Elevated LDL-C Cardiovascular Pathobiology MEDX Dallas/Fort Worth - PDF document

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? THE CRUCI AL PROBLEM OF ASCVD Can New Therapeutic Options Resolve I t? Jam es A. Underberg, MD, MS, FACPM, FACP, FNYAM, FASPC, FNLA Lipidology and Cardiovascular Disease Prevention Clinical Assistant Professor of Medicine NYU Medical School and NYU Center for CV Prevention Director, Bellevue Hospital Lipid Clinic Past President, National Lipid Association New York, NY Twitter: @LipidDoc Jointly provided by and This activity is supported by educational funding provided by Amgen. Elevated LDL-C Cardiovascular Pathobiology MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? Support for LDL-C Causality in ASCVD • Four compelling lines of evidence – Experimental models – Observational human data – Genetic studies – Interventional human trials ASCVD = atherosclerotic cardiovascular disease Substantial CVD Risk Remains after ACS Substantial CVD Risk Remains after ACS 43,810 Patients with ACS in GRACE Registry: 6-month Death Rate 43,810 Patients with ACS in GRACE Registry: 6-month Death Rate 16 12 STEMI Death (%) NSTEMI 8 UA 4 0 0 30 60 90 120 150 180 Days GRACE = global registry of acute coronary events STEMI: ST-segment elevation MI NSTEMI: nonST-segment elevation MI UA: unstable angina Fox KAA et al . BMJ. 2006;333:1091. MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? Disease Trajectories and CVD Risk Reduction Disease Trajectories and CVD Risk Reduction Packard CJ et al. Vasc Pharmacol. 2015;71:37-39. LDL-C Reduction Cardiovascular Benefits MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? Table 6. Risk-Enhancing Factors for Clinician– Patient Risk Discussion Risk ‐ Enhancing Factors  Family history of premature ASCVD (males, age <55 y; females, age <65 y)  Primary hypercholesterolemia (LDL ‐ C, 160–189 mg/dL [4.1–4.8 mmol/L); non– HDL ‐ C 190–219 mg/dL [4.9–5.6 mmol/L])*  Metabolic syndrome (increased waist circumference, elevated triglycerides [>175 mg/dL], elevated blood pressure, elevated glucose, and low HDL ‐ C [<40 mg/dL in men; <50 in women mg/dL] are factors; tally of 3 makes the diagnosis)  Chronic kidney disease (eGFR 15–59 mL/min/1.73 m 2 with or without albuminuria; not treated with dialysis or kidney transplantation)  Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDS  History of premature menopause (before age 40 y) and history of pregnancy ‐ associated conditions that increase later ASCVD risk such as preeclampsia  High ‐ risk race/ethnicities (e.g., South Asian ancestry) Table 6 (continued) Risk ‐ Enhancing Factors  Lipid/biomarkers : Associated with increased ASCVD risk Persistently* elevated, primary hypertriglyceridemia ( ≥ 175 mg/dL); o If measured: o  Elevated high ‐ sensitivity C ‐ reactive protein ( ≥ 2.0 mg/L)  Elevated Lp(a): A relative indication for its measurement is family history of premature ASCVD. An Lp(a) ≥ 50 mg/dL or ≥ 125 nmol/L constitutes a risk ‐ enhancing factor especially at higher levels of Lp(a).  Elevated apoB ≥ 130 mg/dL: A relative indication for its measurement would be triglyceride ≥ 200 mg/dL. A level ≥ 130 mg/dL corresponds to an LDL ‐ C >160 mg/dL and constitutes a risk ‐ enhancing factor  ABI <0.9 MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? Treatments for Hypercholesterolemia Lifestyle Change Pharmacologic Therapy • Physical activity • Statins • Cholesterol absorption inhibitors • Medical nutrition therapy • Bile acid sequestrants • Smoking cessation • Fibrates • Omega-3 fish oil • PCSK9 inhibitors • MTP inhibitors • Antisense apo B oligonucleotide • Combination therapies Jellinger P et al. Endocr Practice . 2017;23:479-497. Statins The Gold Standard for LDL-C Reduction and ASCVD Prevention MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? Statins Protect against Recurrence in ASCVD Patients Secondary Prevention Statin Trials: CHD Event Rates - P=placebo; -AT=atorvastatin; -PR=pravastatin O’Keefe JH et al. J Am Coll Cardiol . 2004;43:2142-2146. Lower On-treatment LDL-C with Statins Predicts Lower On-treatment LDL-C with Statins Predicts Lower ASCVD Risk Lower ASCVD Risk ≥ 175 150 − <175 LDL-C Levels LDL-C (mg/dL) and Risk of 125 − <150 CV Events 100 − <125 75 − <100 50 − <75 <50 0.25 0.5 0.75 1 Adjusted Hazard Ratio 95% Cl Boekholdt SM et al. J Am Coll Cardiol. 2014;64:485-494. MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? Elevated LDL Causes ASCVD LDL-C lowering Reduces ASCVD • Cumulative LDL burden → atheroprogression • ↓ On-treatment LDL-C → ↓ ASCVD – Best evidence is for ↑ LDL receptors – But likely not exclusive to this mechanism • Early treatment to ↓ LDL-C is better than late treatment • Lowest LDL-C is best Ference BA et al. Eur Heart J . 2017;38:2459-2472. Primary Prevention: LDL-C ≥ 190 mg/dL (24.9 mmol/L) No risk assessment; High-Intensity statin Assess ASCVD Risk in Each Age Group (Class I) Emphasize Adherence to Healthy Lifestyle Diabetes mellitus and age 40-75 y Moderate-Intensity statin (Class I) Age 0-19 y Age 20-39 y Age 40-75 y and LDL-C Lifestyle to prevent or reduce Estimate lifetime risk ≥ 70-<190 mg/dL Diabetes mellitus and age 40-75 y Risk ASCVD risk to encourage lifestyle to ( ≥ 1.8-<4.9 mmol/L) assessment to consider high-intensity Diagnosis of Familial reduce ASCVD risk without diabetes mellitus statin Hypercholesterolemia statin Consider statin is family 10 year ASCVD risk percent history premature (Class IIa) begins risk discussion ASCVD and LDL-C >160 mg/dL (>4.1 mmol/L0 Age >75 y Clinical assessment, Risk reduction MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? <5% 5% - <7.5% ≥ 7.5% - <20% ≥ 20% “Low Risk” “Borderline Risk” “Intermediate Risk” “High Risk” Risk discussion: Risk discussion: Risk discussion: Risk discussion: Emphasize lifestyle Initiate statin to If risk enhancers If risk estimate + risk to reduce risk factors reduce LDL-C ≥ 50% present then risk enhancers favor (Class I) (Class I) discussion statin, initiate regarding moderate- moderate-intensity intensity statin statin to reduce LDL- therapy (Class IIb) C by 30% - 49% (Class I) If risk decision is uncertain: Consider measuring CAC in selected adults: CAC = zero (lowers risk; consider no statin, unless diabetes, family history of premature CHD, or cigarette smoking are present) CAC = 1.99 favors statin (especially after age 55) CAC = 100+ and/or ≥ 75th percentile, initiate statin therapy Secondary Prevention MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? Table 4. Very High-Risk* of Future ASCVD Events Major ASCVD Events Recent ACS (within the past 12 mo) History of MI (other than recent ACS event listed above) History of ischemic stroke Symptomatic peripheral arterial disease (history of claudication with ABI <0.85, or previous revascularization or amputation) Table 4 (continued) High-Risk Conditions Age ≥ 65 y Heterozygous familial hypercholesterolemia History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s) Diabetes mellitus Hypertension CKD (eGFR 15-59 mL/min/1.73 m 2 ) Current smoking Persistently elevated LDL-C (LDL-C ≥ 100 mg/dL [ ≥ 2.6 mmol/L]) despite maximally tolerated statin therapy and ezetimibe History of congestive HF MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? Intensive Statin Therapy Reduces MACE Intensive Statin Therapy Reduces MACE PROVE IT - TIMI 22: Study Design PROVE IT - TIMI 22: Study Design 4,162 patients with an Acute Coronary Syndrome <10 days ASA + Standard Medical Therapy Double-blind “Standard Statin Therapy” “Intensive StatinTherapy” Pravastatin 40 mg Atorvastatin 80 mg 2x2 Factorial: Gatifloxacin vs placebo Duration: Mean 2 year follow-up (>925 events) Primary Endpoint: Death, MI, documented UA requiring hospitalization, revascularization (>30 days after randomization), or stroke Cannon CP et al. N Engl J Med. 2004;350:1495-1504. Intensive Statin Therapy: PROVE IT-TIMI 22 All-Cause Death or Major CV Events 30 Intensive Statin Therapy Pravastatin 40mg 25 % of Patients with MACE (26.3%) 20 Standard Statin Therapy Atorvastatin 80mg 15 (22.4%) 10 16% RR 5 ( P =0.005) 0 0 3 6 9 12 15 18 21 24 27 30 Months of Follow-up Cannon CP et al. N Engl J Med . 2004;350:1495-1504. MEDX Dallas/Fort Worth – November 17, 2018