高TG与大微血管风险

1、2型糖尿病患者不容忽视的大微血管风险提纲2型糖尿病患者的微血管风险管理12型糖尿病患者的剩留心血管风险管理2总结3微血管风险？为什么要关注微血管病变是糖尿病血管病变的重要组分NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2006.脑血管疾病和中风增加24倍中风4/5糖尿病患者死于心血管事件预期寿命减少35年心血管疾病美国每年24,000例成人新发失明病例的主要原因糖尿病视网膜病变每年44%成人终末期肾病新发病例中的主要原因糖尿病肾病每年60%非创伤性截肢术新发病例的主要原因 糖尿病神经病变中国糖尿病视网膜病变流行现状严峻中华

2、医学会糖尿病学分会. 中国2型塘尿病防治指南(2010年版).中国医学前沿杂志(电子版), 2011, (06):54-109.20-40%糖尿病患者视网膜病变视力丧失8%（人数约930万）2010中国2型糖尿病治疗指南中国糖尿病肾病发病率非常高2010中国2型糖尿病治疗指南中华医学会糖尿病学分会. 中国2型塘尿病防治指南(2010年版).中国医学前沿杂志(电子版), 2011, (06):54-109.34.7%糖尿病肾病微血管风险？能否仅靠强化降糖、降压控制nUKPDS:降低血压（150/85mmHg）可使视敏度缺失的发生减少47%（p=0.0004），但在神经病变或肾脏疾病的风险上无明显

3、改变。1nADVANCE强化降低血压（收缩压:5.60.2mmHg,舒张压:2.20.1mmHg ）在微血管事件风险上无明显作用。2nDIRECT-Protect 2坎地沙坦阻断肾素-血管紧张素系统（RAS），并不明显延缓2型糖尿病患者的糖尿病视网膜病变的进展。3积极血压控制并不能完全减少微血管并发症风险1.UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type

4、 2 diabetes: UKPDS 39. BMJ, 1998, 12;317(7160):713-20.2.Patel A, ADVANCE Collaborative Group, MacMahon S, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised contro

5、lled trial. Lancet, 2007, 370(9590):829-40.3.Sjlie AK, Klein R, Porta M, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet, 2008, 372(9647):1385-93.nUKPDS1:糖化血红蛋白（HbA1c）每降低1%，微血管的联合终点降低37%。n需

6、要激光治疗的视网膜病变n玻璃体出血n致死性或非致死性肾衰n ADVANCE:强化血糖控制（HbA1c6.5%）组中，肾脏病变降低了21%，但对视网膜病变无明显作用。2强化血糖控制并不能完全防治微血管并发症1.Stratton IM1, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ, 2000, 321(7

7、258):405-12.2.ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med, 2008, 358(24):2560-72.2型糖尿病患者的微血管剩留风险不容忽视Gaede P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial intervention o

8、n mortality in type 2 diabetes. N Engl J Med, 2008, 358(6):580-91.58684655512501020304050607080周围神经病变视网膜病变肾病普通干预强化干预患者比例*强化干预：口服降糖药物、抗高血压药物、降脂药物+饮食和生活方式改变，平均随访13.3年p=0.89p=0.01p=0.004剩留风险剩留风险剩留风险STENO-2研究: 强化干预*疗效微血管风险？他汀是否能很好地控制糖尿病肾病视网膜病变他汀对微血管事件的疗效非常有限1. Colhoun HM, Betteridge DJ, Durrington PN, e

9、t al. Lancet 2004;364:685-96.2. Baigent C, Keech A, Kearney PM, et al. Lancet 2005;366:1267-78.3. Athyros VG, Papageorgiou AA, Mercouris BR, et al. Curr Med Res Opin 2002;18:220-8.4. Colhoun HM, Betteridge DJ, Durrington PN, et al. Am J Kidney Dis 2009;54:810-9.5. Collins R, Armitage J, Parish S, Sl

10、eigh P, Peto R. Lancet 2003;361:2005-16.截肢CARDS1 (n=2,838) p=ns蛋白尿CTTC*2 (n= 90,056) 不确定肌酐CTTC*2 (n=90,056) p=nsCARDS4 (只在亚组获益)HPS5 (n= 20,536) p=ns甘油三酯与微血管风险TG水平升高增加2型糖尿病患者微血管病变风险Circulation, 2014, 129:999-1008Sacks FM, Hermans MP, Fioretto P, et al. Association between plasma triglycerides and hig

11、h-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries. Circulation,2014,129:999-1008.l一项在13个国家完成的病例、对照研究，纳入2535例糖尿病患者，其中1891例伴肾脏疾病，1218例伴视网膜病变。旨在观察甘油三酯和高密度脂蛋白对患者肾脏微血管病变和视网膜的影响。结果显示，甘油三酯水平升高增加2型糖尿病患者

12、微血管病变风险。 TG每升高0.5mmol/L,微血管病变风险16%2型糖尿病患者肾病风险随TG水平的升高而增加Circulation, 2014, 129:999-1008Sacks FM, Hermans MP, Fioretto P, et al. Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global cas

13、e-control study in 13 countries. Circulation,2014,129:999-1008.TG水平增加T2DM糖尿病肾病风险 TG每升高0.5mmol/L,糖尿病肾病风险20%非诺贝特循证支持，微血管获益非诺贝特有显著的微血管获益Lancet. 2005;366:18491861 FIELD研究-31%-14%-36%-40%-35%-30%-25%-20%-15%-10%-5%0%需激光治疗的视网膜病变白蛋白排泄率非创伤性截肢相对风险降低l 获益独立于血糖 (HbA1c) 和血压控制或合并症Keech A, Simes RJ, Barter P, et a

14、l. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005 Nov 26;366(9500):1849-61.p0.001p=0.002p=0.02糖尿病肾病糖尿病视网膜病变糖尿病截肢糖尿病视网膜病变发病机制Dodson PM. Diabetic retinopathy: treatment and prev

15、ention. Diab Vasc Dis Res, 2007, 4 Suppl 3:S9-S11.微血管阻塞微血管渗漏视网膜缺血血眼屏障破坏棉絮状渗出点毛细血管闭塞新血管形成视网膜出血、渗出/水肿VEGFVEGF，血管紧张肽IGF-1，GH，FGFIGF-1 = 胰岛素样生长因子-1；GH = 生长激素FGF = 纤维母细胞生长因子；VEGF = 血管内皮生长因子微血管病变毛细血管阻塞非诺贝特阻断VEGF介导的血管异常增生Panigrahy D, Kaipainen A, Huang S, et al. PPARalpha agonist fenofibrate suppresses tum

16、or growth through direct and indirect angiogenesis inhibition. Proc Natl Acad Sci U S A, 2008, 105(3):985-90.非诺贝特非诺贝特能够显著减少DR激光治疗的需求FIELD 研究4.9%3.4%0.0%0.5%1.0%1.5%2.0%2.5%3.0%3.5%4.0%4.5%5.0%安慰剂非诺贝特31%患者比例1. Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treat

17、ment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet, 2007, 370(9600):1687-97.2. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled t

18、rial. Lancet, 2005, 366(9500):1849-61.10.9%6.9%0.0%2.0%4.0%6.0%8.0%10.0%12.0%安慰剂非诺贝特37%患者比例糖尿病视网膜病变激光治疗的需求1糖尿病视网膜病变的累积激光治疗2非诺贝特联合他汀显著降低糖尿病视网膜发生和进展风险ACCORD-EYE分支研究ARR = 3.7%NNT = 2710.26.50.05.010.0辛伐他汀+安慰剂辛伐他汀+非诺贝特40%p=0.006OR 0.60 95% CI 0.42-0.87主要终点发生率 (%)ACCORD Study Group; ACCORD Eye Study Grou

19、p, Chew EY, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010 Jul 15;363(3):233-44非诺贝特是唯一有循证证据降低DR风险的降脂药物糖尿病视网膜病-发表于2012年3月新英格兰医学杂志Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 2012 Mar 29;366(13):1227-39.2014年7月发表中国2型糖尿病防治

20、指南(2013年版):非诺贝特可减缓糖尿病视网膜病变进展中国2型糖尿病防治指南(2013年版)中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2013年版). 中华糖尿病杂志, 2014, 6(7):447-497.最新指南糖尿病肾病糖尿病视网膜病变糖尿病截肢ACCORD血脂研究1非诺贝特显著减少蛋白尿以尿白蛋白/肌酐比值表示 mg/g白蛋白尿发生率 (%)辛伐他汀+非诺贝特(n=2,765)辛伐他汀(n=2,753)下降率p 值微量蛋白尿 (30 to 300mg/g)1,050(38.2%)1,137(41.6%)-8.17%0.01大量蛋白尿(300 mg/g)289(10.5%)33

21、7(12.3%)-14.63%0.03l 与既往DAIS/FIELD研究2,3结论 一致1.ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med, 2010, 362(17):1563-74.2.Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events

22、 in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005 Nov 26;366(9500):1849-61.3.Ansquer JC1, Foucher C, Rattier S, et al. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results f

23、rom the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis. 2005 Mar;45(3):485-93.非诺贝特显著减少首次微血管病变相关截肢的需求FIELD研究0.690.370.000.200.400.600.80安慰剂非诺贝特47%p=0.027微血管病变截肢患者比例 (%)Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 pe

24、ople with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet, 2005, 366(9500):1849-61.提纲2型糖尿病患者的微血管风险管理12型糖尿病患者的剩留心血管风险管理2总结3他汀是否能完全解决糖尿病患者的心血管风险？对于2型糖尿病患者，即使使用他汀治疗，仍会有很高的心血管剩留风险多项他汀研究1.HPSCG. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20

25、536 high-risk individuals: a randomised placebo-controlled trial. Lancet , 2002, 360: 7-22. 2.Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Sca

26、ndinavian Cardiac Outcomes TrialLipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet, 2003, 361:1149-1158.3. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastat

27、in Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet, 2004, 364: 685696.4. Shepherd J, Barter P, Carmena R, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to N

28、ew Targets (TNT) study. Diabetes Care, 2006; 29: 1220-1226. 5. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med, 2005, 353:238-248. 6.Rober h, Knopp RH , Michael E, et al. Efficacy and Safety of Atorvastatin in the Prevent

29、ion of Cardiovascular End Points in Subjects With Type 2 Diabetes. The Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) . Diabetes Care, 2006, 29:1478-1485. 7. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Re

30、search Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA, 2002, 288: 2998-3007.78%84%63%75%82%90%89%0102

31、030405060708090100辛伐他汀HPS阿托伐他汀ASCOT-LLA阿托伐他汀CARDS阿托伐他汀TNT阿托伐他汀4D阿托伐他汀ASPEN普伐他汀ALLHAT-LLT糖尿病患者心血管相对剩留风险123456734.924.829.619.4010203040DiabetesNo Diabetes主要血管事件b发生率(%)有冠心病史的糖尿病患者有冠心病史的非糖尿病患者对于2型糖尿病患者，即使使用他汀治疗，其心血管风险仍比未经治疗的非糖尿病患者更高CTT荟萃分析： 14项他汀试验a a. 平均4.3 年随访，18,686 例糖尿病患者; 71,370例非糖尿病患者b. 非致死MI，CHD

32、 死亡, 卒中, 冠脉血运重建 不论治疗组或对照组，糖尿病患者CVD风险均高于非糖尿病患者对照他汀治疗Cholesterol Treatment Trialists (CTT) Collaborators, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet, 2008, 371(9607):117-25.甘油三酯与心血管

33、风险仍有许多他汀单药治疗的2型糖尿病患者的TG未达标41.7%45.5%46.3%0 5 10 15 20 25 30 35 40 45 50 HDL-C1.0mmol/L(男性男性)HDL-C1.2mmol/L(女性女性)空腹空腹TG1.7mmol/L他汀单药治疗的糖尿病患者血脂未达标情况在使用他汀治疗的2型糖尿病患者中，仍有超过40%患者血脂指标未达标使用他汀治疗的2型糖尿病患者血脂未达标比例 Feher M, Greener M, Munro N. Persistent hypertriglyceridemia in statin-treated patients with type 2

34、 diabetes mellitus. Diabetes Metab Syndr Obes, 2013, 6:11-5.在LDL-C不高的人群中，高TG与冠心病风险显著相关中国多省份15年随访Cohort研究Liu J, Wang W, Wang M, et al. Impact of diabetes, high triglycerides and low HDL cholesterol on risk for ischemic cardiovascular disease varies by LDL cholesterol level: a 15-year follow-up of the

35、 Chinese Multi-provincial Cohort Study. Diabetes Res Clin Pract, 2012, 96(2):217-24.LDL-C3.4mmol/L，TG1.7mmol/L对比TG1.7mmol/LCHD风险74%本研究中，超过2/3的缺血性心血管事件发生在LDL-C水平较低的人群里TG是心血管风险的独立危险因素：仅使用他汀无法解决高TG带来的心血管风险20.320.020.522.624.724.827.326.826.829.11217222732207心血管事件发生率（%）TG水平（mmol/L）普伐他汀组安慰剂组斜率=0.029P0.00

36、1斜率=0.018P=0.02CARE和LIPID研究N = 13,173尽管使用他汀可以降低心血管风险，但当TG水平升高时，其心血管事件风险仍会显著升高。Sacks FM, Tonkin AM, Shepherd J, et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation, 2000, 102(16):1893-900.2.3高T

37、G和低HDL-C的糖尿病患者的心血管风险显著高于其他患者ACCORD研究他汀+安慰剂组患者LDL-C=2.06mmol/L+70%*主要心血管事件定义为心血管疾病死亡，非致死性心肌梗塞及非致死性中风 (主要治疗指标)平均随访4.7年，主要心血管事件的发生率（%）05101520TG2.3mmol/L和HDL-C0.88mmol/L（n=456）所有其他患者（n=2,284）10.117.3ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes

38、 mellitus. N Engl J Med, 2010, 362(17):1563-74.非诺贝特减少T2DM伴血脂异常患者的心血管风险非诺贝特可以显著减少既往无心血管疾病史的糖尿病患者的心血管风险-25%-19%-30%-25%-20%-15%-10%-5%0%CHD事件*总CVDFIELD研究Rohana AG, Ismail BY, Narayikin AW, et al. The influence of fenofibrate on lipid profile, endothelial dysfunction, and inflammatory markers in type 2 diabetes mellitus patients with typical and mixed dyslipidem. J Clin Lipidol, 2013; 7:446-453.*: Post-hoc analysis相对风险 (%)既往无心血管