Absence of Clinical Outcome Trials in Treating Hypertriglyceridemia: What is a Clinician To Do?

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1 Absence of Clinical Outcome Trials in Treating Hypertriglyceridemia: What is a Clinician To Do? Terry A. Jacobson MD FAHA FNLA Director, Lipid Clinic and Cardiovascular Risk Reduction Program Professor of Medicine Emory University Atlanta, GA

2 Outline Prevalence of hypertriglyceridemia (HTG) Epidemiology and genetics of HTG and CV Disease Relationship of HTG and other atherogenic lipids (Non-HDL-C, Apo B, LDL-P, and low HDL) Guidelines for HTG management HTG management: lifestyle and drug therapy

3 Overall Prevalence of Hypertriglyceridemia in NHANES (%) Triglyceride Cut Points, mg/dl Demographic Overall (age 20 y) Men Women Mexican American Non-Hispanic, black Non-Hispanic, white Miller M et al. Circulation. 2011;123(20):

4 TG Levels in Patients Hospitalized with Coronary Artery Disease in US ( ) TG (mg/dl) <150 >150 N=136,905 Patients (%) % had TG >150 mg/dl (1.7 mmol/l) TG Level (mg/dl) Sachdeva A et al. Am Heart J. 2009;157: e2.

5 Groups 10 years 5902 <10 years 4256 Sex TG and CHD Risk: Meta-Analysis of 29 Studies Male 7728 Female 1994 Fasting Status Fasting 7484 Nonfasting 2674 Adjusted for HDL Yes 4469 No 5689 CHD Cases Decreased Risk Sarwar N, et al. Circulation. 2007;115: CHD Risk Ratio* (95% CI) Overall CHD Risk Ratio* 1 Increased Risk *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 (95% CI, ) 2 N=262,525

6 TG Level Is an Excellent Predictor of CV Risk in Apparently Healthy Women Direct comparison of 26 lipid fractions as predictors of first-ever CV events in 27,533 apparently healthy women Median F/U 17.2 yrs 1070 coronary events Total HDL NMR particles 0.91 Medium HDL NMR particles 1.00 LDL NMR size (lowest quintile)* 1.06 Small HDL NMR particles 1.22 VLDL NMR size 1.37 Large LDL NMR particles 1.44 Medium VLDL NMR particles 1.46 IDL NMR particles 1.48 HDL NMR size (lowest quintile) 1.54 LDL NMR size (lowest quintile) 1.56 Small VLDL NMR particles 1.56 Apolipoprotein A-1 (lowest quintile) 1.59 Small LDL NMR particles 1.63 Total VLDL NMR particles 1.71 Large HDL NMR particles (lowest quintile) 1.72 LDL-cholesterol 1.74 Large VLDL NMR particles 1.77 HDL-cholesterol (lowest quintile) 1.92 Total cholesterol 2.08 LDL NMR : HDL NMR particles 2.25 Total LDL NMR particles 2.51 Non-HDL cholesterol 2.52 Apolipoprotein B Triglycerides 2.58 Apolipoprotein B 100 : apolipoprotein A Total cholesterol: HDL cholesterol Adjusted hazard ratio (95% CI) for incident CV disease (log scale) Data are shown for the top vs bottom quintile of each lipid fraction, unless otherwise indicated. *Additionally adjusted for total LDLnmr particle concentration. Additionally adjusted for the other NMR proteins. LDL-C was measured directly; Non-HDL-C was calculated; Apo B was measured with immunoassay; LDL-P was measured with NMR spectroscopy. Mora S et al. Circulation. 2014;129:

7 APOC3 Loss-of-Function Mutations with Risk of Coronary Heart Disease among 110,970 Participants in 15 Studies The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. N Engl J Med 2014;371:22-31

8 Cumulative Probability of Freedom from Coronary Heart Disease (CHD) According to Plasma Level of APOC3 at Baseline in the Framingham Heart Study The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. N Engl J Med 2014;371:22-31

9 Statins Reduce CVD Events in HTG Patients (HTG Subgroup Data) 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) Risk difference vs placebo (P-value) All subjects HTG subgroup 31% (<0.001) 32% (0.003) 24% (0.003) 15% (0.07) 23% (<0.001) 15% (0.029) 34% (<0.001) 52% (<0.001) 44% (<0.001) 21% (NS) CTT (TG >177) (Various) Median follow-up: 5 yrs. 21% (<0.001) 24% (<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 CM et al. Circulation. 2001;104: CTT Collaborators. Lancet. 2005;366: Maki KC et al. J Clin Lipidol. 2012;6:

10 Residual Cardiovascular Disease Risk in Major Statin Trials On-treatment LDL-C (mg/dl) Patients Experiencing Major CHD Events, % CHD events occur in patients treated with statins S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/ TexCAPS 6 JUPITER 7 N , S Group. Lancet. 1994;344: LIPID Study Group. N Engl J Med. 1998;339: Sacks FM et al. N Engl J Med. 1996;335: Secondary High Risk Primary Placebo Statin ,802 4 HPS Collaborative Group. Lancet. 2002;360: Shepherd J et al. N Engl J Med. 1995;333: Downs JR et al. JAMA. 1998;279: Ridker PM et al. N Engl J Med. 2008;359:

11 TG 150 mg/dl Predicts Higher CHD a Risk Despite Having an LDL-C <70 mg/dl on a Statin PROVE IT- TIMI 22 Trial b (N=4162) CHD Event Rate after 30 Days c (%) % HR: 0.72 P=0.017 LDL-C <70 mg/dl TG <150 mg/dl 16.5% HR: 0.84 P=0.192 TG 150 mg/dl Referent LDL-C 70 mg/dl TG 150 mg/dl Event Rate=17.9% a Death, MI, and recurrent ACS. b ACS patients on atorvastatin 80 mg or pravastatin 40 mg. c Adjusted for age, gender, low HDL-C, smoking, hypertension (HTN), obesity, diabetes, prior statin therapy, prior ACS, peripheral vascular disease, and treatment. CHD=coronary heart disease; HR=hazard ratio; PROVE IT-TIMI=Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis In Myocardial Infarction. Miller M et al. J Am Coll Cardiol. 2008;51:

12 Non-HDL-C Includes Cholesterol in All Atherogenic Lipoproteins Non HDL-C (TC HDL-C) VLDL IDL LDL Lp(a) Very-low-density lipoprotein Made in the liver, takes lipids to periphery Apo-B, C-I, C-II, C-III, -E) TG >> CE Intermediate-density lipoprotein Formed from VLDL with loss of TG Apo E>>Apo B TG CE Low-density lipoprotein Formed from IDL with loss of TG; main plasma cholesterol carrier; Apo B CE >> TG Lipoprotein (a) Formed from LDL plus Apo (a) Very atherogenic/pro-oxidative HDL CE=cholesterol ester; TC=total cholesterol. High-density lipoprotein Apo A Removes cholesterol from peripheral tissue

13 The Framingham Study: Non HDL-C Is Superior to LDL-C in Predicting CHD Risk Within non HDL-C levels, no association was found between LDL-C and the risk for CHD In contrast, a strong positive and graded association between non HDL-C and risk for CHD occurred within every level of LDL-C Non HDL-C is a stronger predictor of CHD risk than LDL-C Relative CHD Risk < LDL C, mg/dl <160 Non HDL C, mg/dl Liu J, et al. Am J Cardiol. 2006;98:

14 Non-HDL-C 130 mg/dl Is a Better ASCVD Risk Predictor Compared With LDL-C 100 mg/dl Meta-analysis data at baseline and at 1-year follow-up from 62,154 patients enrolled in 8 randomized controlled statin trials published Target Level LDL-C (mg/dl) Non- HDL-C (mg/dl) Major CV Events (n) Subjects (n) HR (95% CI) , ( ) 100 < ( ) < ( ) <100 < , [ref.] Boekholdt M et al. JAMA. 2012;307: HR (95% CI)

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16 ATP III Treatment Recommendations for Elevated TGs TG (mg/dl) ATP III Classification Primary Target of Therapy Treatment Recommendations Borderline High TG LDL-C goal Weight reduction, increased physical activity High TG LDL-C goal Weight reduction, increased physical activity; consider drug therapy to achieve non HDL-C goal (intensify LDL-C lowering with statin or lower VLDL-C by adding niacin or fibrate) 500 Very High TG Reduce TG to prevent acute pancreatitis Very low fat diet (fat 15% of total calories), weight reduction, increased physical activity, and drug therapy with niacin or fibrate ATP III Panel. Circulation 2002; 106(25):

17 ATP III LDL-C Goals and Cut-points for Drug Therapy Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy High risk: CHD or CHD risk equivalents (10-year risk >20%) Moderately high risk: 2+ risk factors* (10-year risk 10% to 20%) Moderate risk: 2+ risk factors* (10 year risk <10%) Lower risk: 0-1 risk factor* <100 mg/dl (optional goal: <70) <130 mg/dl (optional goal: <100) 100 mg/dl 130 mg/dl >100 mg/dl (<100 mg/dl: consider drug options) >130 mg/dl ( mg/dl: consider drug options) <130 mg/dl 130 mg/dl >160 mg/dl <160 mg/dl 160 mg/dl >190 mg/dl ( mg/dl: LDL-C lowering drug optional) *Risk factors for CHD include: cigarette smoking, hypertension (blood pressure >140/90 mmhg or on antihypertensive medication, HDL-C <40 mg/dl (>60 mg/dl is a negative risk factor), family history of premature CHD, age >45 years in men or >55 years in women ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes Source: Grundy S et al. Circulation 2004;110:

18 ADA/ACC 2008 Consensus Statement Treatment Goals in Patients with Cardiometabolic Risk and Lipoprotein Abnormalities Goals LDL-C Non-HDL C Apo B Highest-Risk Patients Known CVD Diabetes plus 1 additional major CVD risk factor a High-Risk Patients No diabetes or known CVD but 2 major CVD risk factors a Diabetes but no other major CVD risk factors a <70 mg/dl <100 mg/dl <80 mg/dl <100 mg/dl <130 mg/dl <90 mg/dl In individuals on statin therapy who continue to have low HDL-C or elevated non-hdl C, especially if Apo B levels remain elevated, combination therapy is recommended. a Major risk factors beyond dyslipidemia include smoking, hypertension, and family history of premature CHD Brunzell JD, et al. Diabetes Care. 2008;31:

19 NLA: Targets of Therapy Atherogenic Cholesterol Atherogenic cholesterol (non-hdl-c and LDL-C) levels are the primary targets of therapy Non-HDL-C is listed first because the panel consensus was that it is a better primary target than LDL-C Non-HDL-C is more predictive of ASCVD risk than LDL-C in observational studies, and with regard to changes or on-treatment levels in clinical trials When non-hdl-c and LDL-C are discordant, risk is more closely aligned with non-hdl-c Non-HDL-C testing is universally available, requires no additional cost, and may be obtained in the non-fasting state Jacobson TA et al. J Clin Lipidol. 2014;8:

20 Risk Category 2014 NLA Recommendations: Criteria for ASCVD Risk Assessment, Treatment Goals, Levels at which to Consider Drug Therapy Criteria Treatment Goal Consider Drug Therapy Low 0 1 major ASCVD risk factors Consider other risk indicators, if known Moderate 2 major ASCVD risk factors Consider quantitative risk scoring Consider other risk indicators High 3 major ASCVD risk factors Diabetes mellitus* (Type 1or 2) 0 1 other major ASCVD risk factors, and No evidence of end organ damage Chronic kidney disease stage 3B or 4 LDL C 190 mg/dl (severe hypercholesterolemia) Quantitative risk score reaching the high risk threshold Very High ASCVD* Diabetes mellitus* (Type 1or 2) 2 other major ASCVD risk factors or Evidence of end organ damage <130 <100 <130 <100 Non HDL C mg/dl LDL C mg/dl *For patients with ASCVD or diabetes mellitus, consideration should be given to use of moderate or high intensity statin therapy, irrespective of baseline atherogenic cholesterol levels. 20 <130 <100 <100 <

21 National Lipid Association Recommendations: Drug Therapy For TG Reduction A drug targeting TG reduction should be considered for first-line therapy in those with TG 500 mg/dl TG lowering drug therapies include fibric acids, high-dose longchain omega-3 fatty acids, and nicotinic acid A statin may be a reasonable first-line agent if TG is 500 mg/dl but <1000 mg/dl, and no history of pancreatitis Combination therapy with a statin plus a second (or third) agent may be considered for patients who have not reached their treatment goals for atherogenic cholesterol levels, particularly in those at high and very high risk Jacobson TA et al. J Clin Lipidol. 2014;8:

22 NLA: Targets of Therapy Triglycerides An elevated TG level is not a target of therapy per se, except when very high (severe; 500 mg/dl) When TG levels are between mg/dl, the targets of therapy are non-hdl-c and LDL-C When the TG concentration is very high ( 500 mg/dl, and especially if 1000 mg/dl), reducing the concentration to <500 mg/dl to prevent pancreatitis becomes the primary goal of therapy Jacobson TA et al. J Clin Lipidol. 2014;8:

23 Effects of Nutrition Practice Changes on TG Lowering Can Be Dramatic Dietary Change TG Lowering Weight loss of 5% to 10% of body weight 20% Mediterranean-style diet (vs high-carbohydrate diet) 10% 15% Add marine-derived PUFA (EPA/DHA) (per gram) 5% 10% Decrease carbohydrates: 1% Energy replacement with MUFA/PUFA 1% 2% Each 1% replacement of trans fatty acids for MUFA or PUFA 1% MUFA= monounsaturated FA; PUFA=polyunsaturated FA. Miller M et al. Circulation. 2011;123:

24 AHA Scientific Statement: Treatment Effect by Drug Class for Lowering Triglyceride Levels Drug Fibrates Immediate release niacin Omega 3 Extended release niacin Statins Ezetimibe % Triglyceride Reduction Miller M et al. Circulation. 2011;123:

25 Fibrates: Helsinki Heart Study 4,081 men aged yrs with non-hdl cholesterol 200 mg/dl, initially free of coronary disease. LDL-C 11%, HDL-C + 11% 34% reduction in CHD endpoints. Greatest benefits when initial triglyceride high and initial HDL-C low. LDL-C/HDL-C > 5.0 and TRIG >200 mg/dl risk reduced by 71% Cumulative MIs+CV Deaths, % Years 25 Frick MH, et al. N Engl J Med. Nov ;317(20):

26 Helsinki Heart Study: Incidence of CHD Events Incidence of Cardiac Events, per Person-Years Gemfibrozil Placebo 0 mg/dl: TG 200 TG 200 HDL-C 42 TG 200 TG 200 HDL-C 42 Manninen V, et al. Circulation. 1992;85:37-45.

27 Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) Double-blind study Gemfibrozil (600 mg BID) versus placebo 2,531 men with CHD, LDL-C 140 mg/dl, and HDL- C 40 mg/dl Mean age: 64 y (76.5% aged > 60 y) Study duration: 7 y Median follow-up: 5.1 y Primary end point: nonfatal MI or coronary death Rubins HB et al. N Engl J Med 1999;341:

28 The VA High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT): Baseline Values Placebo, Gemfibrozil, Characteristic n=1267 n=1264 Age, y 64±7 64±7 Age >60 years, % Prior MI, % Time since MI, y 6±6 6±6 Diabetes, % Insulin resistant, % Hypertension, % LDL-C, mg/dl 112±23 111±22 HDL-C, mg/dl 32±5 32±5 Triglycerides, mg/dl 160±67 161±68 Plus minus values are means ± SD. Rubins HB, et al. N Engl J Med. 1999;341: Robins SJ, et al. Diabetes Care. 2003;26:

29 VA-HIT: Cumulative Incidence of CHD Death and Nonfatal MI Cumulative Incidence, % Placebo Gemfibrozil -22% p=0.006 Rubins HB, et al. N Engl J Med. 1999;341: Year 29

30 Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Design: Multicenter, randomized, double-blind, placebo-controlled trial Subjects: 9,795 patients with type 2 diabetes aged years with and without CHD Entry lipid criteria: TC = mg/dl, plus either TC-to-HDL-C ratio >4 or TG > 89 mg/dl Excluded TG > 443mg/dl Treatment: Fenofibrate 200 mg once daily or placebo for 5 years Primary end point: CHD death plus nonfatal MI Keech A, et al. Lancet. Nov ;366(9500):

31 FIELD: Primary and Secondary End Points 11% Reduction P = Placebo Fenofibrate Event Rate, % % Reduction P = % Reduction P = % Increase P = % Reduction P = CHD Events* (Primary EP) Nonfatal MI CHD Death *Nonfatal MI and CHD death. MI, stroke, CVD death, revascularizations. Keech A, et al. Lancet. 2005;366: Keech A, et al. Atheroscler Suppl. 2006;7:342. Abstract We-S15:2. Total CVD Events (Secondary EP) Coronary Revascularization

32 FIELD: Baseline Characteristics Characteristic Placebo (n = 4,900) Fenofibrate (n = 4,895) Male, % No Prior CVD, % Lipid parameters, nmol/l TC LDL-C HDL-C TG Dyslipidemic*, % *TG >150 and HDL-C <40 mg/dl for men or <50 mg/dl for women The FIELD Study Investigators. Lancet. 2005; 366(9500):

33 Statin and Fenofibrate in DM ACCORD Trial N Engl J Med 2010;362:1563

34 ACCORD: Statin and Fenofibrate in DM Fenofibrate Placebo Hazard ratio P value Subgroup % of events (n) (95% CI) for interaction Fenofibrate Placebo better better N Engl J Med 2010;362:1563

35 Fibrates in Patients with High TG and Low HDL-C: A Meta-analysis of Randomized Fibrate Trials A Subjects with Dyslipidemia B Subjects without Dyslipidemia B Complementary Subgroups Without Dyslipidemia With Dyslipidemia = TG 204mg/dL and HDL-C 34mg/dL Sacks FM, Carey VJ, Fruchart JC. N Engl J Med. 2010;363(7): Copyright 2010 Massachusetts Medical Society.

36 AIM HIGH Study Design: ER Niacin Added to Statin Therapy Open-Label Run-In: Up-Titrate Niacin from 500mg to 2,000mg/day 4-8 weeks ER Niacin mg/day simvastatin Adjust simva to LDL mg/dl R Placebo mg/day simvastatin Follow to end of study Months Relative to Randomization

37 AIM HIGH-Primary Outcome Cumulative % with Primary Outcome Monotherapy Combination Therapy HR 1.02, 95% CI 0.87, 1,21 Log-rank P value= 0.79 Combination Therapy Monotherapy N at risk Time (years) % 16.2%

38 Post-hoc Analysis of AIM-HIGH: Niacin ER in Patients with HTG & Low HDL-C # Patients with CV Events ERN ERN HR (% of Category) Better Worse (95% CI) P-value *Highest tertile of TG and lowest tertile of HDL-C. Heterogeneity by treatment. All measurements in mg/dl. ER=extended release. Guyton JR et al. J Am Coll Cardiol. 2013;62: Guyton JR et al. Paper presented at: AHA SS; Nov. 6, 2012; Los Angeles, CA.

39 HPS2-THRIVE: Randomized Placebocontrolled Trial of ERN and LRPT N=25,673 with Pre-existing CVD Baseline Lipids on Statin-based Rx Lipid Mean (SDM) at baseline, mg/dl TC 128 (22) Direct LDL 63 (17) HDL-C 44 (11) TG 125 (74) Patients Suffering Events (%) Effect of ERN / LRPT on Major Vascular Events* Risk ratio 0.96 (95% CI ) Log-rank P= % 14.5% 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. HPS2-THRIVE=Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events; LRPT=laropiprant; SDM=standard deviation of the mean. HPS2-THRIVE Collaborative Group. N Engl J Med. 2014;371:

40 HPS2-THRIVE: MAJOR VASCULAR EVENTS by baseline lipids mg/dl (mmol/l) Randomized allocation ERN/LRPT Placebo (12838) (12835) Risk ratio & 95% CI HDL cholesterol <35 (0.9) 388 (15.8%) 399 (16.3%) < (13.7%) 546 (13.5%) (p=0.66) 43 (1.1) 748 (11.9%) 813 (12.8%) LDL cholesterol <58 (1.5) 724 (14.7%) 679 (13.8%) < (12.4%) 761 (13.7%) (p=0.02) 77 (2.0) 287 (12.0%) 318 (13.5%) Triglycerides <89 (1.0) 541 (13.2%) 563 (13.4%) < (12.8%) 712 (13.2%) (p=0.42) 151 (1.7) 461 (13.9%) 483 (14.8%) Het or trend Χ² (uncorrected p value) All 1696 (13.2%) 1758 (13.7%) 3.5% SE 3.3 reduction ERN/LRPT better Placebo better

41 n > 18,000 (Japan) All administered statins 1 o & 2 o prevention 5 yr f/u 1,800 mg EPA/day Mean TG= 150 mg/dl Yokoyama M et al. Lancet 2007;370:215

42 Addition of Eicosapentaenoic Acid (EPA) to Statin Therapy in Japanese Patients Major CHD Events * Lipid Effects Event rate (%) % Reduction P= Change from baseline (%) Statin (n=9319) Statin + EPA 1.8 g (n=9326) P< Statin -40 LDL-C TC TG *Sudden cardiac death, fatal and non-fatal MI, unstable angina, angioplasty, stenting, or CABG. CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; TC=total cholesterol. Yokoyama M et al. Lancet. 2007;369:

43 Patient Subgroup TG >150 mg/dl and HDL <40 mg/dl: JELIS Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: Sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS) Saito S, et al. Atherosclerosis. 2008;199:

44 Mozaffarian, D. et al. JAMA 2006;296:

45 Ongoing Trials Investigating Treatment of HTG in Patients on Statin Therapy OM-3 type Dose REDUCE-IT 1 (Ongoing) EPA 4 g/day STRENGTH 2 (Ongoing) EPA+DHA (FFA) 4 g/day Population International International N ~8000 Estimated 13,000 Gender Accrual ongoing Initiating accrual Risk Profile TG >150 mg/dl +CHD or CHD risk High CV risk (50%), prior ASCVD (50%) Follow-up 4 6 years (planned) 3-5 years (planned) Statin Use Primary End Point 100% (at LDL-C goal) Expanded Major adverse cardiac event 100% (at LDL-C goal) Expanded Major adverse cardiac event Result Powered for 15% RRR Powered for 15% RRR Baseline TG >200 mg/dl 200 mg/dl, <500 mg/dl 1,2.

46 Summary Hypertriglyceridemia is increasing in prevalence due to increasing obesity, type II DM, and insulin resistance in the population Although statin treatment effectively reduces CVD risk in most populations, residual CVD risk remains high in CHD and DM patients, likely due to the presence of other atherogenic lipoproteins (Non-HDL-C,Apo B, LDL-P) Combination therapy with statins and TG lowering drugs shows great promise in correcting most atherogenic lipid abnormalities, with subgroup analysis suggesting more benefits in those with HTG and low HDL-C Maximizing the statin dose first is the best initial CV risk reduction strategy in patients with HTG ( mg/dl), followed by the use of evidence based TG lowering therapy

47 Clinical Outcome Studies Evaluating High TG Subgroups Trial (Drug) Primary Endpoint: Entire Cohort (P-value) Lipid Subgroup Criterion Primary Endpoint: Subgroup (P-value) Pre-statin era HHS (Gemfibrozil) -34% (0.02) TG > 204 mg/dl LDL-C/HDL-C > % (0.005) BIP (Bezafibrate) -9.4% (0.26) TG > 200 mg/dl HDL-C <35 mg/dl -42% (0.02) Some statin use FIELD (Fenofibrate) (no statins at entry) -11% (0.16) TG > 150 mg/dl -12% (0.07) Statin addon ACCORD (Fenofibrate/simva) -8% (0.32) TG > 204 mg/dl HDL-C < 34 mg/dl -31% (0.0567) JELIS (ethyl EPA) (simva & prava) -19% (0.011) TG > 150 mg/dl HDL-C < 40 mg/dl -53% (0.043)