the SBP, the greater the absolute excess risk for patients with diabetes, indicating a greater potential for prevention of CV death among patients with diabetes by control of elevated blood pressure.3 1 Epstein and Sowers, 1992. 2 Hypertension in Diabetes Study Group, 1993b. 3 Stamler et al, 1993. 收缩压 (mmHg) <120 120-139 140-159 160-179 180-199 200 多种危险因子干预试验（MRFIT）： 比较两组中男性收缩压（SBP）及其它CV风险因子与CV死亡的关系。 Stamler J, et al. Diabetes Care. 1993;16:434-444.

糖耐量异常人群的血栓性疾病危害 -----卒中发生率增高 168例心梗患者中,IGT113例 vs.55例OGTT正常者, 糖耐量异常人群的血栓性疾病危害 -----卒中发生率增高 4.5% GAMI研究 4.0% 卒中发生相对频率 3.5% 3.0% 糖耐量正常 2.5% 糖耐量异常 2.0% GAMI研究证实：糖耐量异常人群的心衰、再梗死、卒中、死亡等事件的发生率均较糖耐量正常人群显著增高。 AIMS: Recent data revealed that patients with myocardial infarction (MI) have a high prevalence of previously unknown diabetes mellitus (DM) and impaired glucose tolerance (IGT). The added prognostic importance of this finding has not been prospectively explored. To investigate whether a newly detected abnormal glucose tolerance (IGT or DM) assessed early after an MI, is related to long-term prognosis. METHODS AND RESULTS: Patients (n=168; age 63.5±9.3 years) with MI, no previous DM and admission blood glucose <11.0 mmol/l were followed for major cardiovascular events defined as the composite of cardiovascular death, non-fatal MI, non-fatal stroke or severe heart failure (HF). According to an oral glucose tolerance test (OGTT) before hospital discharge, 55 patients had normal and 113 abnormal glucose tolerance (GT). During the follow-up of median 34 months there were eight cardiovascular deaths, 15 patients had a recurrent MI, six had a stroke and ten severe HF. All patients who died from cardiovascular causes had abnormal GT. The composite cardiovascular event occurred in 31 (18%) patients. The probability of remaining free from cardiovascular events was significantly higher in patients with normal than abnormal GT (p=0.002). Together with previous MI, abnormal GT was the strongest predictor of future cardiovascular events (hazard ratio 4.18; CI 1.26-13.84; p=0.019). CONCLUSIONS: Abnormal glucose tolerance is a strong risk factor for future cardiovascular events after myocardial infarction. Since it is common and possible to detect even during the hospital phase it may be a target for novel secondary preventive efforts. 1.5% 1.0% 0.5% 0.0% 168例心梗患者中,IGT113例 vs.55例OGTT正常者, Bartnik et al. Eur Heart J 2004; 25:1990-7.

糖尿病是卒中的独立危险因素 10项临床研究结果分析 3.3（1.9-5.7） 4.8（2.8-8.4） 2.8（2.0-3.7） 卒中类型 病例数 糖尿病 患者比例 相对危险度 男性（95％CI） 女性（95％CI） 任何致命性卒中 16649 4.8 3.3（1.9-5.7） 4.8（2.8-8.4） 347978 1.5 2.8（2.0-3.7） － 16172 0.9 7.9（2.5-19.1） 任何卒中 1298 17.6 1.4（0.4-4.2） 2.2（1.6-3.1） 3778 8.6 1.7（1.0-2.9） 1.3（0.7-2.5） 2432 43.5 2.4（1.2-4.9） 5.5（2.4-12.9） 任何卒中＋TIA 5734 9.3 1.4（1.0-2.0） 1.7（1.2-2.4） 任何缺血性卒中 1624 13.8 2.6 7549 5.9 2.4（1.7-3.5） 10项临床研究结果分析 糖尿病是一种复杂的代谢综合征，对全身及脑血管系统都有显著影响。 糖尿病可使缺血性卒中的发生率和严重程度上升，卒中预后更差。就诊时超过1/3的急性卒中患者伴有高血糖症。多种原因可改变糖尿病相关卒中的预后。缺血发作时高血糖的直接影响可能是最重要的原因。采用检查方法，如MRI查明卒中的局部解剖及病理生理学概况，将有助于明确高血糖对卒中的病理生理影响。评价卒中后高血糖患者最佳治疗的随机临床试验正在进行当中。此类试验将判定积极控制卒中后高血糖的临床受益是否与已观察到的急性心肌梗塞后积极血糖控制受益相似。卒中患者的主治医生应该知道充分的血糖控制对卒中一级和二级预防的重要性 。 Abstract Diabetes mellitus is a complex metabolic syndrome with significant effects on the systemic and cerebral vasculature. The incidence and severity of ischaemic stroke are increased by the presence of diabetes, and outcome from stroke is poorer. More than one third of patients admitted with acute stroke are hyperglycaemic at presentation. Reasons for the altered prognosis in diabetes associated stroke are multifactorial. A direct influence of hyperglycaemia at the time of ischaemia is likely to be important. The use of novel methods to delineate stroke topography and pathophysiology such as MR spectroscopy, diffusion and perfusion weighted MRI appear helpful in delineating the effects of hyperglycaemia on stroke pathophysiology. Randomised clinical trials to determine optimal management for patients with hyperglycaemia following stroke are ongoing. Such trials will determine if aggressive control of acute hyperglycaemia following stroke has similar benefits to that observed following acute myocardial infarction. Clinicians responsible for stroke patients should be aware of the importance of adequate glycaemic control in both primary and secondary prevention of stroke. Baird TA, et al. J Clin Neurosci 2002;9(6):618-626.

糖尿病患者血脂代谢异常增加 52% 48% 58% （%） 总的来说，糖尿病合并血脂异常比例比非糖尿病患者高52%，这亦显示对于糖尿病患者，血脂异常的治疗非常重要，也是随着血糖治疗前提下应当普遍关注的危险因素 中国11省市心血管病危险因素队列研究(CMCS研究)

主要内容 糖尿病患者心血管疾病危害 糖尿病心血管并发症的发病机制 全面干预，终点受益

糖尿病并发心血管疾病的机制-1 血栓 PAI-1  纤溶酶原 CRP FFA 脂代谢紊乱 VLDL (甘油三酯) HDL 肥胖 TNF- Lipaemia AGEs 遗传易感性 高血压 高胰岛素血症 胰腺 肝脏 脂肪细胞 骨骼肌 功能蛋白糖化 高血糖 胰岛素抵抗  FFA 多种作用机制导致2型糖尿病患者发生动脉粥样硬化疾病。多种危险因素聚集在动脉促进了糖尿病患者的动脉粥样硬化的发生。骨骼肌出现胰岛素抵抗，使得其对葡萄糖和游离脂肪酸的射入减少，导致血糖升高，循环游离脂肪酸增多。为了应对胰岛素抵抗，最初胰岛努力分泌更多的胰岛素，产生了超高胰岛素血症，这本身就是动脉疾病的一种危险因素。更多的游离脂肪酸通过门静脉循环增加了肝脏的负荷。过多的游离脂肪酸，产生出了更多的高TG脂蛋白，包括VLDL。相反，在此阶段，2型糖尿病患者的HDL水平下降。此外除了控制TG的摄入，糖尿病患者进餐后，出现了被夸大的脂血现象，表现为试管内的血液上清液上可以出现类似于奶油的脂质层。 脂肪细胞不仅可以释放TNF等促炎性细胞因子直接作用与血管细胞，促进动脉粥样硬化行程，还可以通过肝脏合成急性期的产物，如CRP、增加了纤维蛋白原（血栓形成的底物）、增加了纤维融解酶抑制剂PAI－1。代谢综合征通常包括高血压，也是众所周知的动脉粥样硬化行程的作用因素。遗传因素也是2型糖尿病患者易发生动脉粥样硬化的因素。最后，糖化大分子产生的高级聚糖化终产物，被修饰过多肽链的绿血糖修饰，可以在2型糖尿病患者的动脉管壁上与高级聚糖化终产物结合，发生炎性反应。 Multiple mechanisms contribute to arterial disease in patients with type II diabetes. A variety of risk factors converge on the artery to promote atherogenesis in individuals with type II diabetes (center). Skeletal muscles may be resistant of insulin action, which decreases the utilization of glucose and free fatty acids, causing hyperglycemia and increased levels of circulating free fatty acids. In the face of the insulin resistance, the pancreas initially attempts to compensate by producing more insulin, yielding hyperinsulinemia, itself a risk factor for arteriopathy. A high burden of abdominal fat presents the liver with elevated levels of free fatty acids through the portal circulation. This excess of free fatty acids will drive the overproduction of TG-rich lipoprotein particles, including VLDL. A reciprocal decrease in HDL accompanies the hypertriglyceridemia characteristic of the type II diabetic state. In addition to the increase in fasting TGs, patients with diabetes may have an accentuated response to dietary fat, yielding an exaggerated postprandial lipemia, indicated by the creamy supernatant over the plasma in the test tube. The adipocyte can also release proinflammatory cytokines such as TNF-, which not only have direct effects on vascular wall cells that can promote atherogenesis, but also can elicit the production of acute phase reactants by the liver, including CRP (an independent indicator of cardiovascular risk and of incident diabetes), increased fibrinogen (a substrate for increased thrombosis), and an increase in the inhibitor of fibrinolysis, PAI-1. The “metabolic syndrome” often includes hypertension, a well-known promoter of atherogenesis. Genetic factors may play into susceptibility to type II diabetes and atherosclerosisas well. Finally, the formation of advanced glycation end products from glycated macromolecules, depicted by the green glucose molecules modifying the polypeptide chain, can engage RAGE and compound the inflammatory stimuli encountered by the arterial wall in patients with type II diabetes. VLDL indicates very low-density lipoprotein; TNF-, tumor necrosis factor-; CRP, C-reactive protein; and PAI-1, plasminogen activator inhibitor-1. Libby P, et al. Circulation 2002;106:2760–63.

糖尿病并发心血管疾病的机制-2 心血管并发症 氧化应激 AGEs形成 多元醇通路 血糖  高渗 GLUT 血糖  PKC AGE 受体 MAPK 1.晚期糖基化终末产物(advanced glycation end-products,AGEs)可引起体内组织一系列病理生理改变,是导致糖尿病慢性并发症的重要致病因素。 2.葡萄糖转运蛋白(GLUT) 3.蛋白激酶C(PKC) ：近年研究发现PKC的激活可能是DM多种发病机制相联系的共同纽带 。 4、MAPK：糖尿病状态下,多种因素激活 丝裂原活化蛋白激酶(MAPK)信号转导通路 。 同时，高血糖还通过氧化应激、二酰甘油（DAG）合成或晚期糖基化终末产物（AGEs）激活蛋白激酶C（PKC）而损伤内皮功能。 转录因子 基因表达发生改变 过度增殖 蛋白基因型发生改变 心血管并发症 Schnell O, et al. Klinikarzt 2000;2:29.

胰岛素抵抗、糖尿病和心血管疾病的“共同土壤” 氧化应激——— 胰岛素抵抗、糖尿病和心血管疾病的“共同土壤” 营养过量摄入 缺乏运动 细胞内葡萄糖 和FFA超载 线粒体内 氧化应激 肌肉、脂肪组织 胰岛素抵抗 β细胞胰岛素 分泌减少 内皮细胞 受损 过度热量摄入/运动减少引起细胞内葡萄糖和游离脂肪酸增高,引发β细胞,肌肉,脂肪组织和内皮细胞的氧化应激: β细胞氧化应激→功能降低,发生糖尿病 肌肉,脂肪组织氧化应激→胰岛素抵抗 内皮细胞氧化应激→内皮功能失调→动脉粥样硬化→发生心血管疾病 上述3个氧化应激之间相互影响而加重损害。 Overnutrition and decreased physical activity lead to increased glucose and FFA loads in cells. Their transformation in energy is accompanied by increased free radicals generation (oxidative stress). The muscle cells and adipocytes can protect themselves from this condition, producing a resistance to the action of insulin, aiming to reduce glucose and FFA penetration in the cells. cells and endothelium are insulin-independent tissues. Glucose and FFA overload in these cells and cause oxidative stress, which in turn induces a dysfunction of both B cells and endothelium. Endothelial dysfunction may lead to the development of cardiovascular disease, B cell dysfunction is characterized by an alteration of insulin secretion. This last condition is worsened by the concomitant insulin resistance, which is a condition that requires increased insulin secretion to maintain plasma glycemia in a normal range. -cell dysfunction is particularly characterized by a decreased first-phase insulin secretion, which in turn produces the clinical picture of IGT. This last situation is clinically characterized by increased postprandial hyperglycemia. Postprandial hyperglycemia induces oxidative stress. The persistence of such condition produces an exhaustion of cells, leading to the overt diabetes. Oxidative stress produced both during IGT and overt diabetes may contribute to the development of cardiovascular disease. Moreover, the cluster of the risk factors that accompanies the insulin resistance also contribute to produce cardiovascular disease. 心血管事件 代谢综合征 糖耐量低减(IGT) 2型糖尿病(DM) Antonio Ceriello ，ATVB. 2004;24:816

糖尿病和动脉粥样硬化平行进展 糖尿病诊断前， 动脉粥样硬化进程已经启动 SM Haffner 研究显示,糖尿病和动脉粥样硬化是平行进展的,在糖尿病诊断前,动脉粥样硬化进程就已经启动。 Haffner等还提出糖尿病和动脉粥样硬化本身的“危险相等”。他在〈East-West研究〉中（Haffner SM et al. Mortality from coronary ht. dis in subjects with type 2 diabetes and in nondiabetetic subjects with and without prior MI. NEJM 1998; 339: 229）分析该研究的随后7年中无MI史的糖尿病人与有冠心病史的非糖尿病人的MI发病率相同。在AHA会议上，Haffner报告了他们对CHD与糖尿病相关联的进一步证据。 Type 2 diabetes is associated with a marked increase in the incidence of coronary artery disease (CAD); however, the correlation between glycemia and CAD in patients with type 2 diabetes is only modestly positive. This relatively weak association between glycemia and CAD in subjects with diabetes may be caused by the existence of an atherogenic prediabetic state. In the San Antonio Heart Study, subjects who start with normal glucose tolerance and later develop type 2 diabetes have increased triglyceride levels, increased systolic blood pressure, and decreased levels of high-density lipoprotein cholesterol before the onset of type 2 diabetes. The basis for these atherogenic prediabetic changes may be related to insulin resistance rather than reduced insulin secretion. Recently, interest has focused on a possible role of fibrinolysis and increased subclinical inflammation, as determined by high-sensitivity C-reactive protein (CRP) levels. The Insulin Resistance Atherosclerosis Study found that insulin resistance, as determined by a frequently sampled glucose tolerance test, is significantly related to higher CRP levels, higher fibrinogen, and higher plasminogen activator inhibitor–1 (PAI-1) levels. The investigators also have shown that high PAI-1 and CRP levels are predictors of the development of type 2 diabetes. In addition, the Women’s Health Study has shown that high CRP levels predict type 2 diabetes. Insulin-sensitizing interventions have been demonstrated to reduce these nontraditional risk factors. Rosiglitazone, an agent with insulin-sensitizing properties, decreases PAI-1 and CRP levels. Some of the adverse cardiovascular effects seen in patients with type 2 diabetes may be reversed by insulin-sensitizing agents. 2003 by Excerpta Medica, Inc. Am J Cardiol 2003;92(suppl):18J–26J SM Haffner Haffner Sm，Am J Cardiol。2003；18：92（4A）：18J-26J

主要内容 糖尿病患者心血管疾病危害 糖尿病心血管并发症的发病机制 全面干预，终点受益

糖尿病心血管并发症防治措施 对糖尿病患者应关注什么？ 心血管并发症危害严重 抗栓治疗 降压治疗 调脂治疗 降糖治疗 改善生活方式

3234例空腹血糖和餐后血糖增高的非糖尿病患者,锻炼+饮食调整组vs.二甲双胍vs安慰剂随访2.8年 糖尿病预防计划显示 预防措施使2型糖尿病发生率減少 0.2 0.4 0.6 0.8 锻炼+饮食调整组 二甲双胍组 0.31 糖尿病发病风险降低 背景：美国约有8％的成年人受2型糖尿病的影响。一些危险因素，增加了禁食阶段和口腹葡萄糖负荷后的血糖浓聚物水平，超重和久坐的生活习惯是可以改善的。我们假设生活方式干预计划或二甲双瓜治疗，可能会保护或延缓糖尿病的进展。 方法：我们随机随入选了3234名非糖尿病患者，但是已经出现了糖代谢异常，随机分为安慰剂组、二甲双胍（850mg/bid）、生活方式干预（体重指数降低7％、每周至少进行150分钟的体育锻炼）。平均年龄51岁，平均BMI 34 ，其中女性68％，45％为少数民族。 结果：平均随访2.8年，这三组的糖尿病发病率分别为每年每100人，安慰剂11人、二甲双胍7.8人、生活方式干预4.8人。与安慰剂相比，生活方式干预降低了58％的发病率，二甲双胍降低了31％。生活方式干预比二甲双胍的作用更为显著。在三年中如果要减少一例糖尿病，生活方式干预需要干预6.9人，二甲双胍方式需要干预13.9人。 结论：生活方式的干预和二甲双胍干预都可以减少糖尿病高危人群的发病率。生活方式干预比二甲双胍更有效。 ABSTRACT Background Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors — elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle — are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. Methods We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. Results The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Conclusions Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin. 0.58 3234例空腹血糖和餐后血糖增高的非糖尿病患者,锻炼+饮食调整组vs.二甲双胍vs安慰剂随访2.8年 Knowler WC, et al. Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403

饮食治疗--- 糖尿病全面干预的关键措施之一 饮食治疗--- 糖尿病全面干预的关键措施之一 合理膳食 红、黄、绿、白、黑 每日进食1至2个西红柿，饮少量红葡萄酒 黄色蔬菜，如胡萝卜、红薯、南瓜可提高免疫力 绿茶及深绿色蔬菜。具有防感染、防肿瘤的作用 燕麦粉或燕麦片，食用燕麦对糖尿病患者效果显著。 黑木耳，有助于预防血栓形成

预防糖尿病： 改善生活方式还是服用药物？ 每周运动150分钟 减轻体重5%~7% 3年中每预防1例糖尿病需要治疗的患者例数： 预防糖尿病： 改善生活方式还是服用药物？ 每周运动150分钟 减轻体重5%~7% 3年中每预防1例糖尿病需要治疗的患者例数： 改善生活方式 7 二甲双胍 14

改善生活方式： 步行给糖尿病患者带来的收益 研究调查了健康锻炼与心血管疾病在女性中的关系。研究在宾夕法尼亚州女子大学进行，随机抽取无心血管病史，平均年龄45.5岁的在校女生1564例。研究时间：1962-1993。根据运动消耗能量的多少大致可分为三类： <500, 500–999, 1,000 千卡/周。而运动方式中以步行与心血管风险关系最为密切。结果发现：每周行走路程在3-6公里的人群，心血管疾病风险降低16%，每周行走路程> 6 英里的人群，心血管风险降低33%。 The authors investigated the relation between physical activity and cardiovascular disease (CVD) in women by following 1,564 University of Pennsylvania alumnae (mean age, 45.5 years), initially free of CVD, from 1962 until 1993. Energy expenditure was estimated from the daily number of flights of stairs climbed and blocks walked as well as the sports played and was categorized into approximate thirds (<500, 500–999, 1,000 kcal/week). During 35,021 person-years, 181 CVD cases were identified. After adjustment for coronary risk factors, the relative risks of CVD were 0.99 (95% confidence interval (Cl): 0.69, 1.41) and 0.88 (95% Cl: 0.62, 1.25) for women who expended 500–999 and 1,000, respectively, compared with <500 kcal/week (p for trend = 0.45). Only walking was found to be inversely related to CVD risk (p for trend = 0.054). Compared with women who walked <4 blocks/day, the relative risks of CVD were 0.84 (95% Cl: 0.59, 1.19) and 0.67 (95% Cl: 0.45, 1.01) for women who walked 4–9 and 10 blocks/day, respectively. Finally, an interaction (p = 0.023) between body mass index and physical activity on CVD risk was observed, with an inverse association only for leaner (<23 kg/m2) women. These data showed no overall association of physical activity with CVD risk in women. However, walking 10 blocks/day (approximately 6 miles (9.7 km)/week) was associated with a 33% decreased risk. One explanation for this finding may be that walking was reported more precisely than other kinds of activities. 1,564例最初无心血管疾病的女性,随访31年 心血管疾病风险 ¯16% ¯33% 行走一小步 = 获益一大步 < 3 英里／周 3-6 英里／周 > 6 英里／周 Am J Epidemiol 150: 408-416, 1999

糖尿病患者减轻体重对死亡率的影响 体重降低者各种死亡率显著降低 4,970位超重的糖尿病患者,随访12年 50 40 30 20 10 体重降低者各种死亡率显著降低 调整后死亡率减少率 目的：明确对于超重的糖尿病患者，体重减轻可以带来什么获益。 研究设计和方式：我们从美国癌症协会癌症预防研究I中，入组并随访12年（1959－1972）4970名超重的糖尿病患者，年龄在40－64岁。观察心血死亡率。 结果：34％的患者体重减轻。在改善了BMI后，人口学因素，卫生状况和体育锻炼，体重减轻后，总的死亡率降低25％（RR＝0。75；95％CI 0.67-0.84）， 冠心病和糖尿病的死亡率下降28％（RR＝0.72;0.63-0.82）.体重减轻20－29磅，可以降低最多的死亡率33％。如果体重减轻70磅，死亡率则会带来轻微的升高。 结果：这项观察性研究发现，对于超重的糖尿病患者，体重适当减轻可以降低死亡率！ OBJECTIVE— To estimate the effect of intentional weight loss on mortality in overweight individuals with diabetes. RESEARCH DESIGN AND METHODS— We performed a prospective analysis with a 12-year mortality follow-up (1959–1972) of 4,970 overweight individuals with diabetes, 40–64 years of age, who were enrolled in the American Cancer Society’s Cancer Prevention Study I. Rate ratios (RRs) were calculated, comparing overall death rates, and death from cardiovascular disease (CVD) or diabetes in individuals with and without reported intentional weight loss. RESULTS— Intentional weight loss was reported by 34% of the cohort. After adjustment for initial BMI, sociodemographic factors, health status, and physical activity, intentional weight loss was associated with a 25% reduction in total mortality (RR = 0.75; 95% CI 0.67–0.84), and a 28% reduction in CVD and diabetes mortality (RR = 0.72; 0.63–0.82). Intentional weight loss of 20–29 lb was associated with the largest reductions in mortality (33%). Weight loss 70 lb was associated with small increases in mortality. CONCLUSIONS— Intentional weight loss was associated with substantial reductions in mortality in this observational study of overweight individuals with diabetes. 所有死因 心血管病 糖尿病相关 肥胖相关癌症 4,970位超重的糖尿病患者,随访12年 Diabetes Care 2000 ;23:1499-504

Slide 64 from SMOKING_CESSATION_09[1].26.05_Final 戒烟对糖尿病患者健康的好处 Schroeder 483A 15 年 20 分钟 Schroeder 483B 血压, 心跳和外周循环改善 Schroeder 483C 心肌梗死和卒中的 危险降至非吸烟者水平 Schroeder 483C Schroeder 483D 24 小时 10 年 停止吸烟的时间 肺癌风险下降 50% CO水平降低 戒烟的健康获益： 戒烟可以在任何阶段带来显著快速的收益 戒烟一年，冠心病危险较吸烟者下降1∕2，全因死亡率在第一个2年之内减低。 戒烟15年后，心血管风险降低至与从未吸烟的人群相同的水平。 65岁戒烟的人预期寿命比吸烟者长4年。 罹患癌症的危险率在戒烟10年后下降50%。 Health Benefits of Quitting Quitting brings immediate health benefits at any age. [Schroeder 483A] 1 year after cessation, coronary disease risk drops to ½ of smokers All-cause death rate declines within first 2 years Stroke risk declines at a comparable rate In addition to extra years of life, quality of life is another benefit After 15 years of abstinence, the coronary disease risk falls to the rate of people who never smoked. [Schroeder 483B] Smokers who quit at age 65 can anticipate 4 years more life than those who continue to smoke. [Schroeder 483E] The rate of cancers falls by 50% after a decade of abstinence. [Schroeder 483E] Schroeder SA. What to do with a patient who smokes. JAMA. 2005;294(4):482-487. 48 小时 1 年 心肌梗死下降 50% 味觉和嗅觉提高 2-12 周 3-9 月 肺功能改善 30% 呼吸急促和咳嗽减少 Slide 64 from SMOKING_CESSATION_09[1].26.05_Final

UKPDS –平均HbA1c 降低1%带来的收益 任一糖尿病 相关终点 微血管 病变 白内障 周围血管 病变 心肌梗死 心衰 摘除术 危险下降（ % ） -5 -10 14% 19% 16% -15 21% p<0.0001 p<0.0001 -20 p=0.016 p<0.0001 -25 p<0.0001 p<0.0001 -30 目的：研究2型糖尿病患者中高血糖与大血管或微血管并发症风险的关系 设计：前瞻性观察研究 研究对象：参与UKPDS研究的4585名白种人，亚裔印度人及加勒比黑人患者纳入发病率的研究，随机分配的或未予以治疗3642人纳入相对风险的研究。 方法：主要血栓事件：任意终点或与糖尿病相关死亡和全因死亡率。二级血栓事件：心梗，中风，截肢（包括死于外周血管病变），以及微血管疾病（首选肾脏光凝集治疗）。单独终点事件：非致死性心衰和白内障摘除术。平均HbA1c下降1%的风险被用于检验并已经经过诊断糖尿病的可能混杂因素的校正。 结果：临床并发症的发病率与高血糖显著相关。平均HbA1c的下降1%，则减少糖尿病相关任意终点的21%的风险（95% confidence interval 17% to 24%, P<0.0001），与糖尿病相关的死亡也下降21%(15% to 27%, P<0.0001),心梗下降了14%(8% to 21%, P<0.0001)，微血管并发症下降了37%(33% to 41%, P<0.0001)。任意终点均没有观察到风险的阈值。 结论：2型糖尿病的患者中并发症的风险与之前的高血压有呈强相关性。任何HbA1c的下降可能会减少合并症的风险，那些在正常范围内的HbA1c值的风险最低。 Objective: To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Design: Prospective observational study. Setting: 23 hospital based clinics in England, Scotland, and Northern Ireland. Participants: 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. Outcome measures: Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA1c adjusted for possible confounders at diagnosis of diabetes. Results: The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA1c was associated with reductions in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P<0.0001), 21% for deaths related to diabetes (15% to 27%, P<0.0001), 14% for myocardial infarction (8% to 21%, P<0.0001), and 37% for microvascular complications (33% to 41%, P<0.0001). No threshold of risk was observed for any end point. Conclusions: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range (<6.0%). 37% -35 43% -40 p<0.0001 p<0.0001 UKPDS –平均HbA1c 降低1%带来的收益 UKPDS 35. BMJ 2000; 321: 405–412.

糖尿病患者调脂治疗的收益 减少 增加 非糖尿病 糖尿病 有利于调脂药 有利于安慰剂 总死亡率 冠心病死亡率 主要冠心病事件 脑血管事件 目的：评价合并冠心病的糖尿病患者中，使用辛伐他丁降低胆固醇对冠心病和其他动脉硬化事件的风险的影响。 研究设计和方法：研究采用POST HOC 亚组分析；202名糖尿病患者以及4242名存在心梗或心绞痛的非糖尿病患者，血清总胆固醇为5.5-8.0 mmol/l,血清甘油三酯小于或等于2.5 mmol/l，这些患者曾纳入4S研究。 被试被随机的接受每天20mg辛伐他丁双盲治疗，根据前6-18周血清胆固醇的反映可以在未告知患者情况下剂量增加到40mg每天，终点事件为： 1 总死亡率 2 主要的冠心病事件（死于冠心病或废止死刑心肌梗死）3 其他动脉硬化事件4 心梗后血管手术再通治疗。 >结果：经过中位数为5.4年的随访，糖尿病组服用辛伐他丁所致的平均血脂改变与非糖尿病组无明显差别。使用辛伐他丁的糖尿病患者主要终点事件的相对风险系数为如下： >总死亡率：.0.57 (95% CI, 0.30-1.08; P = 0.087) >主要的冠心病事件 0.45 (95% CI, 0.27-0.74; P = 0.002), >任意动脉硬化事件 (95% CI, 0.43-0.92; P = 0.018) >在非糖尿病患者中分别为 >0.71 (95% CI, 0.58-0.87; P = 0.001), >0.68 (95% CI, 0.60-0.77; P < 0.0001), >0.74 (95% CI, 0.68-0.82; P < 0.0001). >结论：上述结果强烈支持服用辛伐他丁降低血清胆固醇改善合并冠心病的糖尿病患者预后。 >降低胆固醇所带来的收益可能要比那些非糖尿病患者多，因为糖尿病患者复发冠心病事件和其他动脉硬化事件的绝对风险要高。 OBJECTIVE: To assess in diabetic patients with coronary heart disease (CHD) the effect of cholesterol lowering with simvastatin on mortality and the risk of CHD and other atherosclerotic events. RESEARCH DESIGN AND METHODS: A post hoc subgroup analysis was carried out on data from 202 diabetic patients and 4,242 nondiabetic patients with previous myocardial infarction or angina pectoris, serum total cholesterol 5.5-8.0 mmol/l, and serum triglycerides < or = 2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S). Participants in the 4S were randomly assigned to double-blind treatment with simvastatin, 20 mg daily, with blinded dosage titration up to 40 mg daily, according to cholesterol response during the first 6-18 weeks, or placebo. Endpoints were 1) total mortality, 2) major CHD events (CHD death or nonfatal myocardial infarction), 3) other acute atherosclerotic events, 4) myocardial revascularization procedures. RESULTS: Over the 5.4-year median follow-up period, simvastatin treatment produced mean changes in serum lipids in diabetic patients similar to those observed in nondiabetic patients. The relative risks (RRs) of main endpoints in simvastatin-treated diabetic patients were as follows: total mortality 0.57 (95% CI, 0.30-1.08; P = 0.087), major CHD events 0.45 (95% CI, 0.27-0.74; P = 0.002), and any atherosclerotic event 0.63 (95% CI, 0.43-0.92; P = 0.018). The corresponding RRs in nondiabetic patients were the following: 0.71 (95% CI, 0.58-0.87; P = 0.001), 0.68 (95% CI, 0.60-0.77; P < 0.0001), and 0.74 (95% CI, 0.68-0.82; P < 0.0001). CONCLUSIONS: The results strongly suggest that cholesterol lowering with simvastatin improves the prognosis of diabetic patients with CHD. The absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events. P=0.001 P=0.087 P<0.000 P=0.242 P<0.000 P=0.002 P=0.097 P=0.071 P<0.000 P=0.018 总死亡率 冠心病死亡率 主要冠心病事件 脑血管事件 其他动脉粥样硬化事件 0.2 0.4 0.6 0.8 1.0 1.2 1.4 减少 增加 Adapted from Diabetes Care 20: 614-620, 1997

糖尿病患者降低血压的收益 致死性 事件 糖尿病 相关死亡 心血管 死亡率 总 各终点改变率 (%) –32% –37% –38.7% –60 –40 –20 致死性 事件 糖尿病 相关死亡 LIFE-Study Syst-Eur UKPDS HOT CAPPP HOPE -32 % –46% –37% –32% –60% –38.7% –64% 各终点改变率 (%) 心血管 死亡率 总 荟萃分析显示，降低血压可明显降低糖尿病患者的心血管风险。

抗血小板治疗的收益 心肌梗死 每3例减少1例 脑梗死 每4例减少1例 每天一片 阿司匹林 A目的：确定对于高危的动脉粥样硬化患者进行抗血小板治疗的效果。 选择标准：随机分组，抗血小板药物和其它比较，一种抗血小板药物和另一种抗血小板药物在高危动脉粥样硬化患者中比较 研究回顾：一共回顾了287个研究，共入选130 000名患者，其中77 000应用不同的抗血小板药物 结果：对于高危的患者，应用抗血小板治疗可以降低约1/4所有血管事件，对于非致死性心肌梗死降低1/3，非致死性卒中下降1/4，血管性死亡下降1/6。 对于既往心肌梗死的患者，通过两年的抗血小板治疗，每千人可以减少严重血管事件36（SE5）； 急性心肌梗死通过一个月的抗血小板治疗，每千人减少38（SE5）； 卒中和TIA通过两年的抗血小板治疗，每千人减少36（SE6）； 急性卒中通过3月抗血小板治疗，每千人减少9（SE6）； 其它高危人群通过两年治疗，每千人减少22（SE3）；（AP PAD AF均有显著下降） 阿司匹林是研究中使用最多的抗血小板药物，剂量范围是75－150mg是最佳计量范围，小于75mg是无效剂量 结果：阿司匹林（或其它抗血小板药物）可以降低多种类型的高危患者的动脉粥样硬化血管事件，卒中或脑缺血，PAD、房颤。小剂量的阿司匹林（75－150mg daily )是长期抗血小板治疗的有效剂量。但是急性期阿司匹林的初始剂量可以是150mg。如果需要在阿司匹林的基础上加用第二种抗血小板药物，可能会对一些临床事件产生作用，但是需要更多的临床试验来证实！ bstract Objective To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. Design Collaborative meta­analyses (systematic overviews). Inclusion criteria Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded—that is, have study groups that differed only in terms of antiplatelet regimen. Studies reviewed 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens. Main outcome measure “Serious vascular event”: non­fatal myocardial infarction, non­fatal stroke, or vascular death. Results Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non­fatal myocardial infarction was reduced by one third, non­fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P = 0.0005), peripheral arterial disease (P = 0.004), and atrial fibrillation (P = 0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75­150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P < 0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000. Conclusions Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75­150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed. 目的：确定对于高危的动脉粥样硬化患者进行抗血小板治疗的效果。 每天一片 阿司匹林 Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71-86

阿司匹林抗栓治疗提高糖尿病患者生存率 1 2 3 4 5 6 100 90 80 70 生存率 (%) 时间（年） 100 90 80 70 HR=0.7 (95% CI=0.6-1.0) 本研究旨在评价阿司匹林对糖尿病合并冠心病或非糖尿病但有冠心病患者人群心源性及总死亡率的影响。 本观察性研究人群入选自Bezafibrate 心梗预防研究，其中包括2,368例糖尿病合并冠心病患者及8,586例非糖尿病但有冠心病的患者。 结果发现，有52%的糖尿病人群及56%非糖尿病人群接受阿司匹林治疗。随访5.1 ± 1.3 年后，每100名接受阿司匹林治疗的糖尿病人群较非糖尿病人群明显增多。接受阿司匹林治疗的糖尿病人群的心源性死亡率为10.9%，而未接受者为15.9% (P <0.001)；总死亡率则分别为18.4% 与26.2% (P <0.001).较正各项因素后，无论在糖尿病人群还是非糖尿病人群，接受阿司匹林治疗都是降低心源性及总死亡率的独立预测因子。 Abstract PURPOSE: The benefit of aspirin treatment among diabetic patients with chronic coronary artery disease is not well established. The purpose of this study was to assess the effect of aspirin on cardiac and total mortality in a large cohort of diabetic patients with established coronary artery disease and to compare it with the effect of aspirin in nondiabetic counterparts. PATIENTS AND METHODS: In this observational study among patients screened for participation in the Bezafibrate Infarction Prevention Study, the effects of aspirin treatment in 2,368 non-insulin-dependent diabetic patients with coronary artery disease were compared to those in 8,586 nondiabetic patients. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated with proportional hazards models. RESULTS: Fifty-two percent of diabetic patients and 56% of nondiabetic patients reported aspirin therapy. After 5.1 ± 1.3 (mean ± SD) years of follow-up, the absolute benefit per 100 patients treated with aspirin was greater in diabetic patients than in nondiabetic patients (cardiac mortality benefit: 5.0 versus 2.1, and all-cause mortality benefit: 7.8 versus 4.1). Overall cardiac mortality among diabetic patients treated with aspirin was 10.9% versus 15.9% in the nonaspirin group (P <0.001), and all-cause mortality was 18.4% and 26.2% (P <0.001). After adjustment for possible confounders, treatment with aspirin was an independent predictor of reduced overall cardiac (HR = 0.8; 95% CI: 0.6–1.0) and all-cause mortality (HR = 0.8; 95% CI: 0.7–0.9) among diabetic patients, similar to those in nondiabetic patients. CONCLUSION: Treatment with aspirin was associated with a significant reduction in cardiac and total mortality among non-insulin-dependent diabetic patients with coronary artery disease. The absolute benefit of aspirin was greater in diabetic patients than in those without diabetes. 非糖尿病患者(8568) 生存率 (%) HR=0.8 (95% CI=0.7-0.9) 2型糖尿病患者(2368) 阿司匹林治疗组 对照组 1 2 3 4 5 6 时间（年） Am J Med 105: 494-499, 1998

阿司匹林使糖尿病患者 首次心肌梗死危险显著降低 阿司匹林使糖尿病患者 首次心肌梗死危险显著降低 首次致死性 MI 66％ 糖尿病亚组首次MI 61% 30 15 26 致死性心肌梗死病例数 20 10 心肌梗死发病率% 10.1 5 4 内科医生健康研究是阿司匹林一级预防的里程碑研究，是随机、双盲、安慰剂对照研究，旨在确定小剂量阿司匹林是否能减少心血管死亡以及β胡萝卜素是否能降低肿瘤的发生。共22, 071例无心肌梗死、卒中、TIA病史的美国健康男性医生参加了这项研究，阿司匹林组服用阿司匹林325mg/次，隔天服用一次，平均随访时间为60.2个月。该研究原计划进行8年，但是由于阿司匹林疗效显著，伦理委员会在研究进行到第5年时提前中止试验，以保护安慰剂组受试者的利益。 在此项研究中，阿司匹林组共发生139起心肌梗死事件，安慰剂组为239起，相对危险为0.56（95％CI 0.45-0.70， P<0.00001），这意味着阿司匹林组心肌梗死发生率显著降低了44％，而且阿司匹林使致死性和非致死性心肌梗死都有显著下降。阿司匹林组发生10起致死性心肌梗死，安慰剂组为26起，相对危险为0.34（95％CI 0.15-0.75，P=0.007），阿司匹林显著降低死亡率达66％。糖尿病亚组分析结果显示糖尿病患者从阿司匹林治疗中获益更多。 10 10 安慰剂组 阿司匹林组 安慰剂组 阿司匹林组 内科医师健康研究（PHS), N=22071,ASA325mg/隔日vs. Placebo，5yrs Physician’s Health Study, N Engl J Med 1989,321:129-35

阿司匹林使糖尿病患者 首次脑梗死危险显著降低 阿司匹林使糖尿病患者 首次脑梗死危险显著降低 RR值 P值 脑卒中 0.83 0.04 脑梗死 0.76 0.009 脑卒中* 0.46 0.01 脑梗死 * 0.42 0.01 女性健康研究（Women’s Health Study，WHS)是使用低剂量阿司匹林和维生素E对女性心血管疾病和肿瘤进行一级预防的研究，该研究历经10年，是针对女性、规模最大的随机、双盲、安慰剂对照研究。共有39876名45岁（包括）以上女性参加了该研究，她们均没有冠心病、脑血管疾病、肿瘤以及其他慢性疾病史。平均随访10.1年，主要终点为首次主要心脑血管事件（非致死性心肌梗死、非致死性中风以及心脑血管疾病引起的死亡）；次要终点包括一过性脑缺血发作、冠状动脉重建以及总死亡率。WHS受试者使用的试验药物是拜耳公司提供的拜阿司匹灵。 研究表明，小剂量阿司匹林显著降低45 岁健康女性的首次卒中危险达17%，降低首次脑梗死24%。此前，关于阿司匹林在心脑血管事件一级预防领域的研究大多证实：阿司匹林可以显著降低健康人群心肌梗死的发生危险。但是关于卒中的证据很少。WHS首次明确证实阿司匹林可以降低健康人群的卒中危险。此外，WHS的这一结果与临床实践相符，因为与心肌梗死不同，女性的卒中危险高于男性。1而且，女性的首次卒中比男性更为严重，致残率、死亡率更高——16%女性死于卒中，而男性仅为8%。 2因此，女性卒中预防研究较男性更容易出现阳性结果。 对于65岁以上老年女性的亚组分析证实，阿司匹林给老年女性带来双重收益。阿司匹林使这一亚组的首次心脑血管事件危险降低26%，其中，心肌梗死危险降低34%，缺血性卒中危险降低30%，均有统计学显著性.糖尿病亚组中，脑梗死发生率下降55%（P=0.01）。 0.5 1 利于阿司匹林 利于安慰剂 糖尿病亚组 女性健康研究(WHS), N=39876, ASA100mg/隔日 vs. Placebo,10yrs Women’s Health Study, N Engl J Med 2005, 352:1295

Archives of Ophthalmology, 1995.113 阿司匹林不增加糖尿病患者眼部出血 40 玻璃体/视网膜前出血发生率% 32 30 30 P=0.48 20 10 糖尿病视网膜病变早期治疗研究（ETDRS） 研究简介： 目的 探讨氩激光光凝和阿司匹林对单纯性糖尿病视网膜病变（BDR）或早期增殖性糖尿病视网膜病变（PDR）的疗效。（包括二级预防） 对象及方法 ETDRS由美国国立眼科研究所组织进行的关于糖尿病视网膜病变早期治疗的试验，是一项多中心随机临床对照研究，美国22个临床机构参加，共纳入3711名18～70岁糖尿病患者，且均伴有轻至重度非增殖性或早期增殖性糖尿病视网膜病变，治疗组服用阿司匹林650mg/天。1979年12月～1985年6月，历时5年。 结果 阿司匹林组的玻璃体/视网膜前出血发生率与安慰剂组相比没有统计学差异（P=0.43）。 阿司匹林组心肌梗死危险显著下降达28%(RR 0.72, 95%CI: 0.55-0.95)。 结果解析： 在 BDR或早期PDR患者，阿司匹林对视网膜病变的进展未起作用，但也是无害的，不增加玻璃体出血的危险性，因此心血管疾病或其他疾病患者要用阿司匹林时，没有禁忌。阿司匹林可以减少心血管疾病发生率，有心脏病或脑中风发病危险的糖尿病患者，应听从医生指导，每天服用阿司匹林。 OBJECTIVE: To assess whether the use of aspirin exacerbates the severity or duration of vitreous/preretinal hemorrhages in patients with diabetic retinopathy. DESIGN: The Early Treatment Diabetic Retinopathy Study (ETDRS), a multicenter randomized cl; inical trial, was designed to assess the effect of photocoagulation and aspirin on 3711 patients with mild to severe nonproliferative or early proliferative diabetic retinopathy. INTERVENTION: Patients were randomly assigned to either an aspirin (650 mg/d) or a placebo group. One eye of each patient was randomly assigned to early photocoagulation and the other to deferral of photocoagulation. MAIN OUTCOME MEASURES: The severity and duration of the vitreous/preretinal hemorrhages were determinedfrom gradings of the annual, seven standard stereoscopic field, fundus photographs. Clinical examinations scheduled every 4 months also provided information on the presence and duration of hemorrhages. RESULTS: Annual fundus photographs of eyes assigned to deferral of photocoagulation revealed vitreous/preretinal hemorrhages at some time during follow-up in 564 patients (30; ) assigned to the placebo group and 585 patients (32; ) assigned to the aspirin group (P = .48). Based on gradings of fundus photographs, there were no statistical differences in the severity of vitreous/preretinal hemorrhages (P = .11) or their rate of resolution (P = .86) between the groups. Clinical examination of eyes assigned to deferral of photocoagulation revealed721 eyes (39; ) assigned to the aspirin group and 689 (37; ) assigned to the placebo group that had vitreous/preretinal hemorrhages during the course of the study (P = .30). Again, no statistically significant difference was found between the rates ofresolution, as assessed clinically, between the two treatment groups (P = .43). CONCLUSIONS: As previously reported, the use of aspirin did not increase the occurrence of vitreous/preretinal hemorrhages in patients enrolled in the ETDRS. The data presented in this report demonstrate that the severity and duration of these hemorrhages were not significantly affected by the use of aspirin and that there were no ocular contraindications to its use (650 mg/d) in persons with diabetes who require itfor treatment of cardiovascular disease or for other medical indications. 安慰剂 阿司匹林 ETDRS研究： 3711例糖尿病性视网膜、玻璃体病变患者 阿司匹林325mg bid vs 安慰剂，随访5年以上 Archives of Ophthalmology, 1995.113

小剂量阿司匹林显著降低糖尿病患者 致死性心脑血管事件 小剂量阿司匹林显著降低糖尿病患者 致死性心脑血管事件 0.8 % 0.8% P=0.0037 阿司匹林组 非阿司匹林组 心脑血管事件死亡率. 0.6% 0.4% J-PAD研究是全球第一项针对小剂量阿司匹林一级预防2型糖尿病患者血栓性事件的随机临床对照研究，也是第一个专注于亚洲人群的阿司匹林一级预防研究。目的在于调查小剂量的阿司匹林对2型糖尿病患者一级预防动脉粥样硬化事件的有效性。 这是一项多中心、前瞻性、随机、标签公开、设盲的试验，从2002年12月至2008年4月，来自日本163个医学中心的2539例30到85岁无心血管疾病史的2型糖尿病患者参与该研究。病人被随机分配至每日接受81mg或100mg小剂量阿司匹林组（n = 1,262）或非阿司匹林组（n = 1,277）。病人的平均年龄为65岁， 55%的患者是男性。一级终点为动脉粥样硬化性事件，包括致死性或非致死性缺血性心脏病、致死性或非致死性中风及外周动脉性疾病，二级终点包括一级终点和一级终点的混合事件以及任何原因引起的死亡。 平均随访的4.37年结果发现：阿司匹林能显著降低2型糖尿病患者首次致死性冠心病和脑血管事件风险。 he combined end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (5 fatal myocardial infarctions and 5 fatal strokes) in the nonaspirin group (HR, 0.10; 95% CI, 0.01-0.79; P=.0037). 0.08 % 0.2% n = 1262 n = 1277 J-PAD研究：2539例30~85岁无心血管疾病史的2型糖尿病患者，随机分配至每日 接受81mg或100mg小剂量阿司匹林组或非阿司匹林组，平均随访4.37年。 JAMA. 2008 Nov 12;300(18):2134-41. Epub 2008 Nov 9.

尽早加强对心血管并发症的全面干预，是 迅速降低糖尿病死亡率的关键措施之一，包括降压达标、抗栓治疗 糖尿病患者单纯降糖治疗 远远不够！ 尽早加强对心血管并发症的全面干预，是 迅速降低糖尿病死亡率的关键措施之一，包括降压达标、抗栓治疗

Treat every diabetic as if they have already had a heart attack!!! 全面干预，终点受益 “糖尿病是CHD的等危症” 将糖尿病列为冠心病的等危症，意指在冠心病一级、二级预防中对冠心病危险因素如高血压、高脂血症等的处理中，要求达标的目标值，糖尿病患者（尚无冠心病）和已有冠心病者相同。有流行病学资料证明这两种病理状态在7年随诊时死于心肌梗死者概率相近。 Treat every diabetic as if they have already had a heart attack!!! NCEP-ATPⅢ Haffner SM et al. N Engl J Med 1998;339:229–34

谢 谢