Cholesterol Medicines New & Old: What to Use When

Cholesterol Medicines New & Old: What to Use When Patrick E. McBride, M.D., M.P.H. Division of Cardiovascular Medicine Preventive Cardiology Program Disclosures McBride no conflicts of interest Outline New lipid guidelines Overview of key points Evidence of statins and PCKS - 9 CVD risk prediction Myalgias Beyond the guidelines Do HDL-C and TG matter? When to use non-statin medications The use of niacin and fish oil

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults www.heart.org Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology, Association of Black Cardiologists, Preventive Cardiovascular Nurses Association, and Women Heart: The National Coalition for Women with Heart Disease Guideline Scope Focus on treatment of blood cholesterol to reduce ASCVD risk in adults Emphasize adherence to a heart healthy lifestyle - See lifestyle guidelines Identify individuals most likely to benefit from cholesterol-lowering therapy: statin benefit groups Identify safety issues Advances in the Guidelines 1. Focus is on treatment of LDL-C 2. Treatment is based on risk: not just on LDL-C 3. Risk assessment - evidence to support its use in identifying patients to treat 4. Treatment based on evidence and the intensity of treatment;; no LDL targets

Why Not Continue to Treat to Target? 1. Current RCT data do not indicate precise targets 2. Unknown magnitude of additional ASCVD risk reduction with one target compared to another target 3. Unknown rate of additional adverse effects from multidrug therapy used to achieve specific goals 4. Unknown net benefit from treat-to-target approach No LDL Targets or Measurements? No targets does not mean not measuring panel to see if appropriate intensity achieved (hypo-responders) Adherence! < 50% take medicine as prescribed LDL-C <40 mg/dl is too low - lower statin dose Consider adjusting therapy (lifestyle, other) if LDL-C not low enough for risk Statin Benefit Groups Clinical ASCVD (includes stroke and PAD) LDL-C 190 mg/dl w/out secondary cause Primary prevention Diabetes mellitus (DM) and 40-75 years old: LDL-C 70-189 mg/dl Primary Prevention: No DM and age 40-75 years: LDL-C 70-189 mg/dl, if ASCVD risk 7.5% Requires risk discussion consider statin therapy after lifestyle trial

Intensity of Statin Therapy Use evidence-based therapy High risk patients = high intensity Rx 10 year ASCVD risk 7.5% (I, A) Moderate risk = moderate intensity Rx 10 year ASCVD risk 5%-7.5% (IIA, B) Consider if LDL-C > 160 mg/dl, genetic dyslipidemia, family hx of premature heart disease, hscrp> 2 mg/l, CAC >300 or 75 th %tile, ABI 0.9, or high lifetime risk (IIB, C) Primary Prevention: Global Risk Assessment www.heart.org To estimate 10-year / lifetime ASCVD risk New Pooled Cohort Risk Equations White and black, men and women More accurately identifies higher risk individuals for statin therapy Focuses statin therapy on those most likely to benefit Consider not initiating statin therapy in high-risk groups not found to benefit from statins (advanced HF, hemodialysis) Primary Prevention: Statin Therapy Thresholds for initiating statin therapy derived from RCTs Before initiating statin therapy, engage in a discussion of the potential for ASCVD risk reduction benefits, potential for adverse effects, medication interactions, and patient preferences

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;;376:167 0 CTT Collaborators Improved CVD 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 CVD events 26% reduction in MI or CHD death 24% reduction in PCI/CABG 15% reduction in stroke Lancet 2010;;376:167 0 CTT Collaborators Subgroups

Intensity of Statin Therapy*** *Individual responses to statin therapy varied in RCTs - expected to vary in clinical practice. Simvastatin 80 mg was evaluated in RCTs but is not recommended by the FDA due to the risk of myopathy & rhabdomyolysis Safety RCTs & meta-analyses used to identify important safety considerations Allow estimation of net benefit from statins Expert guidance on management of statinassociated adverse effects, including muscle symptoms Advise use of additional information including pharmacists, manufacturers prescribing information, & drug information centers for complex cases Creatinine Kinase and ALT Baseline/ongoing measures of CK and ALT not needed (Routine CK Class III) Consider if underlying muscle or liver disease or patient at increased risk Family or personal history Concomitant meds that may interact Clinical problems that predispose Measure if patient is symptomatic

Management of Mild-Moderate Statin-Associated Myalgias Discontinue statin until sx are evaluated Evaluate the patient for other conditions that might increase the risk for muscle symptoms* Hypothyroidism, kidney/liver disease, rheumatologic disorders (PMR), steroid myopathy, low Vitamin D status, or primary muscle diseases If after 2 months without statin Rx, muscle sx or elevated CK levels do not resolve completely, consider other causes of muscle sx Management of Severe Myalgia or Fatigue on Statin Therapy Promptly discontinue the statin Evaluate for rhabomyolysis CK Creatinine Urine analysis for myoglobinuria Statin Safety - Neurocognitive Meta-analysis of 23,443;; statin exposure 3-25 years No adverse effect of statins on cognition long-term data may support a beneficial role for statins in the prevention of dementia 29% RRR incident dementia (HR 0.71, CI: 0.61-0.82) Systematic review Published data do not suggest an adverse effect of statins on cognition But: issues of selection and ascertainment Strength limited, esp. with high intensity statin Swiger KJ, et al. Mayo ClinProc2013;;88:121 Richardson K, et al. Ann Inter n Med 2013;;159:688

IMPROVE-IT Evidence for Ezetimibe RCT: N=18,144 Post-ACS 10 days LDL-C 50 125 mg/dl ( 100 mg/dl if lipidtx) Standard treatment and interventions Simva 40 mg vs. simva 40/ezetimibe 10 mg QD Increase to simva 80 mg if LDL-C >70 mg/dl >90% power to detect a 9% w/5250 events 1 Endpoint: CV death, MI, hospital admission for UA, coronary revascularization, or stroke Cannon CJ, et al. N Engl J Med 2015;;372:2387 IMPROVE-IT Statin + Ezetimibe: Absolute Benefit 2% Cannon CP et al. N Engl J Med 2015;;372:2387-2397. PCKS-9 Inhibitors Proprotein convertase subtilisin / kexin type 9 Enzyme that modulates LDLR density on hepatocytes (and intestines, kidneys, CNS) Secreted from hepatocytes bindsldlreceptor endocytosis and degradation in lysosomes Inverse relationship between the blood PCSK9 level and LDLR density Inhibition of PCSK9 prevents LDLRdegradation and preserves LDLR recycling to the hepatocyte surface Each receptor normally recycles approximately 150x MAb prevents binding of PCSK-9 to the LDL / LDLR complex greater LDLR density LDL-C clearance

Beyond the Guidelines Low HDL-C Hypertriglyceridemia Combined dyslipidemias Lipoprotein evaluation / treatment No RCTs / recommendations Biomarkers Atherosclerosis imaging Medications for VLDL / TGs / HDL Fibrates (e.g. fenofibrate / gemfibrozil) increase lipoprotein lipase production and decrease VLDL production Niacin (vitamin B3) decreases VLDL production Omega 3 fatty acids e.g. fish oil, flax oil reduce VLDL production Use of Non-Statin Lipid Therapies If TGs >500 mg/dl Fibrates (or niacin or fish oil) Prevent pancreatitis and hepatic steatosis (non-guideline) Consider addition of a non-statin medication Statin intolerance Persistent, less than therapeutic response Assure compliance with meds and lifestyle High-intensity: if LDL <50% or >100 mg/dl Moderate intensity: <30% decrease Use the maximum tolerated dose of statin

Use of Non-Statin Lipid Therapies Risk-reduction benefits should outweigh potential for adverse effects Focus on: Clinical ASCVD <75 years of age Baseline LDL-C 190 mg/dl (genetic) Diabetes mellitus, 40-75 years of age Prefer non-statin cholesterol-lowering medication that reduced ASCVD events in RCTs Use of Non-Statin Lipid Therapies Evidence to support monotherapy with niacin and bile acid resins in individuals with high total or LDL cholesterol (older studies CDP, LRC-CPPT) Evidence for using niacin and fibrates as monotherapy in individuals with high TG and low HDL-C (VA-HIT, HHS) Residual CVD Risk on Statins CV Event Rate (%) 30 25 20 15 10 5 0 4S CARE HPS PROVE-IT Control Statin TNT

HDL Atherosclerosis Treatment Study (HATS) N = 160 CAD patients HDL-C: women 40 mg/dl, men 35 mg/dl Baseline lipids: TC 199, HDL-C 32, TG 203, LDL-C 127 mg/dl Randomized, 2 x 2 factorial Simvastatin and niacin Antioxidants (C and E, -carotene, selenium) Outcomes after 3 years Brown BG, et al. N Engl J Med. 2001;;345:15 83 HATS: Clinical Endpoints -89% Composite Event Rate (%) 25 20 15 10 5 0 23.7 2.6* 21.4 14.3 Coronary Death, MI, Stroke, or Revascularization Placebo Simva + niacin Antioxidants S + N + AV Brown BG, et al. N Engl J Med. 2001;;345:15 83 * p=0.003 vs placebo AIM-HIGH N=3,414 men and women with Atherosclerotic vascular disease HDL-C 40 (men);; 50 mg/dl (women) TG 150-400 mg/dl LDL-C 180 mg/dl Randomized to simvastatin vs. simvastatin + ER niacin 1 endpoint: CHD death, MI, stroke, high-risk ACS, or symptom-driven coronary or cerebral revascularization The AIM-HIGH Investigat ors. N Engl J Med 2011;;365:22 55

AIM-HIGH Power: 85% for 25% CVD event reduction with N=850 events ER niacin: 500 mg/d, titrated to 2000 mg/d over 4-8 weeks (open-label run-in) If tolerated 1500 mg/d randomized to maximally tolerated dose of ER niacin or a placebo spiked with 50 mg of IR niacin Simvastatin adjusted during the first 6 months to a LDL-C target of 40-80 mg/dl Ezetimibe added to reach LDL-C goal The AIM-HIGH Investigat ors. N Engl J Med 2011;;365:22 55 AIM-HIGH After 1 year, ER niacin/statin vs. statin HDL-C (mean 35 mg/dl) by 23% vs. 9% TG (mean 163 mg/dl) by 28% vs. 5% LDL-C (mean 74 mg/dl) by 10% vs. 4% Non-HDL-C from 108 to 90 mg/dl vs. 108 to 102 mg/dl Stopped for futility after a mean of 3 years Primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (HR 1.02;; p=0.79) The AIM-HIGH Investigat ors. N Engl J Med 2011;;365:22 55 AIM-HIGH The AIM-HIGH Investigat ors. N Engl J Med 2011;;365:22 55

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;;62:158 0 HPS2-THRIVE Prospective RCT to determine if Niacin + laropiprant prevents CVD events on a background of statin therapy High-risk patients receiving intensive LDLlowering tx N=25,673, aged 50-80 years old All had ASCVD All on simvastatin 40 mg (+ ezetimibe 10 mg/d, if needed to get TC <135 mg/dl) Randomized to niacin 2 g/d + laropiprant 40 mg/d vs. placebo The HPS2-THRIVE Collabor ative Gr oup. N Engl J Med 2014;;371:203 HPS2-THRIVE After a median of 4 years HDL-C (mean 44 mg/dl) by 6 mg/dl TG (mean 125 mg/dl) by 33 mg/dl LDL-C (mean 63 mg/dl) by 10 mg/dl Niacin-laropiprant had no sig. effect on ASCVD (13.2% vs. 13.7%;; RR 0.96;; p=0.29) Absolute 3.7% increase in serious side effects esp. DM, infection, GI, and myalgia (in China: RR 5.2 vs 1.5 in Europe) The HPS2-THRIVE Collabor ative Gr oup. N Engl J Med 2014;;371:203

HPS2-THRIVE The HPS2-THRIVE Collabor ative Gr oup. N Engl J Med 2014;;371:203-212 HDL and Niacin Niacin AIM-HIGH: Niacin as add-on to effective statin tx does not reduce events HPS-THRIVE: Supports AIM-HIGH, though risks may be due to laropiprant or niacin Main effect may be LDL-lowering: main use as 2nd line for residual high LDL-C As in AIM-HIGH and ACCORD, the subgroup with TG > 200 mg/dl and HDL < 40 had significant benefit Voight BF, et al. Lancet 2012;; 380: 572 Holmes, MH. Eur Heart J 2014: doi:10.1093/ eur he ar tj /e ht 57 1 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

ACCORD Lipid Changes N Engl J Med 2010;; 362:1563 ACCORD CVD Outcomes + revasc, hosp. CHF N Engl J Med 2010;; 362:1563 ACCORD - Subgroups N Engl J Med 2010;; 362:1563

Fish Oil Capsules Omega 3 s www.healthdecision.org Must use total daily dose of 4000 mg of DHA + EPA Divide BID Look at back of label! Many say 1000 mg on front, but low DHA + EPA Cholesterol Medications LDL Statins (best evidence most effective) Ezetimibe Bile Acid Resins PCKS-9 Inhibitors (new, very expensive, limited evidence) Triglycerides / HDL Fibrates Niacin Fish Oil Thank You! Questions?

Cholesterol Medications: Sites of Actions Decrease lipoprotein synthesis: Statins (HMG CoA reductase inhibitors) PCKS 9 inhibitors Niacin - Omega 3 s Fibrates - CETP inhibitors Decrease Cholesterol Absorption Ezetimibe Bile acid resins Plant Sterols / Stanol esters Fibers (psyllium, oat bran, etc) Use of Biomarkers and Imaging Apo B, LDL particles, Lp(a): ungraded;; future question hscrp (IIB for primary prevention) Mendelian randomization studies suggest it is a marker and not causal Intermediate/residual risk on statin (not guideline) JUPITER-type patients (not guideline) Ridker BMJ 2011;;342:d54 8 PM et al. N Engl J Med 2008;;359 Use of Imaging ABI, CAC, carotid IMT All IIB, except misgraded carotid IMT (III) No RCT data Future question: how can noninvasive imaging guide treatment? BMJ 2011;;342:d54 8 Stein JH, Tattersall M. J Am Coll Cardiol 2014:63:2301

JUPITER RCT of 17,802 healthy individuals Men >50, women >60 years LDL-C <130 mg/dl hscrp >2.0 mg/l Rosuvastatin 20 mg daily vs. placebo Stopped early after 1.9 years Baseline (median) characteristics Age 66 yrs, LDL-C 108 mg/dl BMI 28.3 kg/m 2, 41% Metabolic Syndrome Ridker PM et al. N Engl J Med 2008;;359 JUPITER HPS2-THRIVE The HPS2-THRIVE Collabor ative Gr oup. N Engl J Med 2014;;371:203

CTT Collaborators Subgroups Japan EPA Lipid Intervention Study (JELIS) RCT of 18,645 subjects with TC >253 Pravastatin/simvastatin + EPA 1800 mg vs. statin alone (open-label) 1 endpoint: SCD, fatal and non-fatal MI, unstable angina, PCI/CABG Mean follow-up 4.6 years Baseline lipids: HDL-C 59, TG 154, LDL-C 183 mg/dl Lancet 2007;; 369:1090 JELIS LDL-C 25% in both arms;; TG 9 vs 4% (p<0.001) all primary secondary 1 endpoint: 262 (2.8%) EPA vs. 324 (3.5%) controls = 19% RRR;; 0.7% ARR (p=0.011) In those with CAD: 158 (8.7%) EPA vs. 197 (10.7%) controls = 19% RRR;; 2% ARR (p=0.048) Lancet 2007;; 369:1090

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;;357:13 01 Why Do We Have HDL? Reverse cholesterol transport unlikely to be selected for until recent increase in CVD deaths Anti-inflammatory effects Host defense and immunity Protection from endotoxin Protection from trypanosomes Low HDL-C Increases CHD Risk, Even if LDL-C is Low: Framingham Heart Study Patient 1 LDL-C 100 HDL-C 25 Patient 2 LDL-C 220 HDL-C 45 CHD Relative Risk 3 2 1 0 1 2 100 160 220 85 65 45 25 HDL-C, mg/dl LDL-C, mg/dl Kwiterovich PO, Am J Cardiol 1998;;82:19Q

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;;229 2 Holmes, MH. Eur Heart J 2014: doi:10.1093/ eur he ar tj /e ht 57 1 Go D, Nature Genetics 2013:45;; 1345 UW Preventive Cardiology Program Physicians: Lipid, Advanced Hypertension, or Preventive Cardiology Clinics EPIC order or call Exercise Prescription or Nutrition EPIC: Consult to Preventive Cardiology enter request in comments Call: 263-7420