Disclosure Robert B. Baron, MD MS No relevant financial Professor - PDF document

Robert Baron MD, MS Management of Hyperlipidemia and Cardiovascular Risk MANAGEMENT OF LIPID DISORDERS: Balancing Benefits and Harms Disclosure Robert B. Baron, MD MS No relevant financial Professor and Associate Dean relationships UCSF School of Medicine baron@medicine.ucsf.edu Placebo-Controlled Statin Trials EXPLAINING THE DECREASE IN DEATHS FROM CVD Reductions in Major Coronary Events Relative to Placebo 1980 to 2000: death rate fell by approximately 50% in both men and women 2000 to 2010: Death still falling: down 31% • About 1/2 from acute treatments, 1/2 from risk factor modification: • Predominantly cholesterol (1/4), BP, smoking simva 20-40 mg prava 40 mg prava 40 mg simva 40 mg prava 40 mg lova 80 mg 1

Robert Baron MD, MS Management of Hyperlipidemia and Cardiovascular Risk ACC/AHA Guidelines A RISK-BASED APPROACH  4 groups of patients who benefit from statins  Identifies high and moderate intensity statins Risk $$ Harm  No LDL treatment targets reduction  Non-statin therapies no not provide acceptable risk reduction  Estimate 10-year ASCVD risk with new equation The benefit from any given intervention is a function of: 1) The relative risk reduction conferred by the intervention, and 2) The native risk of the patient Heart Protection Study: Vascular ACC/AHA Guidelines Events by Baseline LDL-C Four Groups of Patients Who Benefit From Statins No. Events  Individuals with clinical ASCVD Risk Ratio and 95% Cl Baseline Statin Placebo Statin better Statin Feature (10,269) (10,267)  Individuals with primary elevations of LDL worse ≥ 190 LDL (mg/dL) <100 285 360  Individuals age 40-75 with diabetes and LDL ≥ 100 <130 670 881 ≥ 70 ≥ 130 1087 1365 24% reduction  Individuals without ASCVD or diabetes, age ( p <0.00001) ALL PATIENTS 2042 2606 (19.9%) (25.4%) 40-75, with LDL ≥ 70, and 10 year risk 7.5% or higher 0.8 1.0 1.2 1.4 0.4 0.6 2

Robert Baron MD, MS Management of Hyperlipidemia and Cardiovascular Risk ACC/AHA Guidelines Heart Healthy Diet 2017 Importance of Lifestyle Recommendations  Two dietary factors increase LDL:  Heart healthy diet  Saturated fat  Regular aerobic exercise  Total Calories  Desirable body weight  Restriction of dietary cholesterol is  Avoidance of tobacco no longer recommended (Dietary Guidelines 2015) Saturated Fat 2017 ACC/AHA Guidelines What Statin for Each Group?  Observational studies: no association between sat fat and CVD  Individuals with clinical ASCVD:  But: RCTs that replace sat fat with unsat fat reduce total and LDL  Treat with: high intensity statin, or moderate cholesterol and CVD events and intensity statin if > age 75 mortality  Individuals with primary elevations of LDL ≥ 190:  And: replacing sat fat with carb reduces total and LDL cholesterol but increases  Treat with: high intensity statin triglycerides and HDL and does not lower CVD events 3

Robert Baron MD, MS Management of Hyperlipidemia and Cardiovascular Risk ACC/AHA Guidelines ACC/AHA Guidelines What Statin for Each Group? High Intensity vs. Moderate Intensity Statin  Individuals 40-75 with diabetes and LDL ≥  High Intensity: lowers LDL by >50% 70:  Atorvastatin 40 - 80  Rosuvastatin 20 - 40  Treat with: moderate intensity statin, or high intensity statin if risk over 7.5%  Moderate Intensity: lowers LDL by 30-50%  Individuals without ASCVD or diabetes, 40-  Atorvastatin 10 - 20 75, with LDL ≥ 70, and 10 year risk 7.5% or  Rosuvastatin 5 – 10 higher:  Simvastatin 20 - 40  Treat with: moderate-to-high intensity statin  Pravastatin 40 – 80  Lovastatin 40 How Best To Calculate 10 Year Risk? Pooled Cohort Risk Assessment Equations  Age Pooled Cohort Risk Assessment Equations: hard  Gender CHD events and stroke  Race (White/African American)  Total cholesterol (170 mg/dl)  http://my.americanheart.org/professional/State mentsGuidelines/PreventionGuidelines/Preventi  HDL cholesterol (50 mg/dl) on-Guidelines_UCM_457698_SubHomePage.jsp  Systolic BP (110 mmHg  Yes/no meds for BP  Yes/no DM  Yes/no cigs  Outcome: 10-year risk of total CVD (fatal and non-fatal MI and stroke) 4

Robert Baron MD, MS Management of Hyperlipidemia and Cardiovascular Risk Percent of U.S. Adults Who Would Be Eligible for Statin Therapy for Do the Pooled Cohort Risk Assessment Primary Prevention, According to Set of Guidelines and Age Group. Equations Overestimate Risk? Pencina, N Engl J Med 2014 How Best To Calculate 10 Year Risk? How Best To Calculate 10 Year Risk? Baron Approach 2017 Mayo Clinic Statin Choice Decision Aid:  Use both CHD (hard end points) calculator and new CV risk  http://statindecisionaid.mayoclinic.org/ind calculator ex.php/statin/index?PHPSESSID=0khk8n m14h9vubjm3423e6h6b2  Include both in shared decision- making discussion 5

Robert Baron MD, MS Management of Hyperlipidemia and Cardiovascular Risk The best next step in lipid management is: 63 yo woman; s/p MI 1. Atorvastatin 40 mg LDL 115 2. Rosuvastatin 10 mg HDL 45 3. Pravastatin 40 mg 4. Simvastatin 40 mg TG 160 5. Lovastatin 40 mg 6. Whatever works to get her LDL below 70 mg/dl 2013 ACC/AHA Guidelines The best next step in lipid What Statin for Each Group? management is:  Individuals with clinical ASCVD: 1. Atorvastatin 40 mg  Treat with: high intensity statin, or moderate 2. Rosuvastatin 10 mg intensity statin if > age 75 3. Pravastatin 40 mg 4. Simvastatin 40 mg 5. Lovastatin 40 mg 6. Whatever works to get her LDL below 70 mg/dl 6

Robert Baron MD, MS Management of Hyperlipidemia and Cardiovascular Risk The best next step in lipid 63 yo woman; s/p MI. On management is: atorvastatin 80. 1. Continue current therapy LDL 95 2. Switch to rosuvastatin 40 mg HDL 40 3. Add fenofibrate 4. Add fish oil TG 200 5. Add niacin 6. Add ezetimibe Summary Lipid-Lowering Drugs Summary Lipid-Lowering Drugs • Statins are treatment of choice based on RCT • Ezetimibe study: (IMPROVE-IT) to decrease risk 18,000 ACS patients (40% from North America) • No evidence to support adding niacin or fibrates to statins RCT: Simvastatin vs simvastatin + ezetimibe. Took 7 years. Death, MI, Stroke • If completely statin-intolerant, niacin may reduce CVD risk (weak evidence) Simvastatin: 34.7% vs Simva/ezetimibe 32.7% (270 fewer events over 7 years) • Fibrates appear to lower MI risk, but no other CVD endpoints 7

Robert Baron MD, MS Management of Hyperlipidemia and Cardiovascular Risk PCSK9 Inhibitors FOURIER TRIAL  Evolocumab (Repatha) and alirocumab  27,564 patients, CV disease, on statin, LDL >70, (Praluent)—monoclonal antibodies that reduce 2.2 years liver LDL-receptor degradation  Evolocumab vs placebo (SQ injections)  Reduce LDL by 50%. Injectable Q2 – 4 weeks  Primary composite CV endpoint: death, MI,  Approved for FH or patients with CVD “who need stroke, ACS revascularization additional LDL lowering.”  Secondary endpoint: CV death, MI, stroke FOURIER TRIAL FOURIER TRIAL  LDL reduced 59% (92 mmol/L to 30)  NNT 66 over 2 years  No reduction in death  Primary composite endpoint:  No obvious safety concerns  1344 (9.8%) vs 1563 (11.3%) 15% reduction   Reflections:  Evolocumab reduces risk  Secondary endpoint: CV death, MI, stroke  Risk reduction less than hoped/thought  816 (5.9%) vs 1013 (7.4%) 20% reduction   $14,000 per year 8

Robert Baron MD, MS Management of Hyperlipidemia and Cardiovascular Risk 63 yo woman, no traditional risk The best next step in lipid factors management is: LDL 155 HDL 55 1. Continue current therapy TG 160 2. Switch to rosuvastatin 40 mg (Also potentially SBP 120 correct, but medication still on patent) 3. Add fenofibrate No BP meds 4. Add fish oil No DM 5. Add niacin Nonsmoker 6. Add ezetimibe The best next step in lipid 63 yo woman, no risks management is to calculate 10 year risk and: LDL 155, HDL 55, TG 160 SBP 120, No BP meds 1. Continue current therapy (no meds) Nonsmoker, No DM 2. Begin atorvastatin 40 3. Begin atorvastatin 10 10 yr CHD risk (old calculator): 2%… 4. Begin simvastatin 20 10 yr CV risk (new calculator): 4.5%… 5. Begin sustained release niacin 6. Begin red yeast rice Therefore no medication recommended 9

Robert Baron MD, MS Management of Hyperlipidemia and Cardiovascular Risk The best next step in lipid 63 yo man, no traditional risk management is to calculate 10 factors year risk and: LDL 155 1. Continue current therapy (no meds) HDL 55 2. Begin atorvastatin 40 TG 160 3. Begin atorvastatin 10 SBP 120 4. Begin simvastatin 20 No BP meds 5. Begin sustained release niacin 6. Begin red yeast rice No DM Nonsmoker 63 yo man, no risks LDL 155, HDL 55, TG 160 SBP 120, No BP meds Nonsmoker, No DM 10 yr CHD risk (old calculator): 10%… 10 yr CV risk (new calculator): 10.8%… “Toss-up.” Shared decision making. If start statin (per new guidelines), can start with moderate intensity statin 10