强化降糖与心血管受益之追本溯源 ——UKPDS/DCCT之遗憾

目 录 UKPDS/DCCT，糖尿病领域研究的里程碑 血糖与心血管疾病相关性研究

糖尿病并发症是否可以预防 ——始于60年代的辩论 1966年和1974年出版的《内科学争端》中对“糖尿病并发症是否可以预防”进行辩论。 可以! 不可以! 1923年以前，糖尿病患者高死亡率，饮食控制可以延缓部分患者的生命 胰岛素发明后，是否还需进行饮食治疗成为早期争论焦点 Tolstoi医生在纪念胰岛素发现25周年的专刊上高呼糖尿病只需“单纯的症状治疗” 争论无果，需要进行前瞻性研究 于是开始了“宽松”还是“严格”控制血糖的半个世纪的争论 哈佛Joslin糖尿病中心 耶鲁大学 争论的结果：需要前瞻、干预性临床试验 Ingelfinger FJ etal. Controversies in internal medicine ⅡPhiladelphia: WB Saunders,1966:489

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 严格控制血压（150/85）可否能减少并发症的危险性 比较不同降糖、降压治疗的特殊优缺点

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:强化治疗降低微血管并发症发生率 累积发生率: 346 of 3867 Patients (9%) 25% 常规治疗(n=1138) 强化治疗 (n=2729) 20% P=0.0099 15% Patients with events 10% 5% Risk reduction 25% (95% CI: 7% - 40%) 0% 3 6 9 12 15 随访年 UKPDS Group. Lancet. 1998;352:837-853.

UKPDS:心血管事件收益在显著性边缘(P=0.052） 心梗患者 (%) 随访（年） 30 20 10 0 3 6 9 12 15 风险降低 16% (95% CI: 0%-29%) P=0.052 传统治疗 强化治疗 Intensive glucose control significantly reduced any diabetes-related end point, but had no effect on mortality. The predominant effect of tighter control was a reduction of microvascular disease by a quarter, largely due to a reduction in laser photocoagulation. There was also a trend, just short of statistical significance, towards a reduction in macrovascular disease. No threshold was seen, i.e. any improvement in glycaemic control is beneficial. These findings are similar to those of the DCCT and a more recent study in Japanese patients with type 2 diabetes, in whom 6 years’ intensive therapy with insulin reduced the incidence of microvascular complications [15]. That the reduced occurrence of myocardial infarction was not significant may be due to type 2 statistical error. The study was set up to detect a 15% difference in events over the 10 years’ study period, and a larger number of macrovascular than microvascular events occurred, but the separation of HbA1c between intensive and conventionally treated groups was disappointingly low: 0.9% (half that in the DCCT). Had the separation of HbA1c between groups been greater, a significant effect of intensive control on macrovascular disease might have been demonstrated. UKPDS=UK Prospective Diabetes Study. UKPDS Group. Lancet. 1998;352:837-853.

Adjusted incidence per 1000 person-years UKPDS：并发症与HbA1c线性相关 80% 70% Myocardial infarction 60% Microvascular endpoints 50% Adjusted incidence per 1000 person-years 40% 30% 20% 10% 0% 5 6 7 8 9 10 11 Updated mean A1c (%) Stratton IM et al. BMJ 2000; 321:405–412.

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

UKPDS：流行病学分析与临床试验的差异

UKPDS结果提示 HbA1C 水平与并发症危险之间存在连续性关系 强化降糖并不存在阈值，在患者能够耐受的前提下，HbA1C 水平越低越好 Relation to trial data This observational analysis provides an estimate of the reduction in risk that might be achieved by the therapeutic lowering of haemoglobin A1c by 1.0%, but it is important to realise that epidemiological associations cannot necessarily be transferred to clinical practice. Tissue damage from previous hyperglycaemia may not promptly be overcome, but the results are not inconsistent with those achieved by the policy of intensive glucose control in the clinical trial.1 This suggests that the reduction in glycaemia obtained over a median 10 years of follow up of the trial, comparing median haemoglobin A1c 7.0% with 7.9%, provided much of the benefit that could be expected from that degree of improved glycaemic control. Our results suggest that intensive treatment with sulphonylurea or insulin does not have an effect beyond that of lowering blood glucose concentration with respect to altering risk. The 16% risk reduction (P=0.052) in myocardial infarction in the clinical trial in the group allocated to a policy of intensive blood glucose control (associated with a 0.9% difference in haemoglobin A1c) was similar to the 14% risk reduction seen in the epidemiological analysis, which was associated with a 1% reduction in concentration of updated mean haemoglobin A1c. The UKPDS clinical trial evaluated a policy of intensive glucose control based primarily on single pharmacological treatments to enable evaluation of the individual treatments. Now that the UKPDS has shown that improved glucose control reduces the risk of complications and that the treaments used are safe in clinical practice, a larger reduction in haemoglobin A1c might be achieved by the earlier use of combination treatments or by the use of newer treatments, which could further reduce the risk of myocardial infarction. What is already known on this topicThe risk of developing complications of diabetes increases with increasing concentrations of hyperglycaemiaReduction of hyperglycaemia in these individuals reduces the risk of complicationsWhat this study addsThere is a direct relation between the risk of complications of diabetes and glycaemia over timeNo threshold of glycaemia was observed for a substantive change in risk for any of the clinical outcomes examinedThe lower the glycaemia the lower the risk of complicationsThe rate of increase of risk for microvascular disease with hyperglycaemia is greater than that for macrovascular disease

强化降糖的美好愿景 至接近正常水平 更多 ？ 强化降糖 心血管收益 趋于正常水平

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，1993年发表结果 强化治疗组较常规诊疗组 视网膜、肾脏、神经病变的发生率减少了39％～76％ 严格控制血糖对预防糖尿病人的慢性并发症有重要意义

主要终点事件: 非致死性心梗, 中风, 心血管死亡, 确诊的心绞痛, 血管重建 研究设计 DCCT 1型糖尿病, 年龄 13 to 40 岁 N = 1441 强化治疗组* 传统治疗组† 平均随访: 6.5年 (1983–1993) EDIC n = 1394 (97%) 所有患者接受强化治疗 随访: 11 年 (1994–2005) 主要终点事件: 非致死性心梗, 中风, 心血管死亡, 确诊的心绞痛, 血管重建 *≥3 胰岛素注射 or 胰岛素泵治疗/日 †1–2 注射/日 DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-53.

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%

强化治疗组较常规诊疗组视网膜、肾脏、神经病变的发生率减少了39％～76％ DCCT：糖化血红蛋白与并发症线性相关 强化治疗组较常规诊疗组视网膜、肾脏、神经病变的发生率减少了39％～76％ Relative Risk 视网膜病变 肾脏病变 神经病变 微量白蛋白尿 HbA1c (%) 15 13 11 9 7 5 3 1 6 8 10 12 Adapted with permission from Skyler J. Endocrinol Metab Clin North Am. 1996;25:243 DCCT Research Group. N Engl J Med. 1993;329:977

Epidemiology of Diabetes Interventions and Complications EDIC-DCCT后续研究 1993年公布的DCCT研究发现，积极的降糖治疗能够降低糖尿病肾病、视网膜病变和神经病变的发生。但是，由于DCCT研究随访期相对较短，未对血糖控制与心血管风险的关系做出判断 1441名在DCCT研究开始就接受观察的患者中，有1422名完成DCCT观察。其中1394（97%）同意接受长期的DCCT/EDIC随访研究，在这其中，有1340名完成了最终的EDIC研究。DCCT/EDIC研究的结果于2005年2月公布

DCCT/EDIC 早期强化治疗对心血管事件 发病危险的影响 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

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 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 Nathan DM, et al. N Engl J Med. 2005 ,22;353(25):2643-53

DCCT和UKPDS 使争论谢幕 英国UKPDS研究：平均随访10年，发现糖化血红蛋白每降低1％，微血管并发症的风险降低35％ 20世纪末完成的这两项研究得出一个明确的结论：严格控制血糖可改善预后，结束了有关治疗的这个核心问题长达50年的争论

UKPDS/DCCT采用的血糖评价指标： 糖化血红蛋白 糖化血红蛋白（GHb）是葡萄糖与成熟细胞中的血红蛋白（HbA）的结合物，其结合比例与血中葡萄糖平均浓度有直接关联。正常人约3—6%的血红蛋白被糖基化；糖尿病患者被糖化的血红蛋白可高达正常人的两倍甚至三倍 ； 能评价总体血糖控制情况，不受短期血糖波动影响； HbA1c最初被看作自我血糖监测（SMBG）十分有用的补充。在今天HbA1c被看作血糖控制的“金标准”，在评价临床血糖控制总体情况及临床研究中均广泛采用 1968年偶然发现葡萄糖可以与血红蛋白结合，而电泳分析发现在糖尿病患者血红蛋白中只占少量的部分却显著异常。在70年代晚期，糖化血红蛋白检测获得了快速推广。目前最常检测的是HbAlc，它提供了一个实用而客观的手段以评价约2个月前的平均血糖 水平，并已证明是SMBG十分有用的补充 Rajbar S Clin Chim Acta. 1968 Oct;22(2):296-8

PUBMED上最早的糖化血红蛋白文章 —1977年 糖尿病病人糖化血红蛋白与长期血糖控制 长期 血糖控制 HbA1c Standardisation: History, Science and Politics W Garry John,1* Andrea Mosca,2 Cas Weykamp,3 and Ian Goodall4 It is fascinating to consider the analytical improvements that have occurred since glycated haemoglobin (GHb), measured as total HbA1, was first introduced into clinical laboratories for diabetes monitoring around 1977; at that time methods displayed poor precision, there were no calibrators or material with assayed values for quality control purposes. Many methods for the measurement of GHb have been developed; these mainly make use of charge or structural differences between the glycated and non-glycated species of haemoglobin.

DCCT对HbA1c标准化的贡献 DCCT的结果确立了糖化血红蛋白值可以作为反映平均血糖值的一个指标 根据DCCT的数据，以下的直线回归方程式可以将糖化血红蛋白值用来估计平均血糖值： MBG估计值＝30.9×（糖化血红蛋白值）－60.6 美国临床化学协会（AACC）在1993年成立了一个标准化委员会来致力于糖化血红蛋白的标准化。这个努力的结果导致了全国糖化血红蛋白标准化项目（NGSP）的建立 当实验室采用了NGSP认可的检测方法之后，它所提供的是一个经过标准化的糖化血红蛋白值，与DCCT的结果互相吻合。

HbA1c能代表血糖控制水平，能代表血糖控制质量吗？ 6.0 % HbA1c 6.0 % 时间 HbA1c能代表血糖控制水平，能代表血糖控制质量吗？ 生理性HbA1c6.0%是否等于病理性6.0％？

目 录 UKPDS/DCCT，糖尿病领域研究的里程碑 血糖与心血管疾病相关性研究

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

Diabetes and cardiovascular disease. The Framingham study 通过对以前患有糖尿病的研究对象随访20年发现，动脉粥样硬化性疾病发生风险增加2到3倍 通过对以前患有糖尿病的研究对象随访20年发现，动脉粥样硬化性疾病发生风险增加2到3倍。

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 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。 事件数/百人年 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.

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.

糖尿病患者心血管死亡危险显著增加 C D C D C D C D 总死亡率 心血管死亡率 男性 P<0.001 % % 男性 P<0.001 女性P<0.001 男性 P<0.001 女性P<0.001 50 50 40 40 D－糖尿病组 C－对照组 30 30 20 20 同时糖尿病患者的总死亡率和心血管死亡率也大大增加。这是一项对277名受试者的长达15年的前瞻性研究，在基线和5年后及10年后评估两组患者的心血管危险因素发现，2型糖尿病患者与对照组相比总死亡率和心血管死亡率不分男女性别均显著升高。 10 10 5年 10年 15年 C D C D C D C D n＝277 15年前瞻性研究 Niskanen et al Diabetes Care 1998;21:1861-1869

DECODA研究 心血管死亡风险增加主要是由于餐后高血糖 (n=6,817) 空腹血糖 (mmol/L) 经2小时血糖校正 0.5 1.0 1.5 2.0 2.5 3.0 3.5 全因死亡 心血管死亡 <6.1 6.1–6.9 ≥7.0 <7.8 7.8–11.0 ≥11.1 p=0.81 p=0.83 p<0.001 多变量风险率 DECODA研究是一项在亚洲13家医学中心进行，旨在评估空腹和餐后血糖对糖尿病诊断和心血管危险影响的大型研究。这是DECODA研究的数据经过校正之后的结果，除外空腹血糖的影响，餐后高血糖是全因死亡率、心血管死亡率上的独立危险因素。而当对2小时血糖进行校正后，空腹血糖水平与全因死亡率、心血管死亡率无关。 Nakagami T, et al. Diabetologia 2004;47:385–94.

以已知糖尿病为参照，FPG和2hPG不同浓度区间心血管疾病死亡率危险比 DECODE研究 真正预测心血管死亡风险的是餐后血糖 2hPG FPG 风 险 比 DECODE研究比较了空腹血糖与负荷后血糖对死亡率的预测价值。图中是以已诊断糖尿病为参照，不同FPG和2hPG区间心血管死亡率的风险比。根据2hPG≥11.1mmol/L诊断的新发糖尿病，与已知糖尿病的心血管死亡风险无差别, 而根据FPG≥7.0mmol/L诊断的新发糖尿病，其心血管死亡风险低于已知糖尿病患者。因此2hPG较之FPG是心血管死亡率更好的预测指标。 以已知糖尿病为参照，FPG和2hPG不同浓度区间心血管疾病死亡率危险比 (The DECODE Study Group. Diabetes Care. 2003;26:688-696.

餐后高血糖和心血管疾病危险密切相关 相关研究 主要发现 DECODE 研究2001 餐后2小时血糖是死亡和CVD更好的预测因素 RIAD研究2000 餐后血糖与颈动脉内膜增厚的关系强于空腹血糖 DECODE研究1999 CVD死亡率与餐后2h血糖的相关性优于FPG且FPG不能判定CVD的危险人群 Honolulu心脏规划1999 CHD的发病率和死亡率随着糖耐量减少而逐步增加 Funagata糖尿病研究1999 糖耐量降低是CVD的危险因素 Paris前瞻性研究1999 CHD死亡率随着餐后血糖水平的升高而增加 Whitehall研究1999 无糖尿病的餐后2h血糖异常升高大于10%者CHD死亡率增高 HOORN研究1999 餐后急性高血糖是所有原因和心血管事件和CVD死亡率的危险因素 Rancho Bernardo研究1999 单独餐后高血糖使老年妇女的致死性CVD风险增加2倍以上，仅用空腹血糖筛查可遗漏很多CVD高危人群 糖尿病干预研究1996 餐后急性高血糖与 CVD死亡率有关 除以上两个研究外，已经有多个研究从不同角度证实餐后高血糖与心血管疾病危险密切相关！

Thinking…… 血糖水平与心血管事件呈线性相关，为什么降低血糖不能使心血管事件发生降低达统计学差异？ “The most appropriate targets for future interventional trials that deal with the effect of hyperglycemia on CV risk are postprandial hyperglycemia or A1C.”