Lipid Management: Beyond LDL

Transcription

1 Lipid Management: Beyond LDL Lisa R. Tannock MD Division of Endocrinology and Molecular Medicine University of Kentucky Overview Discuss the concept of residual risk Review current evidence-based medicine for therapies other than statins 1

2 Major CVD Risk Factors High LDL/ Low HDL Smoking Diabetes Hypertension Age Gender Prevalence of CVD* in Adults * Includes CHD, CHF, stroke and HTN 2

3 Burden of Coronary Artery Disease in the US 24 Americans die of CVD each day CVD deaths equal cancer, respiratory diseases, accidents and diabetes combined If all forms of major CVD were eliminated, life expectancy would increase 7 yrs; cancer 3 yrs American Heart Association. 22 Heart and Stroke Statistical Update. LDL-C Lowering With Statins: Reduced CHD Events 25 Secondary Prevention Primary Prevention 4S-PL CARE-Rx LIPID-Rx HPS-Rx TNT-1 TNT-8 ASCOT-Rx 4S-Rx LIPID-PL CARE-PL HPS-PL AFCAPS-PL ASCOT-PL AFCAPS-Rx WOSCOPS-Rx WOSCOPS-PL LDL Cholesterol (mg/dl) Adapted from Illingworth DR. Med Clin North Am. 2;84:

4 HPS: Statin Benefit Independent of Baseline LDL Risk ratio and 95% CI Lipid Levels at Entry Simvastatin (1,269) Placebo (1,267) STATIN Better PLACEBO Better LDL cholesterol (mg/dl) < < ALL PATIENTS % SE 3 reduction (2P<.1) HPS Collaborative Group. Lancet. 22;36:7-22. Summary of Clinical Trial Findings in LDL-C results in in CHD morbidity/ mortality Studies support treatment in various patient groups women elderly diabetics more moderate hyperlipidemia 4

5 Risk Assessment - LDL Goals Risk Category 1 Year Risk LDL Goal (mg/dl) LDL level for Drug Rx CHD or equivalent (Diabetes) >2% <1 Optional: <7* 1* (>1 optional) 2+ risk factors 2% <13 <1 optional* 13 (1-2% risk) (>1 optional) 16 (<1% risk) -1 risk factor <1% <16 19 NCEP ATP III guidelines, with 24 update* ATP III: JAMA 21; 24 update: Circulation 24 Relative Risk Reduction in Major Coronary Events, % Despite LDL Lowering: Residual Risk S 34% 24% CARE 31% WOSCOPS 24% LIPID 4% AFCAPS HPS 27% Residual Risk 19% PROSPER 36% ASCOT 1 5

6 Patients at or Below LDL-C of 1 mg/dl Have Events 67% n=2,191 33% Of 2,191 statin-treated patients who experienced a CV/CB event, 67% were at LDL-C of 1 mg/dl Among patients with a CV/CB event and With LDL-C <1 mg/dl, 38.6% had low HDL-C and/or elevated triglycerides With LDL-C >1 mg/dl, 43.9% had low HDL-C and/or elevated triglycerides LDL-C <1 mg/dl LDL-C >1 mg/dl CV=cardiovascular; CB=cerebrovascular. Patients were on statin therapy 6 weeks; >2 years pre- and post-statin history with laboratory data; no concomitant lipid-lowering drugs; and 1 complete lipid profile pre- and post-statin initiation. Patients were followed for up to 5 years. Phatak H et al. Poster presented at the European Atherosclerosis Society Congress; June 1 13, 27: Helsinki, Finland. Poster P Beyond LDL Low HDL and elevated TG and sdldl closely correlate Typically seen in central obesity and metabolic syndrome patients TG: Non-HDL is secondary target with goal 3 mg/dl higher than LDL goal Low HDL: Levels > 4 mg/dl desirable but no target yet defined Other lipid parameters 6

7 CV Risk: HDL-C and LDL-C Interaction Data From Framingham Study 3. For any level of LDL-C, HDL-C is inversely related to CHD risk isk of CHD R LDL-C (mg/dl) Gordon T et al. Am J Med 1977;62: Hypertriglyceridemia Increases CHD Risk in Patients with Low HDL-C Levels Prospective Cardiovascular Münster Study Incidence per 1, (in 6 years s) 25 TG < 2 mg/dl * TG 2 mg/dl > 5. LDL-C/HDL-C ratio * Bar represents 5% of subjects in which 25% of CHD events occurred. Assmann G, Schulte H. Am J Cardiol 1992;7: Copyright 1992, with permission from Excerpta Medica Inc. 7

8 Non-Fasting TGs Predictive of Risk Odds Ratio (CV Death h, MI, CVA, Revascularizati ion) st Non-Fasting TG Fasting TG 2nd P-trend =.1 P-trend =.9 Tertile of Baseline TG CVD=cardiovascular disease; TG=triglyceride; CV=cardiovascular; MI=myocardial infarction; CVA=cerebrovascular accident; F/U=follow-up Bansal S et al. JAMA 27;298: rd Women s Health Initiative 2,118 Fasting 6,319 Non-fasting (<8 hr) Baseline demographics Baseline bloods 11.4-year mean F/U Fasting time documented Endpoint: CV death, MI, CVA, Revascularization 1,1 events Best risk discriminant = TG 2 4 hours Mechanisms By Which HDL May Be Anti-atherogenic Reverse cholesterol transport Antioxidant effects Inhibition of adhesion molecule expression Inhibition of platelet l t activation Prostacyclin stabilization Promotion of NO production 8

9 HDL-C, RCT and Atherosclerosis Liver FC Bile LDL-C Receptor CE SR-BI Mature HDL-C A-I CE CETP LCAT HL, EL FC A-I Nascent HDL-C SR-BI Macrophage FC CE B VLDL/LDL-C RCT=reverse cholesterol transport; CE=cholesteryl ester; FC=free cholesterol; LCAT=lecithin-cholesterol acyltransferase; CETP=cholesteryl ester transfer protein; VLDL=very low-density lipoprotein; SR-BI=scavenger receptor class B type I; HL=hepatic lipase; EL=endothelial lipase. Reproduced with permission from Cuchel M et al. Arterioscler Thromb Vasc Biol. 23;23: Declining HDL-C in the Population >12, respondents to a biennial population survey in the Pawtucket Heart Health Program Between 1981 and 1993,.8 mmol/l (3.1 mg/dl) decline Adjusted for other risk factor changes HDL-C (mmol/l) Reprinted from Ann Epidemiol, Vol. 8, Derby CA et al., 84-91, copyright 1998, with permission from Elsevier. Women Men Nonsmokers Smokers Nonsmokers Smokers. Alcohol 1.3 Alcohol No Alcohol 1. No Alcohol. BMI < BMI <24.5 BMI BMI

10 Treating HDL: Non-pharmacologic Methods Exercise overrated HDL only when TG high HDL only with intense, frequent exercise Alcohol Raises TG Affects CETP activity Modest HDL changes Smoking cessation Weight loss Changes in HDL-C oncentration (mg/dl) Co Control Frequent, intense exercise Infrequent exercise Moderate Intense P=.15 Couillard C et al. Arterioscler Thromb Vasc Biol 21;21: Kraus WE et al. N Engl J Med 22;347: Copyright 22 Massachusetts Medical Society. All rights reserved. How Do We Increase HDL? Strategies to raise HDL Niacin Fibrates Thiazolidinediones CETP Inhibitor -? 1

11 Lipid Effects of Niacin Extended-Release (ER) Ch hange from Baseline (%) HDL-C LDL-C Lp(a) TG mg Capuzzi DM et al. Am J Cardiol 1998;82:74U-81U. Niacin Monotherapy: Coronary Drug Project , men with prior MI 5 lipid-influencing drugs Niacin 1 g TID (n=1119); TC 1%, TG 27% 6 years: reduction in MI only in niacin group 15 years: 4% absolute reduction in mortality NNT = 25 Event Rate (%) Coronary Drug Project. JAMA 1975; 231: Canner PL et al. J Am Coll Cardiol 1986;8: Nonfatal Nonfatal MI/ MI CHD Death 26 Stroke/ TIA Placebo Niacin 47 CV Surgery 11

12 Niacin Reasonable alternate in statinintolerant patients Possible consideration for combination therapy Limited by side effects Flushing Gout Peptic ulcer disease Insulin resistance HDL-Atherosclerosis Treatment Study (HATS) Niacin and Statin Outcome Trial % Reduction 21.4 *P<.5 vs Placebo * Placebo S + N AV S + N + AV Coronary Death, MI, Stroke or Revascularization Brown BG et al. N Engl J Med 21;345:

13 HATS: Primary Clinical Endpoint CAD Death, Non-fatal MI, CVA or Revascularization %) Patie ents Free of Events ( Relative Risk =.4 p =.2 Simvastatin-niacini i i No simvastatinniacin 91% 78% ~~ 1st 2nd 3rd Years HATS=HDL-atherosclerosis treatment study; CAD=coronary artery disease; MI=myocardial infarction; CVA=cerebrovascular accident Brown BG et al. N Engl J Med 21;345: Niacin + Statin: ARBITER 2 Concentrations (mg g/dl) Tota al cholest erol Statin + placebo Statin + niacin ER LDL H DL * * TG Patients with Event (%) % P = ARBITER 2 study; Circulation 24 Statin + Placebo Statin + Niacin ER 13

14 Niacin Therapy Start low and titrate dose Take in the middle of a meal Avoid alcohol and hot drinks with dose Pre-treat with ASA 3 mins before dose Warn patients about the flush! Meyers et al; Ann Int Med, 23 Niacin Brands Brands labeled No Flush or Flush- free have no effect Inositol hexaniacinate not metabolized by humans Sustained release or timed release forms have variable effects and increased liver toxicity Meyers et al; Ann Int Med, 23 14

15 Niacin + Statin: Current Recommendations Pending Outcomes Trials AIM HIGH HPS-THRIVE Monotherapy is a suitable alternative in statin intolerant patients Probable benefit from statin combination therapy in high risk Cum mulative Incidence e (%) Fibrate Monotherapy: VA HIT Prevention: Incidence of Death from CHD and Nonfatal MI Placebo Rx HDL 32 34* LDL TG * Placebo Gemfibrozil P= Year * Lipid values significantly different, P<.5 Adapted from Rubins HB et al. N Engl J Med 1999;341:

16 2 Fibrate Monotherapy: Helsinki Heart Study cidence of cardiac eve ents (per 1, person-years s) In ( 1 5 Gemfibrozil 15 Placebo mg/dl: TG 2 TG 2 TG 2 TG 2 HDL-C 42 HDL-C 42 1 Prevention; Manninen V et al. Circulation. 1992;85:37 45 Fibrate Combination Therapy: FIELD Primary Endpoint Secondary Endpoint Non-significant 19% increase in cardiac mortality with feno vs. placebo Lancet, 25 16

17 FIELD: Outcomes Greater use of statins ti in placebo than fibrate groups Less HDL than expected Not clear if statin + fibrate beneficial i Statin + Fibrate Data to establish benefit in outcomes pending (ACCORD trial) Most benefit in Metabolic Syndrome and low HDL patients Safety: no increased risk of rhabdo or renal failure in trial settings Choice of agents doesn't matter; use lower statin doses Statin-Fibrate Safety Report, 24 17

18 Thiazolidinediones Cha ange from baseline at 24 weeks (mg/dl) TG HDL-C Non HDL-C LDL-C Pioglitazone Rosiglitazone Data from Goldberg RB et al. Diabetes Care. 25;28: TZDs: CHD Prevention PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) 5,238 subjects with type 2 DM and macrovascular disease on best usual care Baseline lipids: HDL 42; LDL 112; TG 159; baseline HbA1c 7.8% Concurrent medication use B blockers: 55% ACE inhibitors/ ARBs: 7% Statins: 43% Fibrates: 1% 18

19 PROactive: 1 Endpoint Composite of death, nonfatal MI, stroke, ACS, leg amputation, coronary or leg revascularization PROactive: 2 Endpoint Composite of death, nonfatal MI or stroke 19

20 Pioglitazone: CVD Risk Death, MI or Stroke Lincoff et al; JAMA 27; 298: Summary Statins remain the initial therapy Low HDL/ High TG likely l contributes t to residual risk Probable benefit to niacin + statins Evidence unclear for fibrates in monotherapy or with statins Probable benefit to pioglitazone in diabetics 2

21 Encourage Compliance Medications that aren t taken don t work 21