May, 2015
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 2013. DOI: 10.1161/01.cir.0000437738.63853.7a
Statins Reduce CVD Risk
• Cholesterol Treatment Trialists (CTT)
Collaborators
• Prospective meta-analysis of RCTs
conducted from 1994 to 2009
– 129,526 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
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May, 2015
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 40-80
Rosuva 20-40
Atorva 10-20
Rosuva 5-10
Simva 20-40
Prava 40-80
Lova 40
Fluva 80
Pitava 2-4
Simva 10
Prava 10-20
Lovastatin 20
Fluva 20-40
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
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May, 2015
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
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May, 2015
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
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May, 2015
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, 1.27-1.72)
• Higher MI rate for HIV+ vs. HIVacross 3 decades (p<0.05 for all)
– 40 to 49 yo, 2.0 (1.6-2.4) vs. 1.5 (1.3-1.7)
– 50 to 59 yo, 3.9 (3.3-4.5) vs. 2.2 (1.9-2.5)
– 60 to 69 yo, 5.0 (3.8-6.7) vs. 3.3 (2.6-4.2)
Freiberg MS, et al. JAMA Intern Med 2013; 173:614
Statins in Patients with HIV
•
•
•
•
Lower TC and LDL-C; less effective than in HIVImprove 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
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May, 2015
AIM-HIGH
N=3,414 with ASCVD
HDL-C ≤40 (men); ≤50 mg/dL (women)
TG 150-400 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
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May, 2015
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:10.1093/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:10.1093/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
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May, 2015
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
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May, 2015
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 50–125 (<100 mg/dL on tx)
HR 0.90 CI (0.84-0.97)
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 11-2014
James H. Stein, MD
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May, 2015
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
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