Triglyceride as Vascular Risk Factor

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1 Curriculum Vitae Name : Prof. Dr. dr. Idrus Alwi SpPD, KKV, FINASIM, FACP, FACC, FESC, FAPSIC Current Position : - President of the Indonesian Society of Internal Medicine Medical Student : Faculty of Medicine University of Indonesia 1986 Internist : Faculty of Medicine University of Indonesia 1996 Cardiovascular Consultant : The Indonesian Society of Internal Medicine, 2001 PhD : Faculty of Medicine University of Indonesia, 2006 FACC : American College of Cardiology, 2006 FESC : European Society of Cardiology, 2008 FAPSIC : Asia Pacific Society of Interventional Cardiology, 2009 FINASIM : Indonesian Society of Internal Medicine, 2009 FACP : Fellow of American College of Physician, 2013 Advanced Course in Cardiology, Melbourne 1997 Advanced Course on Echocardiography and Others Non Invasive Cardiology, Melbourne Stem cell NOGA course, Cincinnatti, Ohio, 2009 ASAN Interventional Cardiology Course, Seoul, 2011

2 Triglyceride as Vascular Risk Factor Prof. Idrus Alwi MD, PhD, FINASIM, FACP, FACC, FESC, FAPSIC Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia

3 Cumulative incidence of CHD and all-cause mortality Triglycerides as a risk factor for CHD: Copenhagen Male Study % % % mg/dl (n=982) (n=973) >140 (n=951) N=2906; 8years Triglyceride level (mg/dl) Am J Cardiol 1999; 83: 13F-16F

4 Incidence in % of subjects The Association of low HDL-C with Elevated TG Confers a Substantial Risk of CHD Crude incidence of CHD after 8 years of follow-up in the Copenhagen Male Study 15,0% 10,0% 5,0% 0,0% HDL 0,29-1,18 HDL 1,19-1,45 HDL 1,46-3,46 HDL thirds in mmol/l TG 0,44-1,09 TG 1,10-1,59 TG 1,60-22,4 TG thirds in mmol/l The observed relationship holds after multivariate adjustment for potential confounders Jeppesen J et al, Circulation 1998;97:

5 Increased triglyceride levels confer increased risk at all levels of LDL-C CHD cases/1,000 in 8 years PROCAM study: CHD risk according to LDL-C and TG Increased TG confers CHD risk at all levels of LDL-C TG < 200 mg/dl (2.3 mmol/l) TG 200 mg/dl (2.3 mmol/l) < 130 < LDL-Cholesterol (mg/dl, mmol/l) > 190 > 4.9 Adapted from Assman G et al Eur Heart J, Vol. 19,suppl A 1998

6 30-day risk of death, MI or recurrent ACS (%) High TG levels are associated with increased residual macrovascular risk, even when LDL-C is very low Despite achieving LDL-C <70 mg/dl with high-dose statins, patients with TG 200 mg/dl show significantly increased CV risk 25 PROVE IT-TIMI 22 study % p= (n=603) <200 (n=2,796) On-treatment TG (mg/dl) in patients who achieved LDL-C <70 mg/dl on statin therapy Miller M et al. J Am Coll Cardiol. 2008;51:

7 Residual coronary heart disease in statin-treated patients: room for improvement Study 4S 1 CARE 2 WOSCOPS 3 AFCAPS 4 LIPID 5 HPS 6 20, PROSPER ALLHAT-LLT 8 10, ASCOT-LLA 9 10, Total n 30,187 77,817 No. events Control Statin % Risk reduction % Events not avoided Lancet ;344:1383-9; 2 NEJM 1995;333:1301-7; 3 Circulation 1999;99:216-23; 4 JAMA 1998;279: ; 5 NEJM 1998;33: ; 6 Lancet 2002;360:7-22; 7 Lancet 2002;360: ; 8 JAMA 2002;288: ; 9 Lancet 2003;361:

8 5-yr risk major cardiovascular event rate (%) Aggressive LDL-C lowering with maximal doses of statins does not eliminate residual macrovascular risk TNT study % relative risk reduction Modifiable Risk Factors HDL-C, TG Blood Pressure IA Adiposity Insulin resistance Smoke Inflammation, etc. 5 RESIDUAL CV RISK 0 Atorvastatin 10 mg LDL-C 101 mg/dl (n=5,006) 80 mg 77 mg/dl (n=4,995) Non-Modifiable Risk Factors Age Gender Family history * Composite of death from CHD, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke. LaRosa et al., N Engl J Med 2005;352:

9 Managing Residual Vascular Risk: Comprehensive Lipid Approach LDL-C Reduction Reduces Cardiovascular Events YES - Strong Unequivocal Evidence Limitation: 60%-90% of CV events still observed in statin-treated pts Concept of Residual Cardiovascular Risk (RR) Comprehensive lipid management (LDL-C, HDL-C, TG) Low HDL-C and high TG significantly contribute (by 30-40%) to the excess residual risk of CV events on optimal LDL-C levels Therapeutic Approaches for a Comprehensive Lipid Management - Effects on Lipid Profile and Safety: YES - Effect on Clinical Endpoints: Positive Preliminary

10 Features of Atherogenic Dyslipidemia Metabolic syndrome Low HDL-C Diabetes Mellitus T2 PCOS Elevated small-dense LDL particles Elevated TG Atherogenic dyslipidemia is commonly associated with pro-thrombotic and proinflammatory states. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA 2001;285:

11 UKPDS: Typical Lipid Profile in Patients with Diabetes Compared with No Diabetes 6 5,8 5,6 Men Women 4 3,8 3,6 Men Women p< ,4 3,4 5,2 5 no no Total cholesterol (mmol/l) 3,2 3 no no LDL-cholesterol (mmol/l) 1,6 Women p< ,8 Men p<0.001 Women p< ,4 1,2 1 Men p<0.001 no no HDL-cholesterol (mmol/l) 1,6 1,4 1,2 1 no no no Triglycerides (mmol/l) Diabetes Care 1997;20:

12 Observed incidence (%) of stroke in 10 years Observed incidence (%) of myocardial infraction in 10 years Cardiovascular Risk Assessment in MetS view from PROCAM A: Myocardial infarction B: Stroke Control IGT Metabolic syndrome Diabetes mellitus Effect of metabolic syndrome or diabetes mellitus on the incidence of myocardial infraction (A) and stroke (B) in 4818 male PROCAM participants aged 35 to 65 years Assmann G. Endocrinology metabolic clinics of North America June 2004; 33:

13 Classification of Elevated Triglyceride Levels TG levels that are even moderately elevated ( 150 mg/dl) may identify individuals at risk for the insulin resistance syndrome. TG levels 200 mg/dl may indicate a substantial increase in ASCVD risk. Hypertriglyceridemia is also commonly associated with a procoagulant state and hypertension. TG category TG concentration (mg/dl) TG goal Normal <150 Borderline high High <150 mg/dl Very high 500 Abbreviations: ASCVD, atherosclerotic cardiovascular disease; TG, triglycerides. Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):

14 Fenofibrate: mechanisms of action on lipids Liver Apo AI Apo AII ABCA1 Circulation HDL RESULTS Increased HDL production Fibrates increase the expression of proteins in yellow Acyl-CoA synthase FFA Apo CIII TG Acetyl CoA VLDL LDL LPL Decreased VLDL production Increased VLDL clearance Decreased LDL particles and increased particle size Duval C, et al. Trends Mol Med. 2002;8: Lee CH, et al. Endocrinology. 2003;144:

15 Fenofibrate on Peripheral vascular effects Cholesterol efflux Foam cell formation Inflammatory response Vasoconstriction Cell migration Thrombosis Plaque stability Activated PPAR Cell recruitment/ activation Barbier O, et al. Arterioscler Thromb Vasc Biol. 2002;22:

16 Fenofibrate in Atherosclerosis (1) Atherosclerosis is an inflammatory disease involving the immune response, which characterized by a sequential release of anti- and pro-inflammatory cytokines, including IL-10, TNF-α & and P-selectin Fenofibrate (PPAR-α) : prevent atherosclerosis via its pleiotropic antiinflammatory effects plays an important role in regulating fatty acid oxidation, lipid & lipoprotein metabolism, inflammatory & vascular responses, all of which are involved in atherosclerosis Molecular Medicine Reports 9: , 2014

17 Fenofibrate in Atherosclerosis (2) Antiatherogenic effects of Fenofibrate significantly: regresses atherosclerotic lesions induced changes in plaque composition associated more stable phenotype (reduced macrophages and increased smooth muscle cell) # Animal study: NZ white rabbits by a combination of a double-balloon injury and a 9-month hypercholesterolemic diet Atherosclerosis 190 (2007)

18 PPAR- Agonists (Fibrates) and Statins Combination fibrate and statin therapy may significantly improve triglyceride, LDL-C, and HDL-C levels Fibrates plus statins are associated with increased risk for myopathy and rhabdomyolysis Not thought due to cytochrome P450 drug interaction Gemfibrozil may impair glucuronidation of statins (with cerivastatin being more susceptible than other statins such as simvastatin and atorvastatin) Fenofibrate appears to have less potential for impairment of statin metabolism, and thus this may account for the reduced reports of fenofibrate plus statin induced myopathy and rhabdomyolysis compared with gemfibrozil plus statin. Ballantyne CM et al. Arch Intern Med 2003;163: Bays H. Am J Cardiol 2002;90:30K-43K.

19 Relative risk reduction in total CV events (%) FIELD: Patients with atherogenic dyslipidemia target population of fenofibrate treatment 0 Overall population (n=9,795) Low HDL-C (n=5,820) High TG (n=2,517) Low HDL-C + high TG (n=2,014) % p= % p< Low HDL-C (<40 mg/dl for men and <50 mg/dl for women) and high TG ( 200 mg/dl) defined according to ATP III criteria -23% p< % p=0.005 Number needed to treat (NNT) to prevent one CV event in patients with T2D and atherogenic dyslipidaemia treated with fenofibrate: 23 Keech AC et al. Lancet. 2005;366: Scott R et al. Diabetes Care. 2009;31:

20 Relative risk reduction in total CV events (%) Fibrates are specifically effective in Reducing RR of CVD in patients with Low HDL-C and Elevated TG 0 HHS (4,081) HHS (292) BIP (3,090) BIP (1,470) VA-HIT (2,531) VA-HIT (769) FIELD (9,795) FIELD (2,014) % p< % p=ns -25% p= % p= % p= % p= % p= % p<0.005 All Patients Patients with low HDL-C and High TG (Type 2 Diabetes, Metabolic Syndrome) Low HDL-C (<40 mg/dl for men and <50 mg/dl for women) and high TG ( 150 mg/dl) defined according to ATP III criteria Keech et al., Lancet 2005;366: Scott et al., Diabetes Care 2009;31:493 98

21 LIPID MODIFYING EFFICACY FENOFIBRATE ALONE OR IN COMBINATION WITH STATIN in patient with TYPE 2 DIABETES - ( BEST COMBINATION : with ATORVASTATIN )

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23 Fibrate-Statin combination: The optimal therapeutic approach in diabetic patients with combined hyperlipidemia Atorvastatin 20 mg Fenofibrate 200 mg Atorvastatin 20 mg + Fenofibrate 200 mg % change from baseline TC TG LDL N=120; 24 wks HDL -46 Diabetes Care 2002;25:

24 Clinical Trials with Statin-Fenofibrate: Simvastatin + Fenofibrate (SAFARI Trial) Combined hyperlipidemia (n=618) Effects on Lipids % change from baseline Simvastatin Simva + Feno S.M. Grundy et al., Am. J. Cardiol., 95: , LDL HDL TG % Change in LDL SIZE from Baseline 80% 60% 40% 20% 0% Simvastatin 20 mg/day + Fenofibrate 160 mg/day Simvastatin 20 mg/day Simvastatin 20 mg/day + Fenofibrate 160 mg/day Baseline Week Simvastatin 20 mg/day Small LDL Intermediate LDL Large LDL Fewer LDL Better LDL

25 Guidelines recognize importance TG and Non HDL-C Treatment Guidelines 2013 ACC/AHA Guideline American , 2004 National Lipid 2011 AHA TG Diabetes Asscociation 1 NCEP ATP III Scientific 5 Asscociation 2 statements 4 Triglycerides Normal TG level: < 150 mg/dl 1 Primary target, if TG elevated (> 500 mg/dl) 4 Non HDL-C Co-primary target, goal based on risk cathegory (30 mg/dl, > LDL goals) Secondary target when TG elevated (30 mg/dl, > LDL goals) No recommendation or against specific non HDL-C target Life style recommendation Life style changes: diet, exercise, weight reductary ACC : American College Cardiology; AHA: American Heart Asscociation; NCEP: National Cholesterol Education Program; ATP: Adult Treatment Panel 1. J. Clini Lip, 8, (5), 2014; 2. Handelsman, et al, Endocrine practice, Stone et al, Circulation, 2013; 4. Miller et al, Circulation, 2011; 5. NIH Publication, , 2001

26 Fibrates, particularly fenofibrate, may be useful, not only for decreasing high triglyceride concentrations and increasing low HDL-C, but for lowering LDL-C further when used with a statin. There is limited evidence for this combination in terms of a reduction in CVD events. In selected cases, however, this approach may be considered, such as when, during statin treatment, triglycerides remain high and/or HDL-C is very low. Gemfibrozil should not be added to a statin treatment, because of the high potential for interactions

27 American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease Writing Committee Chair: Paul S. Jellinger, MD, MACE Co-Chair: Yehuda Handelsman, MD, FACP, FACE Members: David S. H. Bell, MD, FACP, FACE Zachary T. Bloomgarden, MD, MACE Eliot A. Brinton, MD, FAHA, FNLA Michael H. Davidson, MD, FACC, FACP, FNLA Sergio Fazio, MD, PhD Vivian A. Fonseca, MD, FACE Alan J. Garber, MD, PhD, FACE George Grunberger, MD, FACP, FACE Chris K. Guerin, MD, FNLA, FACE Jeffrey I. Mechanick, MD, FACP, FACE, FACN, ECNU Rachel Pessah-Pollack, MD, FACE Paul D. Rosenblit, MD, PhD, FNLA, FACE Donald A. Smith, MD, MPH, FACE Kathleen Wyne, MD, PhD, FNLA, FACE Reviewers: Michael Bush, MD Farhad Zangeneh, MD Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):

28 Recommendations associated with this question: Question: How are different drugs used to treat dyslipidemia? Statins, Fibrates R55. In individuals at risk for ASCVD, aggressive lipid-modifying therapy is recommended to achieve appropriate LDL-C goals (Grade A, BEL 1). Statins R56. Statin therapy is recommended as the primary pharmacologic agent to achieve target LDL-C goals on the basis of morbidity and mortality outcome trials (Grade A; BEL 1). R57. For clinical decision making, mild elevations in blood glucose levels and/or an increased risk of new-onset T2 associated with intensive statin therapy do not outweigh the benefits of statin therapy for ASCVD risk reduction (Grade A, BEL 1). R58. In individuals within high-risk and very high-risk categories, further lowering of LDL-C beyond established targets with statins results in additional ASCVD event reduction and may be considered (Grade A, BEL 1). R59. Very high-risk individuals with established coronary, carotid, and peripheral vascular disease, or diabetes, who also have at least 1 additional risk factor, should be treated with statins to target a reduced LDL-C treatment goal of <70 mg/dl (Grade A, BEL 1). R60. Extreme risk individuals should be treated with statins or with combination therapy to target an even lower LDL-C treatment goal of <55 mg/dl (Grade A, BEL 1). Fibrates R61. Fibrates should be used to treat severe hypertriglyceridemia (TG >500 mg/dl) (Grade A; BEL 1). R62. Fibrates may improve ASCVD outcomes in primary and secondary prevention when TG concentrations are 200 mg/dl and HDL-C concentrations <40 mg/dl (Grade A; BEL 1). Abbreviations: ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides. Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):

29 Question: How are different drugs used to treat dyslipidemia? Fibrates Fibrates should be used to treat severe hypertriglyceridemia (TG >500 mg/dl). (Grade A; BEL 1). Fibrates may improve ASCVD outcomes in primary and secondary prevention when TG concentrations are 200 mg/dl and HDL-C concentrations <40 mg/dl. (Grade A; BEL 1). Abbreviations: ASCVD, atherosclerotic cardiovascular disease; TG, triglycerides. Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):

30 Summary There is evidence that hypertriglyceridaemia is independently predictive of cardiovascular risk even in the presence of low LDL-Cholesterol levels. Fibrate appear to be particularly effective in patients with type 2 and/or the features of the metabolic syndrome Combination therapy with a statin and a fibrate may be efficacious for treatment of all three lipid fractions.

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