Cholesterol Reduction Therapy in 2018 A Perspective Role Of Statins, Ezetimibe and PCSK9-Inhibitors

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1 USC-April 21, 2018, Los Angeles Cholesterol Reduction Therapy in 2018 A Perspective Role Of Statins, Ezetimibe and PCSK9-Inhibitors P.K.Shah, MD, MACC Shapell and Webb Chair in Clinical Cardiology, Director, Oppenheimer Atherosclerosis Research Center, Director, Atherosclerosis Prevention and Treatment Center, Smidt Heart Institute at Cedars Sinai Med Center, Professor of Medicine at UCLA Disclosure Research support from Sanofi Regeneron and Amgen

2 LDL-C Hypothesis LDL/IDL/VLDL/Lpa Apo B 100 Evidence Epidemiology Genomics Intervention CHD rate LDL-C For very 40 mg/dl change in LDL-C the CHD risk changes by about 20%

3 Genetic LDL-C Lowering vs Statin Induced LDL-C Lowering Genetic Cohen JC: J Clin Lipid 2013

4 Statins Reduce Cardiovascular Events PKShah-CSMC *Approx 20% relative risk reduction( including 10% all cause mortality reduction) for Each 40 mg/dl LDL-C reduction *For every 10,000 subjects at-risk for or with CAD being treated with a statin, each year 100 myocardial infarctions/strokes will be prevented with 1 case of rhabdomyolysis

5 Yusuf S et al: HOPE-3 Trial : NEJM 2016 In an intermediate risk asymptomatic population, 10 mg daily of rosuvastatin reduced LDL-C by 25% and reduced CVD from 4.8% to 3.7% over a 5.6 yr period.

6 Who Needs Lipid Modifying Therapy? New AHA /ACC Guidelines Those with known athero-thrombotic cardiovascular disease 2. Diseases with high CHD risk: Type II Diabetes, AAA, CKD,, Cardiac transplant recipients, (RA,SLE, Psoriasis, HIV??) 3. Asymptomatic subjects at high risk for CHD events with one or more risk factors :a) LDL >190 and b) 10 yr risk of 7.5% using a new risk calculator High dose statin preferred in high risk and moderate dose in lower risk: LDL target not needed

7 Asymptomatic Subjects ( Primary Prevention of CHD) *Risk Assessment *Risk Reduction

8 How Good Is Framingham -NCEP III At Predicting MI in young? 222 patients with 1 st acute MI, no prior known CAD men <55 y/o (75%), women <65 (25%), no DM 10% 18% 72% CSMC--PKS High Risk Intermediate Risk Low Risk Akosah Et al, JACC 2003:

9 How Good Are Different Cardiovascular Risk Scores in Modern Cohorts CSMC--PKS DeFilipps Et al, Ann of Int Med 2015 Observed and expected events for the new AHA/ACC Risk Score Compared with 4 commonly used risk scores using MESA cohort Followed for 10.2 year; N=4227 ; Age=50-74 yrs Sobering Results ACC/AHA and 3 older scores overestimated risk by % in men and by 8-67% in women Reynolds risk score overestimated risk by 9% in men and underestimated Risk by 21% in women

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11 Qazi AH et al: Prog CV Dis 2016

12 Identification of High and Low Risk Subsets Shah PK: Journal of American College of Cardiology- imaging 2013

13 Identification of High and Low Risk Subsets Shah PK: Journal of American College of Cardiology- imaging 2013

14 Limitations of Statins Myalgias (common) Myositis (common) 10-20% Muscle weakness (common) Necrotizing auto immune myositis (NAM) (rare) Rhabdomyolysis ( %) (very rare) PKShah-CSMC

15 New Non-Statin Lipid-Lowering Medications * NPC-1L1 Inhibitor (Ezetemibe) *MTP Inhibitors (lomatipide) approved for HoFH (oral) *Apo B Antisence ( mipomersan) approved for HoFH (SC injection) *PCSK 9 Blockers (evolocumab, alirocumab, bococisumab)? *Thyroid Analogues? *AMP Modulator? *New CETP Inhibitors (anacetrapib, evacetrapib)? *Angiopoetin like 3 (ANGPTL3) Inhibitors * Sort-1 agonists * Antisense for Lpa * ApoCIII Inhibitors LDL-Apheresis Adapted from Chyu KY and Shah PK: Cardiology Clinics 2011

16 LDL-C Levels on Rx Sim: 69 mg/dl ARR=2 Sim+EZ= 53 mg/dl Benefit Largely Seen in Diabetics Only

17 Autosomal Dominant Familial Hypercholesterolemia Without a Mutation in Known Genes (LDL-R and Apo B100) French Proband 49 yr old with Tot Chol= 441 mg/dl LDL-C= 356 mg/dl French Proband 45 yr old with arcus senilis Tot Chol= 402 mg/dl LDL-C= 293 mg/dl Traits linked to chromosome 1 PCSK-9 Marianne Abifadel Necker-Enfants Malades Hospital,Paris Laboratory of Catherine Boileau PKShah-CSMC Abifadel M, et al. Nat Genet. 2003;34:

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20 Sustained LDL-C reduction with SC Injectable (q2-4wks) PCSK9 Inhibitors: Monoclonal Antibodies: Alirocumab and Evolocumab Robinson JG: NEJM 2015 Sabatine M: NEJM 2015 * 20-30% reduction in Lpa; no major effect on HDL or TG *Generally well tolerated; mostly injection site side effects Effects incremental to placebo, statins and or Ezetimibe 20

21 Sabbatine : NEJM 2017 Evolocumab and Clinical Events: Fourier Trial 9.8 vs 11.3 Absolute Risk Reduction Of 1.5%

22 Evolocumab and Clinical Events: Fourier Trial Sabbatine NEJM 2017 Cardiac death: Death from any cause: Myocardial infarction: 1.8 vs 1.7 ( p=ns) 3.2 vs 3.1( p=ns) 3.4 vs 4.6 (p<.001) Absolute RR=1.2% Stroke: 1.5 vs 1.9 (p=0.01) Absolute RR= 0.4% Revasc: 5.5 vs 7.0 ( p,.001) Absolute RR= 1.5% No effect on cardiac or all cause mortality No effect on hemorrhagic stroke No effect on new onset diabetes? Caveat No effect on cognitive function? Caveat No effect on cataract risk? Caveat PKShah-CSMC

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25 Indications of PCSK9 Inhibitors *Statin Intolerant Patients *Statin Insufficient Patients Major Drawbacks *High cost-modest efficacy *SC-Injections q2-4 weeks

26 26 Future Prospects for Lipid Modification ANGPTL-3 Inhibitors Lpa Antisense Apo CIII Inhibitors

27 27 Best Way to Reduce your Risk of CHD Choose Your Parents Wisely Preferably choose those with PCSK9 loss of function mutation