正确认识糖尿病患者的 强化治疗 北京大学人民医院 孙宁玲

强化降糖对于心血管疾病患者 利大于弊

已有临床研究得出心血管收益的重要启示 !

UKPDS：糖尿病领域里程碑式的研究 1977年启动，1998年发表主要结果，治疗的平均时间是11年，耗资3860万美元 来自英国的23个糖尿病中心5102例病人 观察强化血糖治疗（FBG6.0mmol/l,HbA1c7.0%）是否能减少患者病死率和改善生活质量

强化治疗与常规治疗间HbA1c相差0.9% (7.9% vs 7.0% ) 随访年 9 8.7 传统治疗 强化治疗 8.4 8.1 8 7.5 7.4 Median A1C (%) 7 6.6 1: Lancet. 1998 Sep 12;352(9131):837-53 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. [No authors listed] BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED 6 6.2% 正常值上限 3 6 9 12 18 随访年 Adapted with permission from UKPDS Group. Lancet. 1998;352:837

UKPDS流行病学分析:HbA1c降低1%的获益 全部并发症 糖尿病相关死亡 总死亡率 心肌梗死 卒中 微血管病变 –12% –14% –14% –21% –21% –37% UKPDS 35, BMJ 2000; 321: 405-12

1型糖尿病控制及并发症试验 Diabetes Control and Complication Trial (DCCT) 1441例1型糖尿病 为期10年 强化治疗组较常规诊疗组 严格控制血糖对预防糖尿病人的慢性并发症有重要意义

DCCT：常规组与强化组血糖 常规：8.9% 强化：7.1% 常规组与强化组血糖差异：1.8%

DCCT长期随访: 血糖控制达标显著降低心脑血管危险 非致死性心梗、 心血管事件 卒中和心血管死亡 10 42% 57% 相对危险降低（%）（95%CI） P=0.016 P=0.018 -10 -20 -30 -40 -50 -60 通过前面的内容我们了解到：高血糖，特别是餐后高血糖，伴随着极大的心脑血管危险。那么这里DCCT（Diabetes Control and Complications Trial ）研究的长期随访已经证实：糖尿病血糖控制达标对降低心血管事件和非致死性心梗、卒中和心血管死亡都具有显著的收益。由此可见，高血糖人群的血糖控制，尤其是糖尿病患者的血糖控制达标，是降低心脑血管事件危险的关键。 强化组血糖控制目标： 餐前血糖：3.9-6.7 mmol/L 餐后血糖峰值： 10.0 mmol/L 平均随访: 17年（获益60％） ADA 2005, 13 June, San Diego. 10

DCCT/EDIC 早期强化治疗对心血管事件发病危险的影响 非致死性心肌梗死、卒中和心血管死亡相对危险下降 57％，P＝0.02 全部事先定义的心血管终点相对危险下降 42％，P＝0.02 Nathan DM, et al. N Engl J Med. 2005 ,22;353(25):2643-53

阿卡波糖对IGT人群发生心血管事件 相对风险的影响：STOP-NIDDM 研究 研究人群 倾向 倾向 阿卡波糖 安慰剂 阿卡波糖 安慰剂 ( n = 682) ( n = 686) 危险比(95% CI) p- 值 冠心病 心肌梗死 1* 12 0.09 (0.01 - 0.72) 0.0226 心绞痛 5 12 0.45 (0.16 - 1.28) 0.1344 血管成形手术 11 20 0.61 (0.29 - 1.26) 0.1806 心血管死亡 1 2 0.55 (0.05 - 6.11) 0.6298 6.11 充血性心衰 2 --- --- 脑血管事件/中风 2 4 0.56 (0.10 - 3.07) 0.5061 3.07 外周血管病 1 1 1.14 (0.07 - 18.29) 0.9255 18.29 任何心血管事件 15** 32 0.51 (0.28 - 0.95) 0.0326 0.5 1.0 1.5 2.0 *发生一特别心血管事件受试者的数目 **发生任一心血管相关事件受试者的数目 Chiasson, J.-L. et al. JAMA 290: 486-494, 2003 12

阿卡波糖对心肌梗死发生率的影响 13 临床心肌梗死人数 1 12 0.0226* 无痛心肌梗死人数 1 7 0.0390** (n = 682) 安慰剂 (n = 686) P值 临床心肌梗死人数 1 12 0.0226* 无痛心肌梗死人数 1 7 0.0390** 总心肌梗死人数 2 19 0.0002** *根据Cox比例危险率模型 ** 根据2 检验 Adapted from: Chiasson, J.-L. et al. JAMA 290: 486-494, 2003 13

ACCORD研究: 非致死性心梗发生率降低

观点 强化降糖对心血管患者 的预后是有利的

流行病学证据显示: 血糖是心血管疾病的重要危险因素 !

高血糖增加心血管疾病危险因素发生风险 高血糖增加血脂异常发生风险 高血糖增加高血压发生风险 血脂异常患病率 高血压患病率 糖尿病 血脂异常在2型糖尿病患者中较常见。Botnia研究中，4483名35－70岁的男性和女性，其中1697为糖尿病患者、798 为空腹血糖受损。糖尿病患者其低HDL胆固醇（男性， 0.9 mmol/L (35 mg/dL) ,女性，1.0 mmol/L (39 mg/dL) 和/或 血浆高甘油三酯[1.7 mmol/L (151 mg/dL)]的发生率是糖耐量正常的患者的三倍，空腹血糖受损患者其发生率是糖耐量正常患者的两倍。 2型糖尿病患者其高血压发生率是非糖尿病患者的3倍 糖尿病 空腹血糖受损 糖耐量正常 糖尿病 非糖尿病 Ryden L, et al. Eur Heart J. 2007 Jan;28(1):88-136.

Relative Risk for CVD Events 血糖水平与心血管并发症呈线性相关 OBJECTIVE: To assess the relationship between nondiabetic glucose levels and cardio vascular risk. RESEARCH DESIGN AND METHODS: Three independent searches using MEDLINE (1966-1996), followed by a manual search of the references from each retrieved article, were conducted by two physicians and one medical librarian. Data had to be reported in at least three quantiles or intervals so that the nature of the relationship between glucose and cardiovascular events (i.e., linear or nonlinear) could be explored, and to ensure that any incremental cardiovascular risk was consistent across quantiles or intervals. RESULTS: Analyzed studies comprised 95,783 people (94% male) who had 3,707 cardiovascular events over 12.4 years (1,193,231 person-years). Studies reporting fasting glucose levels (n = 6), 2-h glucose levels (n = 7), 1-h glucose levels (n = 5), and casual glucose levels (n = 4) were included. The glucose load used varied from 50 to 100 g. The highest glucose interval for most studies included glucose values in the diabetic range. The relationship between glucose levels and the risk of a cardiovascular event was modeled for each study and the beta-coefficients were combined. Compared with a glucose level of 4.2 mmol/l (75 mg/dl), a fasting and 2-h glucose level of 6.1 mmol/dl (110 mg/dl) and 7.8 mmol/l (140 mg/dl) was associated with a relative cardiovascular event risk of 1.33 (95% CI 1.06-1.67) and 1.58 (95% CI 1.19-2.10), respectively. CONCLUSIONS: The progressive relationship between glucose levels and cardiovascular risk extends below the diabetic threshold. 95783名受试者随访12.4年，发生3707件心血管事件 Diabetes Care. 1999 Feb;22(2):233-40

East－West研究: 高血糖显著增加心血管事件发生风险 无心梗史人群 （n＝2194） 有心梗史人群 （n＝238） 非糖尿病 糖尿病 事件数/百人年 事件数/百人年 早在1998年发表的East－West研究中研究者就已经发现，在2194名没有心梗史的人群中，相对于非糖尿病者而言，糖尿病患者心脑血管事件的发生风险大大增加，约到5～6倍。而对于238名已有心梗史的患者，糖尿病也同样显著增加他们心梗的再发风险和脑卒中件的发生风险。 心肌梗死 卒 中 心肌梗死 卒 中 Haffner SM, et al. N Engl J Med. 1998 Jul 23;339(4):229-34.

EAST-WEST: 糖尿病是冠心病的等危症 非糖尿病患者 (n=1373) 45.0% 糖尿病患者 (n=1059) 7年心肌梗死发生率 (%) 20.2% 18.8% 3.5% No DM, No MI No DM, +MI +DM, No MI +DM, +MI DM=糖尿病 MI=心肌梗死 Haffner et al. N Engl J Med. 1998 20 20

血糖水平与心血管并发症呈线性相关 21 血糖 入院时血糖 即使不达糖尿病诊断标准，也是心血管疾病死亡率的持续危险因素 4 6 8 10 3 2.5 2 1.5 1 12 相对危险 2小时葡萄糖 (mmol/l) (Coutinho et al Diabetes Care 1999, 22: 659) (Norhammar et al Diabetes Care 1999, 22: 1827) 100 80 60 40 20 无事件存活率 (%) 2P = 0.0029 (对数秩检验) P-葡萄糖  中位数 P-葡萄糖 > 中位数 7.4 mmol/l 0 3 6 9 12 15 18 21 24 27 月 血糖 即使不达糖尿病诊断标准，也是心血管疾病死亡率的持续危险因素 入院时血糖 预测无糖尿病的心梗患者的发病率和死亡率 95783名受试者随访12.4年，发生3707件心血管事件 21

AMI患者1年死亡率的时间变化 30 20 糖尿病 10 来自瑞典国家登记处的MI患者 伴糖尿病 (n= 14 873) 和不伴糖尿病 (n=50 009) 30 20 10 糖尿病 伴 死亡率 (%) 不伴 RR 1995-1998 =1.42 RR 1999-2002 =1.31 1995 1996 1997 1998 1999 2000 2001 2002 年 (Norhammar et al Heart J 2007; 93:1577 )

糖尿病及其它心血管危险因素增加死亡率 十年冠心病死亡率（/1000人） 糖尿病 糖尿病 非糖尿病 非糖尿病 806040 30 10 5 十年冠心病死亡率（/1000人） 806040 30 10 5 糖尿病 非糖尿病 糖尿病 非糖尿病 这是一个纳入了347978名35－57岁的男性，平均随访时间12年的队列研究，观测了心血管疾病的死亡率，结果发现糖尿病和高血压、血脂异常等心血管危险因素使死亡率增加，由图中我们可以看出，糖尿病在收缩压和血脂的基础上进一步增加患者的死亡率。 110 120 130 140 150 160 4 5 6 7 收缩压（mmHg） 血脂（mmol/L） n＝347978 随访12年 Stamler J. Diabetes Care,1993,16:434-444.

观点: 血糖是心血管疾病的重要危险因素 是应当有效干预的

——ACCORD/ADVANCE研究 又使强化降糖是否获益 面临巨大的挑战

ACCORD 研究 强化组与常规组 一级终点无显著性差异 强化组任意原因死亡高于常规组 一级终点：心血管死亡，非致死性心梗和非致死性卒中 N Engl J Med 2008;358:2630-33.

糖尿病患者 强化治疗还有没有希望？ 影响到强化降糖获益的因素是什么？ 心血管高危人群（老年、冠心病） HBA1c降的过快、过低出现的低血糖

两组在4个月内HbA1c迅速下降 ACCORD 研究 强化组： 8.1%降至6.7% 常规组： 8.1降至7.5% N Engl J Med 2008;358:2630-33.

强化组 vs 常规组 ACCORD 研究 强化 常规 Alc水平（中位数） 6.4% vs 7.5% 强化 常规 Alc水平（中位数） 6.4% vs 7.5% 药物联合情况（联合服用3-5种降糖药物） 70% vs 45% 使用胰岛素情况 77% vs 55% 口服药与胰岛素联合情况 62% vs 18% 严重低血糖(需要药物治疗的低血糖事件) 10.5% vs 3.5% 体重增加(10公斤以上) 28% vs 14%

ACCORD 研究 总体 从未发生低血糖事件 发生低血糖事件 强化 血糖治疗 1.4％/年 （257例死亡） 1.3％/年 （223例死亡） 2.8％/年 （24例死亡） 标准 1.1 ％/年 （203例死亡） 1.1％/年 （186例死亡） 4.9％/年 （17例死亡） 风险 （95％CI） 1.22 （1.01～1.46） 1.24 （1.02～1.50） 0.54 （0.3～0.96） 发生过严重低血糖事件的受试者死亡的可能性更大

低血糖患者冠心病死亡率显著升高 以色列14670例冠心病患者的8年死亡率随访研究 * 死亡率（％） 低血糖 N=131 血糖正常N=9368 *P<0.0001 死亡率（％） 这是一项以色列对14670例冠心病患者的8年死亡率随访研究，结果显示 血糖正常的患者死亡率为7.9％，低血糖患者的死亡率为9.2％，较 血糖正常者显著升高。 低血糖 n＝131 低血糖 N=131 血糖正常N=9368 Fisman EZ, et al. Eur J Cardiovasc Prev Rehabil. 2004 ;11(2):135-43.

低血糖患者各种死亡率均偏高 以色列14670例冠心病患者的8年死亡率随访研究 * **P<0.02 *P<0.0001 * ** Methods The study included 14 670 CAD patients aged 45–74, divided into six groups: (1) hypoglycaemic (up to 69 mg/dl); (2) low normal (70–79 mg/dl); (3) euglycaemic (80–109 mg/dl); (4) impaired fasting glucose (IFG) (110–125 mg/dl); (5) borderline diabetics (126–139 mg/dl); (6) diabetics (Z140 mg/dl). After adjustment for variables, a significantly higher mortality rate was seen in hypoglycaemics when compared with euglycaemics (P < 0.0001). ** * Fisman EZ, et al. European Journal of Cardiovascular Prevention and Rehabilitation 2004, 11:135–143.

HbAc1标准： 6%、6.5、7%？ 中国糖尿病防治指南: HbA1c 6.5% IDF (国际糖尿病联盟指南):HbA1c 6.5% ADA(美国糖尿病学会指南): HbA1c 7.0% UKPDS ACCORD ADVANCE A1c目标 7% 6% 6.5%

HbA1c是否能够全面反映血糖异常所有损害？ 4 6 8 10 12 14 16 0:05 6:00 7:15 8:00 12:00 13:30 14:00 18:00 19:30 20:00 22:00 23:55 时间 CGMS血糖值（mmol/L） NGT IGT T2DM

HbA1c 对血糖粗线条的评价 HbA1c 6.0 % HbA1c 6.0 % 时间

启示1 应该重视血糖波动监测 不仅要注重HbA1c数字，更应该注重实现目标的治疗策略，减少血糖波动

启示2 治疗个体化，寻求降糖受益与安全性的最佳平衡 病程长的患者 年龄大的患者 并发症及合并症 体重指数（BMI）增加 血糖和糖化水平

强化治疗策略 1、早期 2、综合性强化 3、不发生低血糖 4、个体化治疗

早期干预

糖尿病前期危害巨大 IGT 2型糖尿病 年转化率5%-10% 大血管病变的独立高危因素 心血管死亡率 升高34％ 全因死亡率 升高40％ 如上所述，IGT绝对不是一个健康状态，它可以视为糖尿病的先兆和导致心血管并发症的重要阶段。就像前面提到的，IGT每年有5－10％的比例发展成糖尿病，其转化为糖尿病的危险性是正常人的100倍。 DECODE研究表明，IGT可使心血管疾病的死亡率升高34％，使总死亡率升高40％。其他临床研究也表明，４０％的ＩＧＴ者已经有了大血管的病变，ＩＧＴ人群发生非致死性心肌梗死、心衰、脑血管事件、心血管死亡等的危险显著增加，提示IGT是心血管疾病发生和死亡的独立危险因素，是仅次于心肌梗死的心血管事件预测因素。一旦诊断为IGT，大血管病变的警钟随之响起，心血管危险亦将来临。 在中国，IGT是成人糖调节受损最常见的表现类型。流行病学调查资料显示，在IGR人群中，表现为单纯IGT的高达75％。预计2025年世界IGT人群也将达到3.24亿。如此大量的IGT人群如同随时可能引爆的定时炸弹，严重威胁着广大人民的身体健康。 DECODE Study Group, Lancet. 1999 Aug 21;354 (9179):617-21.

糖尿病发病或诊断之前大血管病变已经存在 胰岛素敏感性 胰岛素分泌 血糖水平 糖尿病 IGT 微血管并发症 大血管合并症 Janka HU. Fortschr Med 1992;110:637–41.

综合的强化治疗

Steno-2研究： 探讨综合因素强化治疗糖尿病 160名2型糖尿病患者 N=80 平均随访7.8年 常规治疗 综合因素强化治疗 N Engl J Med. 2003 Jan 30;348(5):383-93.Related Articles Comment in: ACP J Club. 2003 Sep-Oct;139(2):29. Evid Based Nurs. 2003 Oct;6(4):110. N Engl J Med. 2003 Jan 30;348(5):457-9. N Engl J Med. 2003 May 8;348(19):1925-7; author reply 1925-7. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Steno Diabetes Center, Copenhagen, Denmark. BACKGROUND: Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria. METHODS: The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin. RESULTS: The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79). CONCLUSIONS: A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent. Copyright 2003 Massachusetts Medical Society 主要复合终点事件：心血管死亡、非致死性心梗、非致死性卒中、血管再通术、截肢术 综合因素强化治疗:改善生活方式和药物治疗 （控制高血压、高血糖、高血脂、微蛋白尿及阿司匹林二级预防心血管事件） N Engl J Med. 2003 Jan 30;348(5):383-93.

强化综合治疗组更多患者达到危险因素控制目标值 10 20 30 40 50 60 70 80 强化治疗组 常规治疗组 P<0.001 P=0.21 P=0.19 P=0.001 患者人数（％） P=0.06 糖化血红蛋白 <6.5% 胆固醇 <175mg/dl 甘油三脂 <150mg/dl 收缩压 <130mmhg 舒张压 <80mmhg N Engl J Med. 2003 Jan 30;348(5):383-93

综合因素强化治疗降低复合终点事件发生 常规治疗组：35例患者发生85次事件 强化治疗组：19例患者发生33次事件 随访期内首次事件-时间曲线 44% 24% 复合终点事件发生率（%） 随访期内首次事件-时间曲线 综合因素 强化治疗 常规治疗 N Engl J Med. 2003 Jan 30;348(5):383-93.

糖尿病诊断之前,心血管疾病风险就已经增加 IDF 2006 Meet the Expert 2002年的一项研究证实在糖尿病诊断之前心血管疾病发生风险就已经明显增加，也进一步证实在糖尿病前期大血管病变就已经存在 OBJECTIVE—To examine whether the risk of cardiovascular disease (CVD) is elevated before clinical diagnosis of type 2 diabetes in women. RESEARCH DESIGN AND METHODS—A total of 117,629 female nurses aged 30–55 years who were free of diagnosed CVD at baseline were recruited in 1976 and followed for 20 years. RESULTS—A total of 1,508 women had diagnosed type 2 diabetes at baseline in 1976. During 20 years of follow-up, 110,227 women remained free of diabetes diagnosis and 5,894 women developed type 2 diabetes. During 2.2 million person-years of follow-up, we documented 1,556 new cases of myocardial infarction (MI), 1,405 strokes, 815 fatal coronary heart disease (CHD), and 300 fatal strokes. Among women who developed type 2 diabetes during follow-up, the age-adjusted RRs of MI were 3.75 (95% CI 3.10–4.53) for the period before the diagnosis and 4.57 (3.87–5.39) for the period after the diagnosis, compared with women who remained free of diabetes diagnosis. The multivariate RRs further adjusting for BMI, smoking, and other cardiovascular risk factors were 3.17 (2.61–3.85) and 3.97 (3.35–4.71). The risk of stroke was also significantly elevated before diagnosis of diabetes (multivariate RR = 2.30 [1.76–2.99]). Further adjustment for history of hypertension or hypercholesterolemia did not appreciably alter the results. CONCLUSIONS—Our data indicate a substantially elevated risk of CVD before clinical diagnosis of type 2 diabetes in women. These findings suggest that aggressive management of cardiovascular risk factors is warranted in individuals at increased risk for diabetes. Hu FB, et al. Diabetes Care 2002;25:1129–34.

不仅仅是降糖，危险因素的全方位 糖尿病强化性治疗 控制是糖尿病患者获益的根本 低血糖是导致心血管事件最重要的原因 过快、过低的降低HBA1c抵消了降糖的获益

最后陈述 1、 心血管疾病需要进行血糖评估 2、对有血糖异常者要长期控制血糖 3、应早期干预平稳降低血糖

中国心脏调查： 77% 54% 中国心血管疾病患者高发高血糖 约80%冠心病1患者合并高血糖 超过50%高血压2患者合并高血糖 已知的糖尿病 新诊断的糖尿病 (空腹血糖) 正常血糖 糖尿病前期 (OGTT) 77% 54% 中国心脏调查的结果：这项研究共选取北京、上海等7个城市52家三级甲等医院作为合作研究中心，对3513名入选的冠心病患者进行调查，其中1234例为急诊住院患者，2279例为择期住院患者，结果发现合并糖尿病的患者数占总数的53%，糖尿病前期占24％，共约有77%的冠心病患者合并高血糖。 1、Da-Yi Hu. European Heart Journal (2006) 27, 2573–2579. 2、孙宁玲. 待发.

血糖影响在更长的时间中显现 ADVANCE研究中，治疗5年，已经出现分离的趋势.微血管事件的减少(尤其是肾脏事件的显著降低)可以被转化为后期心血管的保护 在Steno-2研究中，强化治疗和标准治疗在第10年出现差异在第13年，相比于标准治疗组，强化治疗组的心血管死亡显著减少57%，心血管事件显著降低59% ACCORD研究一级终点事件

血糖治疗早期治疗有记忆效应 同时恰当的血糖控制是获益的关键 UKPDS 30年随访 （EASD2008）

Glucose Interventional Trial Intensive Conventional 2,729 Intensive with sulfonylurea/insulin 1,138 (411 overweight) Conventional with diet 342 (all overweight) Intensive with metformin P Trial end 1997 5,102 Newly-diagnosed type 2 diabetes 744 Diet failure FPG >15 mmol/l 149 Diet satisfactory FPG <6 mmol/l Dietary Run-in 4209 Randomisation 1977-1991 Mean age 54 years (IQR 48–60)

Post-Trial Monitoring: Patients 880 Conventional 2,118 Sulfonylurea/Insulin 279 Metformin 1997 # in survivor cohort 2002 Clinic Questionnaire 2007 # with final year data 379 Conventional 1,010 Sulfonylurea/Insulin 136 Metformin P Mortality 44% (1,852) Lost-to-follow-up 3.5% (146) Mean age 62±8 years

Any Diabetes-related Endpoint Intervention Trial Median follow-up 10.0 years Intervention Trial + Post-trial monitoring Median follow-up 16.8 years RR=0.88 (0.79-0.99) P=0.029 Conventional Sulfonylurea/ Insulin 1997-2007 1997-2007 1997-2007

Myocardial Infarction Hazard Ratio (fatal or non-fatal myocardial infarction or sudden death) Intensive (metformin) vs. Conventional glucose control HR (95%CI)

All-cause Mortality Hazard Ratio Intensive (metformin) vs. Conventional glucose control HR (95%CI)

All-cause Mortality Hazard Ratio Intensive (metformin) vs. Conventional glucose control HR (95%CI)

Legacy Effect of Earlier Glucose Control After median 8.5 years post-trial follow-up Aggregate Endpoint 1997 2007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P: 0.0099 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% P: 0.44 0.007 RRR = Relative Risk Reduction, P = Log Rank

Steno-2:主要临床结果 干预4年后微血管病变相对危险下降50%，而且在以后的随访中保持。 干预8年后主要心血管事件相对危险下降50%，而且在以后的随访中保持。 随访13年后死亡的相对危险下降50%。

寻求效益与安全性的最佳平衡点 患者得益 寻求 最佳降糖点 7.0 安全性成为最大的制约因素 6.5 最佳 降糖水平 6.0

糖尿病多重心血管危险因素干预 是预防大血管并发症的主要策略 危险因素 控制目标 HbA1c < 6.5% Bp <130/80mmHg LDL-C <2.5 mmol/l (<95 mg/dl) TG <2.3 mmol/l(<200 mg/dl) HDL-C >1.0 mmol/l (>39 mg/dl) 2005 IDF Guideline

结 论 适当的强化降糖仍然是主流治疗 1、糖尿病患者是需要早期强化治疗（包括IGT) 2、糖尿病患者需要综合性治疗（减重、降压、调 脂） 3、高危糖尿病患者降糖药缓慢，避免发生低血糖 适当的强化降糖仍然是主流治疗

谢 谢