Management of Lipids in 2015: Just Give them a Statin?

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1 Management of Lipids in 2015: Just Give them a Statin? James H. Stein, M.D. Division of Cardiovascular Medicine University of Wisconsin School of Medicine and Public Health Stone NJ, et al. Circulation DOI: /01.cir a Statins Reduce CVD Risk Cholesterol Treatment Trialists (CTT) Collaborators Prospective meta-analysis of RCTs conducted from 1994 to ,526 subjects in 21 statin vs. control 39,612 subjects in 5 more vs. less intensive Median follow-up = 5.1 years Lancet 2010;376:1670 James H. Stein, MD 1

2 CTT Collaborators Improved ASCVD outcomes per 39 mg/dl reduction in LDL-C (all p<0.0001) 10% reduction in all-cause mortality 20% reduction in coronary mortality 21% reduction in major ASCVD events 26% reduction in MI or CHD death 24% reduction in PCI/CABG 15% reduction in stroke Lancet 2010;376:1670 Statin Therapy Intensity High Intensity Mod. Intensity Low Intensity LDL-C 50% 30-50% 30% Daily doses (mg) Atorva Rosuva Atorva Rosuva 5-10 Simva Prava Lova 40 Fluva 80 Pitava 2-4 Simva 10 Prava Lovastatin 20 Fluva Pitava 1 Individual responses to statin therapy varied in RCTs - expected to vary in clinical practice Simva 80 mg not recommended by the FDA due to the risk of myopathy & rhabdomyolysis Statin Benefit Group # 1 ACS, h/o MI, angina, revascularization, TIA, stroke, peripheral arterial disease * Statins contraindicated in pregnancy & lactation James H. Stein, MD 2

3 Statin Benefit Group # 2 Likely have familial hypercholesterolemia * Statins contraindicated in pregnancy & lactation Statin Benefit Group # 3 If younger than 40 or older than 75, consider statin therapy (individualized; expert opinion) * Statins contraindicated in pregnancy & lactation Statin Benefit Group #4 James H. Stein, MD 3

4 Others Who May Be Considered For Statin Therapy Family history of premature ASCVD Elevated lifetime risk of ASCVD LDL-C 160 mg/dl hs-crp 2.0 mg/l Subclinical atherosclerosis CAC score 300 ABI <0.9 Limitations Insufficient RCT evidence for clinical recs clinician judgement Adults <40 years old with low estimated 10-year ASCVD risk but high lifetime ASCVD risk Serious comorbidities with increased ASCVD risk (e.g., individuals with HIV, rheumatologic or inflammatory diseases, solid organ transplantation) CVD Risk Prediction in HIV+ Patients Traditional CVD risk factors (older age, male, smoking, diabetes mellitus, family history, HTN, dyslipidemia,) powerfully predict CVD in the general population and in individuals with HIV Some excess risk related to HIV infection Not established how well ASCVD risk predictors work in HIV-infected James H. Stein, MD 4

5 Veterans Aging Study Virtual Cohort Large registry (N=27,350 HIV+; 55,109 HIV-) Mean age ~48 yo; follow-up ~5.9 years Fully adj. HR = 1.48 (95% CI, ) Higher MI rate for HIV+ vs. HIVacross 3 decades (p<0.05 for all) 40 to 49 yo, 2.0 ( ) vs. 1.5 ( ) 50 to 59 yo, 3.9 ( ) vs. 2.2 ( ) 60 to 69 yo, 5.0 ( ) vs. 3.3 ( ) Freiberg MS, et al. JAMA Intern Med 2013; 173:614 Statins in Patients with HIV Lower TC and LDL-C; less effective than in HIV- Improve endothelial function Uncommon side fx, but more CK and LFTs Drug interactions Bocarra F, et al. J Am Coll Cardiol 2013; 61:511; Stein JH, et al. Am Heart J 2004; 147:e18; Hurlimann D, et al. Heart 2006;92:110; Silvernerg, MJ, et al. Ann Int Med 2009;150:301 Residual CVD Event Rates on Statins are Predicted by HDL-C Levels Post-hoc analysis, TNT RCT of 9770 CHD patients on atorvastatin, 10 or 80 mg Quintiles of HDL-C levels predicted CVD events (p=0.04) Among subjects with LDL-C <70 mg/dl, HDL-C levels independently predicted CVD events (p=0.03) Barter PJ, et al. N Engl J Med 2007;357:1301 James H. Stein, MD 5

6 AIM-HIGH N=3,414 with ASCVD HDL-C 40 (men); 50 mg/dl (women) TG mg/dl LDL-C 180 mg/dl The AIM-HIGH Investigators. N Engl J Med 2011;365:2255 HPS2-THRIVE N=25,673 with ASCVD The HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203 HPS2-THRIVE Absolute 3.7% in serious side effects esp. diabetes mellitus, infection, GI, and myalgia (in China: RR 5.2 vs 1.5 in Europe) The HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203 James H. Stein, MD 6

7 Why Do We Have HDL? Reverse cholesterol transport unlikely to be selected for until recently Anti-inflammatory/anti-oxidant effects Host defense and immunity Protection from endotoxin Protection from trypanosomes HDL-C appears to be a marker not a mediator Mendelian randomization studies do not strongly support causal role Voight BF, et al. Lancet 2012; 380: 572 Holmes, MH. Eur Heart J 2014: doi: /eurheartj/eht571 Triglycerides Controversial as a marker as a cause of CVD risk, because of associations with Obesity Diabetes mellitus Adverse lifestyle habits Inflammation Low HDL-C Small LDL/LDL particle excess Mendelian randomization studies do support causal role; weaker than for LDL-C Miller M, et al. Circulation 2011:123;2292 Holmes, MH. Eur Heart J 2014: doi: /eurheartj/eht571 Go D, Nature Genetics 2013:45; 1345 Action to Control CVD Risk in Diabetes (ACCORD) Study N = 5518 w/type II diabetes mellitus Open-label simvastatin RCT fenofibrate 160 mg vs. placebo 1 outcomes = CVD death, non-fatal MI, non-fatal stroke Mean duration 4.7 years Baseline lipids: TC 175, HDL-C 38, TG 162, LDL-C 100 mg/dl N Engl J Med 2010; 362:1563 James H. Stein, MD 7

8 ACCORD CVD Outcomes + revasc, hosp. CHF N Engl J Med 2010; 362:1563 ACCORD - Subgroups N Engl J Med 2010; 362:1563 AIM-HIGH In a subset of patients with the highest TGs ( 198 mg/dl) and lowest HDL-C (<33 mg/dl), ER niacin showed a trend toward benefit (HR 0.74, p = 0.073) Guyton JR, et al. J Am Coll Cardiol 2013;62:1580 James H. Stein, MD 8

9 Japan EPA Lipid Intervention Study (JELIS) N=18,645 Japanese subjects with TC >253; RCT Pravastatin/simvastatin + EPA 1800 mg vs. statin alone (open-label) Baseline LDL-C 183, HDL-C 59, TG 154 mg/dl LDL-C 25% in both arms; TG 9 vs 4% (p<0.001) all primary secondary ARR 0.7% ARR 2.0% Lancet 2007; 369:1090 Use of Non-Statin Lipid Therapies If TGs >500 mg/dl Fibrates (or niacin or fish oil) Prevent pancreatitis (non-guideline) Use the max tolerated intensity of statin Consider addition of a non-statin medication Statin intolerance Persistent, less than therapeutic response Assure compliance with meds and lifestyle High-intensity: if <50% decrease or LDL-C remains >100 mg/dl Moderate intensity: <30% decrease IMPROVE-IT CV Death, MI, Stroke over 7 Years N = 18,144, post-acs 10 days LDL-C (<100 mg/dl on tx) HR 0.90 CI ( ) p = 0.003, NNT = 56 Simva 40 mg: 22.2% Mean LDL-C 70 mg/dl EZ/Simva 40 mg: 20.4% Mean LDL-C 53 mg/dl Cannon CJ, et al. AHA James H. Stein, MD 9

10 IMPROVE-IT vs. CTT Ezetimibe vs. Statin Benefit IMPROVE-IT CTT Collaboration. Lancet 2005; 366:1267; Lancet 2010;376:1670 Use of Non-Statin Lipid Therapies Evidence to support monotherapy Niacin and bile acid resins in individuals with high total or LDL cholesterol (CDP, LRC-CPPT) Weak: niacin and fibrates in individuals with high TG and low HDL-C (VA-HIT, HHS) Weak evidence to support add-on to statin tx Fish oil and ezetimibe in statin-treated patients (JELIS and IMPROVE-IT) Niacin and fibrates in individuals with high TG and low HDL-C (AIM-HIGH, ACCORD) Summary Use appropriate doses of statins for CVD risk reduction Non-statin therapies are less effective; consider as add-ons when statins not tolerated or suboptimal response Increased CVD risk in HIV Statin effectiveness is lower; more side fx Statin outcome trial to start soon Consider drug interactions when choosing a statin James H. Stein, MD 10