高TG與大微血管風(fēng)險(xiǎn)

1、2型糖尿病患者不容忽視的大微血管風(fēng)險(xiǎn)提綱2型糖尿病患者的微血管風(fēng)險(xiǎn)管理12型糖尿病患者的剩留心血管風(fēng)險(xiǎn)管理2總結(jié)3微血管風(fēng)險(xiǎn)？為什么要關(guān)注微血管病變是糖尿病血管病變的重要組分NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2006.腦血管疾病和中風(fēng)增加24倍中風(fēng)4/5糖尿病患者死于心血管事件預(yù)期壽命減少35年心血管疾病美國每年24,000例成人新發(fā)失明病例的主要原因糖尿病視網(wǎng)膜病變每年44%成人終末期腎病新發(fā)病例中的主要原因糖尿病腎病每年60%非創(chuàng)傷性截肢術(shù)新發(fā)病例的主要原因 糖尿病神經(jīng)病變中國糖尿病視網(wǎng)膜病變流行現(xiàn)狀嚴(yán)峻中華

2、醫(yī)學(xué)會(huì)糖尿病學(xué)分會(huì). 中國2型塘尿病防治指南(2010年版).中國醫(yī)學(xué)前沿雜志(電子版), 2011, (06):54-109.20-40%糖尿病患者視網(wǎng)膜病變視力喪失8%（人數(shù)約930萬）2010中國2型糖尿病治療指南中國糖尿病腎病發(fā)病率非常高2010中國2型糖尿病治療指南中華醫(yī)學(xué)會(huì)糖尿病學(xué)分會(huì). 中國2型塘尿病防治指南(2010年版).中國醫(yī)學(xué)前沿雜志(電子版), 2011, (06):54-109.34.7%糖尿病腎病微血管風(fēng)險(xiǎn)？能否僅靠強(qiáng)化降糖、降壓控制nUKPDS:降低血壓（150/85mmHg）可使視敏度缺失的發(fā)生減少47%（p=0.0004），但在神經(jīng)病變或腎臟疾病的風(fēng)險(xiǎn)上無明顯

3、改變。1nADVANCE強(qiáng)化降低血壓（收縮壓:5.60.2mmHg,舒張壓:2.20.1mmHg ）在微血管事件風(fēng)險(xiǎn)上無明顯作用。2nDIRECT-Protect 2坎地沙坦阻斷腎素-血管緊張素系統(tǒng)（RAS），并不明顯延緩2型糖尿病患者的糖尿病視網(wǎng)膜病變的進(jìn)展。3積極血壓控制并不能完全減少微血管并發(fā)癥風(fēng)險(xiǎn)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:糖化血紅蛋白（HbA1c）每降低1%，微血管的聯(lián)合終點(diǎn)降低37%。n需

6、要激光治療的視網(wǎng)膜病變n玻璃體出血n致死性或非致死性腎衰n ADVANCE:強(qiáng)化血糖控制（HbA1c6.5%）組中，腎臟病變降低了21%，但對(duì)視網(wǎng)膜病變無明顯作用。2強(qiáng)化血糖控制并不能完全防治微血管并發(fā)癥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風(fēng)險(xiǎn)不容忽視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周圍神經(jīng)病變視網(wǎng)膜病變腎病普通干預(yù)強(qiáng)化干預(yù)患者比例*強(qiáng)化干預(yù)：口服降糖藥物、抗高血壓藥物、降脂藥物+飲食和生活方式改變，平均隨訪13.3年p=0.89p=0.01p=0.004剩留風(fēng)險(xiǎn)剩留風(fēng)險(xiǎn)剩留風(fēng)險(xiǎn)STENO-2研究: 強(qiáng)化干預(yù)*療效微血管風(fēng)險(xiǎn)？他汀是否能很好地控制糖尿病腎病視網(wǎng)膜病變他汀對(duì)微血管事件的療效非常有限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) 不確定肌酐CTTC*2 (n=90,056) p=nsCARDS4 (只在亞組獲益)HPS5 (n= 20,536) p=ns甘油三酯與微血管風(fēng)險(xiǎn)TG水平升高增加2型糖尿病患者微血管病變風(fēng)險(xiǎn)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一項(xiàng)在13個(gè)國家完成的病例、對(duì)照研究，納入2535例糖尿病患者，其中1891例伴腎臟疾病，1218例伴視網(wǎng)膜病變。旨在觀察甘油三酯和高密度脂蛋白對(duì)患者腎臟微血管病變和視網(wǎng)膜的影響。結(jié)果顯示，甘油三酯水平升高增加2型糖尿病患者

12、微血管病變風(fēng)險(xiǎn)。 TG每升高0.5mmol/L,微血管病變風(fēng)險(xiǎn)16%2型糖尿病患者腎病風(fēng)險(xiǎn)隨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糖尿病腎病風(fēng)險(xiǎn) TG每升高0.5mmol/L,糖尿病腎病風(fēng)險(xiǎn)20%非諾貝特循證支持，微血管獲益非諾貝特有顯著的微血管獲益Lancet. 2005;366:18491861 FIELD研究-31%-14%-36%-40%-35%-30%-25%-20%-15%-10%-5%0%需激光治療的視網(wǎng)膜病變白蛋白排泄率非創(chuàng)傷性截肢相對(duì)風(fēng)險(xiǎn)降低l 獲益獨(dú)立于血糖 (HbA1c) 和血壓控制或合并癥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糖尿病腎病糖尿病視網(wǎng)膜病變糖尿病截肢糖尿病視網(wǎng)膜病變發(fā)病機(jī)制Dodson PM. Diabetic retinopathy: treatment and prev

15、ention. Diab Vasc Dis Res, 2007, 4 Suppl 3:S9-S11.微血管阻塞微血管滲漏視網(wǎng)膜缺血血眼屏障破壞棉絮狀滲出點(diǎn)毛細(xì)血管閉塞新血管形成視網(wǎng)膜出血、滲出/水腫VEGFVEGF，血管緊張肽IGF-1，GH，F(xiàn)GFIGF-1 = 胰島素樣生長因子-1；GH = 生長激素FGF = 纖維母細(xì)胞生長因子；VEGF = 血管內(nèi)皮生長因子微血管病變毛細(xì)血管阻塞非諾貝特阻斷VEGF介導(dǎo)的血管異常增生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.非諾貝特非諾貝特能夠顯著減少DR激光治療的需求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%安慰劑非諾貝特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%安慰劑非諾貝特37%患者比例糖尿病視網(wǎng)膜病變激光治療的需求1糖尿病視網(wǎng)膜病變的累積激光治療2非諾貝特聯(lián)合他汀顯著降低糖尿病視網(wǎng)膜發(fā)生和進(jìn)展風(fēng)險(xiǎn)ACCORD-EYE分支研究ARR = 3.7%NNT = 2710.26.50.05.010.0辛伐他汀+安慰劑辛伐他汀+非諾貝特40%p=0.006OR 0.60 95% CI 0.42-0.87主要終點(diǎn)發(fā)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非諾貝特是唯一有循證證據(jù)降低DR風(fēng)險(xiǎn)的降脂藥物糖尿病視網(wǎng)膜病-發(fā)表于2012年3月新英格蘭醫(yī)學(xué)雜志Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 2012 Mar 29;366(13):1227-39.2014年7月發(fā)表中國2型糖尿病防治

20、指南(2013年版):非諾貝特可減緩糖尿病視網(wǎng)膜病變進(jìn)展中國2型糖尿病防治指南(2013年版)中華醫(yī)學(xué)會(huì)糖尿病學(xué)分會(huì). 中國2型糖尿病防治指南(2013年版). 中華糖尿病雜志, 2014, 6(7):447-497.最新指南糖尿病腎病糖尿病視網(wǎng)膜病變糖尿病截肢ACCORD血脂研究1非諾貝特顯著減少蛋白尿以尿白蛋白/肌酐比值表示 mg/g白蛋白尿發(fā)生率 (%)辛伐他汀+非諾貝特(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 與既往DAIS/FIELD研究2,3結(jié)論 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.非諾貝特顯著減少首次微血管病變相關(guān)截肢的需求FIELD研究0.690.370.000.200.400.600.80安慰劑非諾貝特47%p=0.027微血管病變截肢患者比例 (%)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.提綱2型糖尿病患者的微血管風(fēng)險(xiǎn)管理12型糖尿病患者的剩留心血管風(fēng)險(xiǎn)管理2總結(jié)3他汀是否能完全解決糖尿病患者的心血管風(fēng)險(xiǎn)？對(duì)于2型糖尿病患者，即使使用他汀治療，仍會(huì)有很高的心血管剩留風(fēng)險(xiǎn)多項(xiàng)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對(duì)剩留風(fēng)險(xiǎn)123456734.924.829.619.4010203040DiabetesNo Diabetes主要血管事件b發(fā)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對(duì)于2型糖尿病患者，即使使用他汀治療，其心血管風(fēng)險(xiǎn)仍比未經(jīng)治療的非糖尿病患者更高CTT薈萃分析： 14項(xiàng)他汀試驗(yàn)a a. 平均4.3 年隨訪，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, 冠脈血運(yùn)重建 不論治療組或?qū)φ战M，糖尿病患者CVD風(fēng)險(xiǎn)均高于非糖尿病患者對(duì)照他汀治療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.甘油三酯與心血管

33、風(fēng)險(xiǎn)仍有許多他汀單藥治療的2型糖尿病患者的TG未達(dá)標(biāo)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他汀單藥治療的糖尿病患者血脂未達(dá)標(biāo)情況在使用他汀治療的2型糖尿病患者中，仍有超過40%患者血脂指標(biāo)未達(dá)標(biāo)使用他汀治療的2型糖尿病患者血脂未達(dá)標(biāo)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與冠心病風(fēng)險(xiǎn)顯著相關(guān)中國多省份15年隨訪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對(duì)比TG1.7mmol/LCHD風(fēng)險(xiǎn)74%本研究中，超過2/3的缺血性心血管事件發(fā)生在LDL-C水平較低的人群里TG是心血管風(fēng)險(xiǎn)的獨(dú)立危險(xiǎn)因素：僅使用他汀無法解決高TG帶來的心血管風(fēng)險(xiǎn)20.320.020.522.624.724.827.326.826.829.11217222732207心血管事件發(fā)生率（%）TG水平（mmol/L）普伐他汀組安慰劑組斜率=0.029P0.00

36、1斜率=0.018P=0.02CARE和LIPID研究N = 13,173盡管使用他汀可以降低心血管風(fēng)險(xiǎn)，但當(dāng)TG水平升高時(shí)，其心血管事件風(fēng)險(xiǎn)仍會(huì)顯著升高。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風(fēng)險(xiǎn)顯著高于其他患者ACCORD研究他汀+安慰劑組患者LDL-C=2.06mmol/L+70%*主要心血管事件定義為心血管疾病死亡，非致死性心肌梗塞及非致死性中風(fēng) (主要治療指標(biāo))平均隨訪4.7年，主要心血管事件的發(fā)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.非諾貝特減少T2DM伴血脂異常患者的心血管風(fēng)險(xiǎn)非諾貝特可以顯著減少既往無心血管疾病史的糖尿病患者的心血管風(fēng)險(xiǎn)-25%-19%-30%-25%-20%-15%-10%-5%0%CHD事件*總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相對(duì)風(fēng)險(xiǎn) (%)既往無心血管