Recent Advances & Emerging Data in the Treatment of Hypertriglyceridemia. Michael Miller, MD, FACC, FAHA, FNLA

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1 Recent Advances & Emerging Data in the Treatment of Hypertriglyceridemia Michael Miller, MD, FACC, FAHA, FNLA Professor of Medicine, Epidemiology & Public Health University of Maryland School of Medicine Baltimore, MD Disclosures Amarin: Consultant and Member, Steering Committee- REDUCE-IT trial. 1

2 Objectives Upon completion of this activity, participants will Evaluate the contribution of elevated triglycerides and non-hdl-c to residual CVD risk that remains even after LDL-cholesterol is well-controlled Describe the clinical trial evidence demonstrating CVD risk reduction using lipid-modifying therapies in patients with atherogenic dyslipidemia and determine which patients would benefit most from combination lipid-modifying therapies Triglycerides - Triacylglycerol Triglycerides are water-insoluble lipids consisting of three fatty acids linked to one glycerol molecule They represent a concentrated source of metabolic energy contributing 9 kcal/gm Citkowitz E, et al. Medscape article. Accessed August 1, Minami Nutrition website. Accessed August 1,

3 Overview of TG Metabolism Dietary Fat Adipose Tissue and Muscle GPIHBP1 Vascular Wall Macrophages E B-100 C-III IDL LPL, HGTL B-100 LPL Miller M, et al. Circulation. 2011;123: CIII B-48 C-II E Chylomicron LDL CII E VLDL B-100 C-III LPL LPL C-III C-III FFAs LDL-R LRP LRP B-100 VLDL B-48 CMR Apo A-V E E B-100 IDL, VLDL-R Metabolic Consequences of Hypertriglyceridemia Insulin Resistance FFA DGAT HDL TG/VLDL-C CETP Apo A-I CE TG HTGL Atherogenic Dyslipidemia HDL-C small-dense VLDL LDL particles VLDL ( LDL-C) TG TG TG TG TG Apo B-100 HDL Apo A-I Small, dense HDL Glycerol CE TG CETP CE HTGL LDL Apo B-100 Liver Miller M, et al. Circulation. 2011;123: Apo B-100 LDL TG Small, dense LDL 3

4 Mechanisms for Enhanced Atherogenesis of Small Dense LDL Mudd JO, et al. J Am Coll Cardiol. 2007;50(18): Cumulative Distribution of Adjusted Plasma TG Levels: LDL Phenotypes A and B Austin M, et al. Circulation. 1990;82:

5 Elevated Triglycerides Are Associated With Increased Small, Dense LDL Particles Fewer Particles More Particles Apo B LDL= 130 mg/dl More Apo B Cholesterol Ester Correlates with: TC 198 mg/dl LDL-C 130 mg/dl TG 90 mg/dl HDL-C 50 mg/dl Non HDL-C 148 mg/dl Correlates with: TC 210 mg/dl LDL-C 130 mg/dl TG 250 mg/dl HDL-C 30 mg/dl Non HDL-C 180 mg/dl Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i. Epidemiology of High TG and CVD Risk 5

6 Designation of Triglyceride Cutpoints 1984 NIH Consensus 1993 NCEP Guidelines 2001 NCEP Guidelines 2011 AHA Statement Optimal <100 Desirable < 250 < 200 < 150 < 150 Borderline High Very High > 1000 > 1000 > 500 > 500 Prevalence of Elevated TG ( ) 20+ yrs >150 >200 > 500 Overall 31% 16% 1.1% Men 35% 20% 1.8% Women 27% 13% 0.5% Heritage Mexican 35% 20% 1.4% African 16% 8% 0.4% European 33% 18% 1.1% Miller M, et al. Circulation. 2011;123:

7 Secondary Causes of Hypertriglyceridemia Estrogen Tamoxifen Alcohol Coffee Hypothyroidism Diabetes Liver disease Nephrotic syndrome Pregnancy Obesity Lipodystrophy Gaucher s disease Glycogen storage disease type I Medications Thiazides Beta blockers Corticosteroids Retinoids Protease inhibitors Long-term interferon Antipsychotic meds Eruptive Xanthomas TG>1000:PE Findings Lipemia Retinalis 7

8 TG and CHD Risk: Meta-Analysis of 29 Studies Groups CHD Cases 10 years 5902 <10 years 4256 Sex Male 7728 Female 1994 Fasting Status Fasting 7484 Nonfasting 2674 Adjusted for HDL Yes 4469 No 5689 Decreased Risk CHD Risk Ratio* (95% CI) Overall CHD Risk Ratio* 1 Increased Risk 1.72 (95% CI, ) *Individuals in top versus bottom third of usual log-tg values, adjusted for at least age, sex, smoking status, lipid concentrations, and (in most studies) blood pressure. Sarwar N, et al. Circulation. 2007;115: N=262,525 Elevated Triglycerides Increase the Risk of CHD at All Levels of LDL-C Incidence of CHD Events According to Serum LDL-C and TG Concentration* CHD Cases / 1000 in 8 Years Baseline TG <200 mg/dl Baseline TG 200 mg/dl Baseline LDL-C (mg/dl) * Lipids from 4849 middle-aged men who were followed up for 8 years to record incidence of CHD. Study demonstrated that fasting levels of TGs were an independent risk factor for CHD events, irrespective of serum levels of LDL-C. The effect of POM3 on the risk of pancreatitis in patients with very high TG levels has not been evaluated. The effect of POM3 on cardiovascular mortality and morbidity in patients with very high TG levels has not been determined. CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; TG=triglyceride. Adapted from Assmann G, et al. Eur Heart J. 1998;19(suppl M):M8-M14. 8

9 Residual CVD Risk in Patients Treated With Statins 40 Residual CVD Risk in Statin vs Placebo Trials CHD Events Occur in Patients Treated with Statins Patients Experiencing Major CHD Events, % Placebo Statin S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/TexCAPS 6 N LDL -35% -25% -28% -29% -26% -25% Secondary High Risk Primary 1 4S Group. Lancet. 1994;344: LIPID Study Group. N Engl J Med. 1998;339: Sacks FM et al. N Engl J Med. 1996;335: HPS Collaborative Group. Lancet. 2002;360: Shepherd J et al. N Engl J Med. 1995;333: Downs JR et al. JAMA. 1998;279:

10 Low HDL-C Increases CVD Risk Even If LDL-C Levels Are Well-Controlled Treating to New Targets (TNT) Study 5-Year Risk of Major CVD Events, % HDL-C Quintiles, a mg/dl Hazard Ratio Versus Q1* Patients With LDL-C 70 mg/dl on Statin a,b TG=186 TG=168 TG=150 TG=142 TG=124 Q1 <37 Q2 37 to <42 Q3 42 to <47 Q4 47 to <55 Q % Lower Risk a On-treatment level (3 months statin therapy); n = 2661 b Mean LDL-C, 58 mg/dl; mean TG, 126 mg/dl *P=.03 for differences among quintiles of HDL-C Barter P, et al. New Engl J Med. 2007;357: TG >150 mg/dl & CHD Events a In Patients With ACS on Statins b PROVE IT-TIMI 22 Trial N = 4162 LDL-C TG CHD Event a Rate, % HR: 0.81 (0.68, 0.96) P=.015 LDL-C 70 LDL-C <70 CHD Event a Rate, % HR: 0.73 (0.62, 0.87) P<.001 TG 150 TG < Days After Month 1 Visit ACS, acute coronary syndrome a Death, MI, and recurrent ACS b Atorvastatin 80 mg or pravastatin 40 mg Lipid values are in mg/dl Reprinted with permission from Miller M, et al. J Am Coll Cardiol. 2008;51: Days After Month 1 Visit Each 10 mg/dl in TG = 1.8% in CHD risk (P<.001) 10

11 TG < 150 mg/dl Associated With Lower Risk of CHD Events a Independent of LDL-C Level PROVE IT-TIMI 22 Trial b Achieving both low LDL-C and low TG (<150 mg/dl) may be important therapeutic strategies in patients after an ACS N = 4162 HR: 0.85 P=.180 Referent CHD Event a Rate After 30 Days c, % HR: 0.72 P=.017 HR: 0.84 P=.192 LDL-C 70 LDL-C <70 a Death, MI, and recurrent ACS TG <150 TG 150 b ACS patients on atorvastatin 80 mg or pravastatin 40 mg c Adjusted for age, gender, low HDL-C, smoking, hypertension, obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment Lipid values are in mg/dl Reprinted with permission from Miller M, et al. J Am Coll Cardiol. 2008;51: Practical Algorithm for Screening and Management of Elevated Triglycerides Miller M, et al. Circulation. 2011;123:

12 Effects of Nutrition Practices on Triglyceride Lowering Nutrition Practice TG-Lowering Weight loss 20% (5% to 10% of body weight) Implement a Mediterranean-style diet 10 15% vs a low-fat diet Add marine-derived PUFA (EPA/DHA) (per gram) 5 10% Decrease carbohydrates 1% Energy replacement with MUFA/PUFA 1 2% Eliminate trans fats 1% Energy replacement with MUFA/PUFA 1% Miller M, et al. Circulation. 2011;123: Effect of Lipid-lowering Therapies on TG Reduction (%) Fibrates 30-50% Niacin 20-50% Omega % Statins 10-30% Ezetimibe 5-10% Clinical Lipidology: A Companion to Braunwald s Heart Disease (Ballantyne CM, ed) 2009;

13 Clinical Trial Evidence Supporting Treating Beyond LDL-C to Reduce CVD Risk Treating Beyond LDL-C: Niacin Therapy 13

14 AIM-HIGH Primary Endpoint: CHD Death, Nonfatal MI, Ischemic Stroke, High-risk ACS, Hospitalization for Coronary or Cerebrovascular Revascularization Baseline Lipid Levels (Monotherapy arm, n=1696) Lipid LDL-C 74.0 (22.7) Cumulative % with Primary Outcome AIM-HIGH Investigators. N Engl J Med. 2011;365: ; Guyton J, et al. JACC. Epub July 20, Combination Therapy Monotherapy Non-HDL-C (26.0) 30 HDL-C 34.9 (5.6) HR 1.02, 95% CI Log-rank P value= % TG % 10 TG 198 mg/dl + HDL-C<33 mg/dl 0 (tertiles) trend toward benefit. N at risk Time (years) Monotherapy (Statin) Combination Therapy (Statin + ERN) HPS2-THRIVE: Randomized Placebo-controlled Trial of ERN and Laropiprant in 25,673 Patients with Pre-existing CVD Baseline Lipids on Statin-based Rx Lipid Mean (SD),mg/dL Total cholesterol 128 (22) Direct-LDL 63 (17) HDL-C 44 (11) TG 125 (74) 5 Placebo ERN/LRPT Years of follow-up *Non-fatal MI or coronary death, any non-fatal or fatal stroke, coronary or non-coronary artery surgery or angioplasty. LRPT= laropiprant. Presented at: ACC.13: American College of Cardiology 62nd Annual Scientific Session. Available at: Patients Suffering Events (%) Effect of ERN/LRPT on Major Vascular Events* 20 Risk ratio 0.96 (95% CI ) Logrank P= % 15 Significant excesses of serious adverse events (SAEs) due to known and unrecognised side-effects of niacin. Over 4 years, ER niacin/laropiprant caused SAEs in ~30 patients per % 14

15 Treating Beyond LDL-C: Fibrate Therapy Meta-analysis of Randomized Trials of Fibrate Drugs Dyslipidemia: TG 204 mg/dl, HDL-C 34 mg/dl Complementary subgroups: TG < 204 mg/dl, HDL-C > 34 mg/dl Odds ratio 35% in dyslipidemia Sacks FM, et al. N Engl J Med. 2010;363(7):

16 Treating Beyond LDL-C: Omega-3 Fatty Acid Therapy OM-3 FA Molecular Structure PUFA=polyunsaturated FA. Adapted from Mozafarian D, Wu JH. J Am Coll Cardiol. 2011;58:

17 Japan EPA Lipid Intervention Study (JELIS) 18,645 subjects, primary and secondary prevention 4 Major CV Events (%) Statin Statin +EPA (1.8g/day) Hazard ratio = 0.81 ( ) p = % Years Adapted from Yokoyama M. Lancet. 2007;369: Clinical Outcome Studies Evaluating High TG Subgroups Trial (Drug) Primary Endpoint: Entire Cohort (P-value) Lipid Subgroup Criterion Primary Endpoint: Subgroup (P-value) Prestatin era HHS (Gemfibrozil) BIP (Bezafibrate) -34% (0.02) -9.4% (0.26) TG > 204 mg/dl LDL-C/HDL-C > 5.0 TG > 200 mg/dl HDL-C <35 mg/dl -71% (0.005) -42% (0.02) Some statin use FIELD (Fenofibrate) (no statins at entry) -11% (0.16) TG > 150 mg/dl -12% (0.07) Statin add-on ACCORD (Fenofibrate/simva) JELIS (ethyl EPA) (simva & prava) -8% (0.32) -19% (0.011) TG > 204 mg/dl HDL-C < 34 mg/dl TG > 150 mg/dl HDL-C < 40 mg/dl -31% (0.0567) -53% (0.043) 17

18 OM-3 Ethyl Esters and Lipid Levels in Patients with TG >500 mg/dl Baseline (mg/dl) TG 816 HDL-C 22 Non-HDL-C 27 TC 296 VLDL-C 175 LDL-C 89 60% P< Change in Median Levels 40% 20% 0% -20% -40% P< P= P= P= P< % Placebo OM-3 Acid Ethyl Esters (4 g/day) Pooled analysis (N=82). Harris WS et al. J Cardiovasc Risk 1997;4: and Pownall HJ et al. Atherosclerosis 1999;143: Median Placebo-adjusted Change (%) MARINE: Icosapent Ethyl (Pure EPA): Median Placebo-adjusted Change from Baseline for Efficacy Endpoints The MARINE Study: TG >500 mg/dl TG Non-HDL-C VLDL-C Lp-PLA 2 Apo B TC ǁ ǁ -8.1 * * NS NS ǁ -6.8 * LDL-C NS NS HDL-C NS NS Icosapent Ethyl 4 g/day (n=76) FDA approved dose 2 g/day (n=73) *P<0.05. P<0.01. P< ǁ P< NS = P P-values reflect differences between icosapent ethyl vs placebo. ITT Population VLDL-TG NS hscrp EPA=eicosapentaenoic acid; ITT=intention to treat; Lp-PLA=lipoprotein-associated phospholipase A; MARINE= Multi-center, Placebocontrolled, Randomized, Double-blind, 12-week Study with an Open-label Extension. Bays HE et al. Am J Cardiol. 2011;108: Bays HE et al. Paper presented at: European Society of Cardiology (ESC) Congress 2011; August 29, 2011; Paris, France NS 18

19 ANCHOR: Icosapent Ethyl (Pure EPA): Median Placebo-Adjusted Change from Baseline for Efficacy Endpoints The ANCHOR Study: TG 200 and <500 mg/dl Median Placebo-adjusted Change (%) TG Non-HDL-C Apo B LDL-C HDL-C Baseline values (mg/dl) ǁ ǁ ǁ -3.8 * NS NS *P<0.05. P<0.01. P< ǁ P< NS = P P-values reflect differences between icosapent ethyl vs placebo Note: EPA is not FDA approved for TG mg/dl 4 g/day (n=233) 2 g/day (n=236) 12-week trial in high-risk statin-treated patients (N=702) with residually TG levels ( 200 and <500 mg/dl) despite LDL-C control ( 40 and <100 mg/dl). ANCHOR= Effect of AMR101 (Ethyl Icosapentate) on Triglyceride (Tg) Levels in Patients on Statins With High Tg Levels ( 200 and < 500 mg/dl). Ballantyne CM et al. Am J Cardiol. 2012;110: Reduction of CV Events with EPA Intervention Trial Men & women 45 yo Prior CHD (70% patients) or T2DM + 1 RF) Atherogenic dyslipidemia: Hx of TC (at LDL-C goal on statin) TG mg/dl N=8000 AMR101, 4 g/day Placebo Primary endpoint: Prevention of 1 st major CV event Study duration ~4 6 yrs Randomized, double-blind, parallel group design Secondary outcome measures: Incidence of additional CV events, lipid and lipoprotein levels, subgroup analyses such as diabetes, etc. Multinational trial Anticipated completion 2016 AMR101=icosapent ethyl REDUCE-IT=Reduction of Cardiovascular Events with EPA -Intervention Trial. A Study of AMR101. NIH website. 19

20 New Drugs in Triglyceride Metabolism Variety of targets DGAT inhibition MTP inhibition Gene therapy Complex pathways, multiple candidates Efficacy (outcomes) and safety remain under investigation Summary Residual CVD risk is high in CHD & diabetic patients treated with statins, likely due to the atherogenic dyslipidemia characteristic of this patient population (elevated TG and low HDL-C) U.S. guidelines recommend that combination therapy may be necessary to achieve primary and secondary (LDL-C, non HDL-C) targets Combination therapy with statins and niacin/ fenofibrate/ fish oil corrects atherogenic lipid abnormalities, with the latter 2 therapies associated with reduced CV risk in subgroup analyses Ongoing clinical trial(s) will assess whether combination therapy is clinically superior to statin monotherapy in hypertg patients 20