Clinical Management of Hypertriglyceridemia: State of the Art 2015

Transcription

1 Clinical Management of Hypertriglyceridemia: State of the Art 2015 National Lipid Association Clinical Lipid Update February 28, 2015, Denver, Colorado Eliot A. Brinton, MD, FAHA, FNLA President, American Board of Clinical Lipidology Director, Atherometabolic Research Utah Foundation for Biomedical Research President, Utah Lipid Center Salt Lake City

2 Speaker Disclosures Dr. Brinton has received: Research funding: Aurora Foundation, Health Diagnostic Laboratory Honoraria as consultant/advisor: Amarin, Amgen, Arisaph, AstraZeneca, Atherotech, Janssen, Kowa, Lilly, Merck, Novartis, Sanofi- Aventis, Synageva Honoraria as speaker: Aegerion, Amarin, AstraZeneca, Genzyme, Janssen, Kowa, Merck, Synageva, Takeda

3 Learning Objectives Participants should be able to: 1. Discuss the prevalence and pathophysiology of hypertriglyceridemia (HTG) 2. Appreciate the likely causal connection of HTG with acute pancreatitis and atherosclerotic cardiovascular disease (ASCVD) 3. Diagnose HTG and its atherogenic sequelae 4. Acknowledge TG-lowering medications in development 5. Implement appropriate management of HTG

4 TG Range (mg/dl) <100 TG Categories: Names, Disease Risks, and Drug Approval Pathways NCEP ATP-III 1 AHA Statement 2 NLA Statement 3 Disease Risk FDA Optimal None Desirable <150 Normal Dyslipidemia Borderline High Borderline More dyslipidemia High High CVD >500 Very High Very High CVD & sl pancreatitis 4 (esp if >2000) No Rx interest Approve if CVD likely Approve if reasonable safety 1. Grundy, S, for the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Circulation. 2002;106: Miller, M, et al. AHA Statement, Circulation. 2011;123(20): All but Optimal are in the NLA Statement: Jacobson, TA, et al. J Clin Lip 2014;8: Risk of acute pancrea s at this level is mainly due to TG variability.

5 Prevalence of HTG in US Adults % 3.4 million Americans have very high TG Triglyceride Level (mg/dl) From Christian et al. Am J Cardiol 2011: 107: 891

6 Increasing Prevalence of HTG Parallels Increased Obesity in the US 15 Adults aged years Adults aged years 5x Abnormal TG (%) x NHANES II ( ) NHANES III ( ) NHANES ( ) Cohen J, et al. Poster at 2008 AHA Scientific Sessions. Ford ES, et al. Arch Intern Med. 2009;169: Christian JB, et al. Am J Cardiol. 2011;107:891-7.

7 Very-High and Severe HTG are Usually Genetic % of General Population 500 mg/dl * 885 mg/dl ** * Very High cutoff per AHA Consensus Panel Statement. ** Severe cutoff per EAS Consensus Panel. Adapted from Hegele et al. Lancet Diabetes & Endocrinology 2014; 2: 655. *Miller, M. Circulation 2011.

8 Metabolism of TG-Rich Lipoproteins

9 Normal Metabolism of TGRLp: Exogenous (Dietary Origin) Small intestine Bloodstream Lipoprotein Lipase Muscle and adipose tissue Fatty Acids Liver Remnant Receptor Hepatocyte Chylomicron Chylomicron Remnant 1. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20): Grundy SM. Atlas of atherosclerosis and metabolic syndrome. Chapters 4 and 5. 4th edition. Current Medicine LLC

10 Normal Metabolism of TGRLp: Endogenous (Hepatic Origin) Glycerol Cholesteryl ester Apo B VLDL TG:CE = 5:1 Triglyceride Fatty Acids TG within VLDL: derived from glycerol + fatty acids from plasma newly synthesized in the liver (fructose driven) Apo, apolipoprotein; VLDL, very low-density lipoprotein; CE, cholesteryl ester Kwiterovich PO. Johns Hopkins Textbook of Dyslipidemia ; Miller M, et al. Circulation. 2011;123: ; Grundy SM. Atlas of atherosclerosis and metabolic syndrome

11 Normal Plasma Metabolism of TGRLp: Hepatic Origin Normal Size VLDL Bloodstream Lipoprotein Lipase Muscle and adipose tissue IDL Fatty Acids Lipoprotein Lipase LDL receptor Hepatocyte LDL LDL receptor clears VLDL remnants, IDL & LDL IDL, intermediate-density lipoproteins; LDL, low-density lipoprotein Kwiterovich PO. Johns Hopkins Textbook of Dyslipidemia Miller M, et al. Circulation. 2011;123: Grundy SM. Atlas of atherosclerosis and metabolic syndrome

12 Cholesterol Enrichment of VLDL and Shrinkage of LDL & HDL Promoted by CETP in HTG VLDL Bloodstream Cholesterolenriched VLDL Muscle and adipose tissue Increased Triglycerides HDL Hepatic TG Lipase Small, Dense HDL HDL, high-density lipoprotein; LDL, low-density lipoprotein; CETP, cholesteryl ester transfer protein Miller M, et al. Circulation. 2011;123: Ginsberg HN. J Clin Invest. 2000;106(4): LDL Hepatic TG Lipase Small, Dense LDL CETP-mediated exchange affects composition and metabolism of VLDL, LDL, and HDL Occurs at all TG levels but is greatly increased w/ HTG, causing Atherogenic Dyslipidemia

13 Lipid Measurements in HTG Patients

14 Increasing Inaccuracy of Friedewald LDL-C with Increasing TG On routine lipid panel, LDL-C is calculated using the Friedewald Formula: LDL-C = Total Cholesterol HDL-C TG/5 Even modest increases in TG result in LDL-C underestimation using Friedewald formula Lindsey CC, et al. Pharmacotherapy. 2004;24: Absolute difference (mg/dl) Absolute underestimation of LDL-C (by Friedewald) by Fasting TG level Triglyceride Level (mg/dl)

15 Increasing Inaccuracy of Friedewald LDL-C with Increasing TG On routine lipid panel, LDL-C is calculated using the Friedewald Formula: LDL-C = Total Cholesterol HDL-C TG/5 Even modest increases in TG result in LDL-C underestimation using Friedewald formula Direct LDL-C solves this problem, but there may be a better solution Lindsey CC, et al. Pharmacotherapy. 2004;24: Absolute difference (mg/dl) Absolute underestimation of LDL-C (by Friedewald) by Fasting TG level Triglyceride Level (mg/dl)

16 What is Non-HDL-C? Triglyceride Cholesterol All atherogenic lipoproteins HDL LDL IDL VLDL Chylomicron remnant Apo AI Apo B100 Apo B100 Apo B Apo B48 non-hdl Non-HDL-C = Total cholesterol HDL-C 16

17 Non HDL-C Is Stronger than LDL-C in Predicting CHD Risk 2.5 Relative CHD Risk < LDL-C, mg/dl Non-HDL-C, mg/dl <160 Liu J, et al. Am J Cardiol. 2006;98: (Framingham Study)

18 Non-HDL-C Advantages vs other Lipid Parameters Stronger CVD risk predictor than TG (less variable, less loss w/ adjustments) Measures chol content of TG-rich lipos Stronger CVD risk predictor than LDL-C More stringent than LDL-C (only ~ ½ of pts at LDL-C goal also at Non-HDL-C goal) Valid non-fasting (not true for LDL-C) Valid in HTG (not true for LDL-C) ~Comparable to apo B/LDL-P, yet Free with basic lipid panel Guideline goal consensus (IAS, NLA, etc.)

19 TG Measurement: Summary Fasting TG is standard (12 hr, water ok) Non-fasting TG predicts CVD risk in populations 1 but too variable in individuals? If NF TG <200 mg/dl fasting TG not neces. 2 SD LDL remains important (see below) Remnant particle testing controversial Post-prandial (cumbersome, no standards) RLP-C easy but?accuracy?validation DGUC apo A-I/Rem ratio? 3 Beta-quant best to R/O type III 4 Other: NMR? ion mobility? Friedewald VLDL-C (=TG/5) is NOT remnants! 5 Non-HDL-C incl. all, is free, has consensus 1. Langsted A, et al. J Intern Med Jul;270(1): Miller, M, et al. Circulation. 2011;123(20): May, HT. Lipids Health Dis Apr 26;12: Hopkins, PN. Current Athero Reports in press. 5. Varbo, A. Circulation epub August 7.

20 Does HTG Cause Disease?

21 Pancreatitis Risk w/ TG >500 mg/dl HTG is the 3 rd biggest cause of acute pancreatitis (~10%) after alcohol & gallstones 1,2 Acute pancreatitis risk 4%/100 mg/dl TG* (HR, 1.04) 3 Crude Incidence (Cases/1000 Patient Years) Incidence of Acute Pancreatitis by TG 3 Group 1 Group 2 Group 3 < Triglycerides (mg/dl) *After adjustment for covariates and removal of patients hospitalized for gallstones, chronic pancreatitis, alcohol-related morbidities, renal failure, and other biliary disease. 1. Cybulska B, Klosiewicz-Latoszek L. Kardiol Pol. 2013;71(10): ; 2. Miller M et al. Circulation. 2011;123(20): ; 3. Murphy M et al. JAMA Intern Med. 2013;173(2): N=n=31,740, 31,887 and 3,642 for 3 TG strata w/ cutpoints 150 and 500 mg/dl

22 Proposed Mechanisms of VHTG-Induced Acute Pancreatitis* Large, TG-rich chylomicrons Impaired pancreatic capillary blood flow Modest pancreatic lipase leak FFA production Ischemia Inflammation ( FFA) Pancreatic acinar cell injury *VHTG = very high triglyceride. Gan SI, et al. World J Gastroenterol. 2006;12:

23 HTG Predicts CHD Risk (Meta-analysis of 29 Studies, N=262,525*) Groups CHD Cases Duration of Follow-up 10 years 5902 <10 years 4256 Sex Male 7728 Female 1994 Fasting Status Fasting 7484 Nonfasting 2674 Adjusted for HDL-C Yes 4469 No 5689 Overall CHD Risk Ratio* Decreased Risk Increased Risk CHD Risk Ratio* (95% CI) 1.72 (95% CI, ) 1 2 *3 rd vs 1 st tertile, adjusted for at least age, sex, smoking, other lipids & BP. Sarwar N et al. Circulation. 2007;115: Also: 22% CVD/ 88 mg/dl TG (61 studies N=330,566) Liu, J. Lipids in Health and Disease 2013, 12:159.

24 TG Predicts CAD Risk Beyond HDL-C Odds Ratio < HDL-C mg/dl < Triglycerides mg/dl Hopkins et al. J Am Coll Cardiol. 2005;45: Cases with Premature Familial CAD.

25 CHD Risk w/ TG 200, if > 500 mg/dl *Triglyceride odds ratio adjusted for HDL-C; n=653 (FHx early CHD), n=1029 (control) Hopkins, Hunt and Brinton. J Am Coll Cardiol. 2005;45:

26 Reduction of TG Pancreatitis & ASCVD (After Baseline TG >500 mg/dl) Pancreatitis < Triglycerides (mg/dl) Cardiovascular Events < Triglycerides (mg/dl) Adjusted Incidence Rate Ratio Repet TG at 6-24 wks. N=41,210 (2 large US claims databases). Christian J et al. Am J Med. 2014;127(1): Similar CHD Results from Copenhagen 4y f/u; N= 75,725. Jorgensen AB et al. New Eng J Med. 2014; 371:32-41.

27 HTG As a Cause of Atherosclerosis & CVD Biological mechanisms (selected) TGRLp Remnants senescence of endothelial precursors ( impaired endothelial repair) 1 Post-prandial TG endothelial microparticles, 2 inflammatory cytokines, 3 apoptosis 4 TG lipolysis FFA endothelial cell inflammation 5 * Apo C-III HTG AND vascular endothelial activation & monocyte adhesion (pro-inflam.) 6 HTG LDL size, HDL size/loss of apo A-I VLDL prod. HTG and apo B (pro-athero.) 1. Liu L, Atherosclerosis. 2009;202: Ferreira AC. Circulation. 2004;110: Norata GD. Atherosclerosis. 2007;193: Shin HK. Circulation. 2004;109: Wang L. J Lipid Res. 2009;50: Zheng C. Eur Heart J 2013;34: Ginsberg, HN. J Clin Invest. 2000;106: *Only factor specific for TG rather than TG-rich Lp

28 ApoC-III is Raises TG and is Anti-Endothelial, Pro-Inflammatory and Pro-atherogenic ApoC-lll TG & HDL metab Endothelial cells Monocytes LPL activity TRL clearance VLDL production HDL catabolism adhesion molecules NO production vasoconstriction ß1-integrin expression, TLR2 activation, and monocyte adhesion HTG/ Remn/ apo AI Endothelial Dysfunction/Inflammation Atherosclerotic Cardiovascular Disease LPL, lipoprotein lipase; TRL, triglyceride-rich lipoprotein; NO, nitric oxide; TLR2, toll-like receptor, 2 (an immune receptor which produces cytokines when activated). Caron S, et al. Circ Res. 2008;103: Pollin TI, et al. Science 2008;322;

29 HTG As a Cause of Atherosclerosis & CVD (cont) Genetic Evidence Mendelian randomization studies strongly suggest HTG causes CVD 1-3 Conclusion: In mild-to moderate [HTG], intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk Do R. Nature Genetics 2013, e-pub 6 October. 2. Hegele RA. Lancet, 2013 epub 23 December. 3. Holmes MV Eur HJ 2014, epub 27 January.

30 Mechanisms of Remnant Lipoprotein (RLP) Atherogenicity -----Arterial Lumen Subendothelial Space----- TG-rich LP Macrophage (MΦ) Foam Cell Lipoprotein Lipase CETP & LPL Inflammatory FFA MΦ Uptake foam cells Lipoprotein Lipase Lipid & Protein Oxidation RLP RLP Inflammatory FFA Cholesterol-rich remnant Lipoprotein (RLP) After McPherson R. J Am Coll Cardiol. 2013;61: and Wang L J Lipid Res. 2009;50; Dysfunctional Endothelium NO production Adhesion Molecules Permeability Plt activation Lipid & Protein Oxidation

31 Genetic Causes of HTG Somewhat Common but Controversial Familial combined hyperlipidemia (FCH) TG and Cholesterol levels (possibly also w/ HBP) believed due to genetic defects in one or more factors of lipoprotein metabolism (including Apo C-II, Apo C-III & CETP?) Familial hypertriglyceridemia (FHT) TG levels only (nl cholesterol), related to hepatic VLDL production and/or polygenic vs environmental LPL activity Relatively Rare to Very Rare Familial dysbetalipoproteinemia (Fredrickson Type III) Lipoprotein lipase (LPL) deficiency Apo C-II deficiency GPIHBP1 deficiency Others Note: genetic testing for HTG is rarely useful clinically and is not recommended for routine use CETP=cholesteryl ester transfer protein After Bays HE. Chapter 21 in The Johns Hopkins Textbook of Dyslipidemia. Kwiterovich, PO, Jr., ed. 2010; p

32 Does LDL Size Contribute to HTG Management?

33 LDL-C Doubly Underestimates CVD Risk With HTG/low HDL-C & Small, Dense LDL Apo B Cholesterol Ester (CE) Large LDL Fewer Particles & Less Risk/Particle Lipid profile: TC 198 mg/dl LDL-C 130 mg/dl TG 90 mg/dl HDL-C 50 mg/dl Non HDL-C 148 mg/dl Same LDL-C (130 mg/dl) Small, Dense LDL More Apo B Less CE/particle so more particles and CVD Risk! More Particles & More Risk/Particle Lipid profile: 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.

34 LDL-C Doubly Underestimates CVD Risk With HTG/low HDL-C & Small, Dense LDL Apo B Cholesterol Ester (CE) Large LDL Fewer Particles & Less Risk/Particle Lipid profile: TC 198 mg/dl LDL-C 130 mg/dl TG 90 mg/dl HDL-C 50 mg/dl Non HDL-C 148 mg/dl Same LDL-C (130 mg/dl) Small, Dense LDL More Particles & More Risk/Particle More Apo B Less CE/particle so more particles and CVD Risk! Basic lipid Lipid profile: panel shows TC 210 mg/dldifferences 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.

35 SD LDL Even at TG <100 mg/dl! 100 mg/dl Packard, C. Intl. J Cardiol 2000;74:S17-S22

36 SD LDL Predicts CVD Regardless of LDL-C SDLDL +/- LDL-C LDL-C +/- SDLDL Hoogeveen, RC. ATVB 2014;34: ARIC Study, N 11,000.

37 Non-HDL-C Best Predicts SD LDL Risk Factor Pearson R R 2 P value Non-HDL-C < Apo B < TG (log) < LDL-C < HDL-C < Hoogeveen, RC. ATVB 2014;34: ARIC Study, N 11,000.

38 SD LDL Summary Biology: SD LDL is pro-atherogenic Easier into subendothelial space Stickier to subendothelial matrix More readily oxidized Carries atherogenic proteins (e.g. apo C-III) Harder to clear via LDL-R Epidemiology: SD LDL predicts ASCVD SD LDL was discounted since not predictive of ASCVD w/ LDL-P; however, Discordance between LDL-P and LDL-C makes sense only re: LDL size, and LDL-P is weighted towards SD LDL, and SD LDL by new assay strongly predicts ASCVD; however, Non-HDL-C captures much of this assoc. Bottom line: LDL size is important mechanistically How to measure? Non-HDL-C, LDL-P, LDL sizing, new assay?

39 Management of HTG Patients

40 Statins do NOT Prevent All CHD Events (Residual Risk ~50-70%) 40 CHD events occur frequently in patients taking statins Patients Experiencing Major CHD Events, % Placebo Statin S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/ TexCAPS 6 N , 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:

41 Statins Reduce CVD Events in HTG Patients HOWEVER Trial (Subgroup, mg/dl) (Drug) WOSCOPS (TG 148) (Pravastatin) CARE (TG 144) (Pravastatin) PPP Project (TG 200) (Pravastatin) 4S (TG >159, HDL-C <39) (Simvastatin) JUPITER (TG 150) (Rosuvastatin) CTT (TG >177) (Various) Median follow-up: 5 yrs. Risk difference vs placebo P-value Main Study HTG Subgroup Main Study HTG Subgroup 31% 32% < % 15% % 15% < % 52% <0.001 < % 21% <0.001 NS 21% 24% <0.001 <0.001 CARE=Cholesterol and Recurrent Events Trial; CTT=Cholesterol Treatment Trialists; JUPITER=Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin; NS=not significant; PPP=Prospective Pravastatin Pooling; 4S=Scandinavian Simvastatin Survival Study; WOSCOPS=West of Scotland Coronary Prevention Study. Ballantyne et al. Circulation. 2001;104: CTT Collaborators. Lancet. 2005;366: Maki et al. J Clin Lipidol. 2012;6:

42 TG >150 mg/dl Increases CHD Risk* Even when LDL-C <70 on a Statin (PROVE IT-TIMI 22 Subanalysis) 17.9% Rate of CHD After 30 days (%) HR 0.72 (0.54,0.94) TG <150 HR 16.5% 0.85 (0.67,1.08) HR P= % (0.65, 1.09) P= % P=0.192 TG 150 Ref LDL-C <70 LDL-C 70 Lipid values in mg/dl *CHD = Death, MI, and recurrent ACS. HR = Hazard Ratio Miller M, et al. J Am Coll Cardiol. 2008;51: N=3718.

43 TG >150 mg/dl Increases CHD Risk* Even when LDL-C <70 on a Statin (PROVE IT-TIMI 22 Subanalysis) Rate of CHD After 30 days (%) TG <150 HR 16.5% 0.85 (0.67,1.08) HR P= % (0.65, 1.09) HR 0.72 (0.54,0.94) P= % P=0.192 TG % Ref Statin monorx is not enough in HTG/lowHDL-C Patients! LDL-C <70 LDL-C 70 Lipid values in mg/dl *CHD = Death, MI, and recurrent ACS. HR = Hazard Ratio Miller M, et al. J Am Coll Cardiol. 2008;51: N=3718.

44 Treatment of HTG: Begin with 2 o Causes High fructose/sucrose/carbohydrate intake Low fiber intake Ethanol (also tobacco? also THC?) Sedentary lifestyle/calorie excess Central obesity/insulin resistance DM2 (or 1) esp. if poor glycemic control Hypothyroidism (check TSH!!) Nephrotic syndrome Medications: Antiretrovirals Oral estrogens Systemic glucocorticoids Retinoic acid derivatives Minor effects (some antipsychotics, nonselective beta-blockers, thiazide diuretics, etc.) After Bays HE. In The Johns Hopkins Textbook of Dyslipidemia. Kwiterovich, PO Jr., ed. 2010;

45 TG-Lowering Medications

46 TG Medications: Which? When? If TG 500 mg/dl: Rx all to prevent pancreatitis (& ASCVD) If TG mg/dl: consider Rx to prevent ASCVD* TG-Lowering 1 o for TG o for TG o for TG o for TG 500 Drug/class Triglycerides Fenofibrate 20-50% Omega-3 oil (EPA +/- DHA; EE vs FFA) 20-45% (pharmacologic doses) Niacin 20-50% Statins** 7-30% **High-intensity statin Rx will TG 20-50% in pts with HTG After: *Expert Panel on Detection, Evaluation & Treatment of High Blood Cholesterol in Adults. JAMA 2001: 285: Robinson JG, Stone NJ. Am J Cardiol 2006; 98(suppl):39i-49i. Robinson JG, Davidson MH. Expert Rev Cardiovasc Ther 2006; 4: Briel M, et al. BMJ 2009: 338:b92. Miller M et al. Circulation. 2011;123: *Chapman MJ et al. Eur Heart J. 2011;32(11):

47 Fenofibrate Formulations: A Confusing Mess! Available Fenofibrate Doses (mg/day) Regular dose Reduced dose* Brand Name ** Lofibra /50 Lofibra /Triglide Lipofen Tricor Trilipix *** Antara Fenoglide Antara Bottom line: pick the one that works best for your patient s payer *primarily for renal or geriatric patients ** also available at 134 mg ***fenofibric acid (See FDA-approved prescribing information for further details)

48 Choice of Prescription Om-3 EE EPA+DHA* EE EPA only** FFA EPA+DHA*** Generic available? Yes No No EPA/DHA (total) 55/45 (84%) 100/0 (98%) 73/27 (75%) Bioavailability (short-term) Good Good Excellent Regimen 2 bid w/ meals 2 bid w/ meals 2 or 4 qd meal indep. Tolerability issues Fishy taste & ±Arthralgia only Fishy eruct, dyspeps, eruct, dyspeps diarrhea, nausea TG-lowering LDL-C effects /± ±/ /± HDL-C effects ±/ CVD? Not at low dose, no ongoing trials Probably (middose) +ongoing trial No data, but ongoing trial *Lovaza PI. Davidson MH et al Clin Ther 2007;29: ORIGIN Investigators. N Engl J Med. 2012;367: Risk & Prevention Investigators N Engl J Med 2013;358: **Vascepa PI. Yokoyama M et al. Lancet. 2007;369: Bays HE, et al. Am J Cardiol. 2011;108: Ballantyne CM et al Am J Cardiol 2012;110: ***Epanova PI. Davidson MH, J Clin Lipidology, 2012, 6:573. Offman E, Vasc Health Risk Manag. 2013; 9; Kastelein, JJP; J Clin Lip 2013 epub 10 Oct.. Maki KC et al Clin Ther 2013;35:

49 Fenofibrate vs Om-3 vs Niacin as TG/HDL Statin Adjuncts Fenofibrate Rx Omega-3 Niacin Δ TG Δ LDL-C to to to to Δ Non-HDL-C to to to Δ HDL-C to to to CVD Efficacy 0 to + 0 to to + Mortality Non-CVD Benefits 0 to ++ 0 to ++? 0 Access (cost/month) $ $ $ Natural Safety + to +++ to 0 Tolerability ++ to ++ to to 0 Ease of use to ++ 71

50 Fenofibrate vs Om-3 vs Niacin as TG/HDL Statin Adjuncts Fenofibrate Rx Omega-3 Niacin Δ TG Δ LDL-C to to to to Δ Non-HDL-C to to to Δ HDL-C to to to CVD Efficacy 0 to + 0 to to + Mortality Non-CVD Benefits 0 to ++ 0 to ++? 0 Access (cost/month) $ $ $ Natural Safety + to +++ to 0 Tolerability ++ to ++ to to 0 Ease of use to ++ 72

51 Fenofibrate vs Om-3 vs Niacin as TG/HDL Statin Adjuncts Fenofibrate Rx Omega-3 Niacin Δ TG Δ LDL-C to to to to Δ Non-HDL-C to to to Δ HDL-C to to to CVD Efficacy 0 to + 0 to to + Mortality Non-CVD Benefits 0 to ++ 0 to ++? 0 Access (cost/month) $ $ $ Natural Safety + to +++ to 0 Tolerability ++ to ++ to to 0 Ease of use to ++ Bottom line: Feno or Om-3 are 1 st line for TG, Niacin for HDL, combos good. 73

52 Investigational TG-Lowering Agents ISIS-APOCIII Rx : apo C-III antisense (ISIS) Pradigastat: intestinal DGAT1 inhibitor (ISIS/Novartis) ARI-3037MO: Niacin analog (Arisaph) CAT-2003: oral -3 + niacin, intracellular (Catabasis) Diazoxide Choline Controlled Release (DCCR): K ATP channel agonist (Essentialis)

53 HTG: Should We Treat? Yes! TG>~100: assume ASCVD risk (statin Rx) TG ASCVD risk even w/ statin! Test for remnants if TC TG & both > ~250 Diet: calories, fructose, EtOH (in ~all) Physical activity (in ~all) Glycemia (if DM or IR) Rx w/ medications: Statins (if ASCVD risk), and If HTG persists: consider fibrate, om-3, niacin TG >500 pancreatitis and ASCVD! Diet: fat, calories, EtOH, ( fructose) Physical activity Glycemia (if DM) Rx: om-3, fibrate, (niacin, statin)