Robert A. Vogel, MD Clinical Professor of Medicine University of Colorado Denver Disclosures: National Coordinator: ODYSSEY Outcomes Study (Phase III Sanofi) Speakers Bureau: Sanofi, Regeneron
Case Report A 67 y/odiabeticm anhaschd and anefof30% (AICD). Hehasbeenangina-freeafteranL AD stenosisw astreated w ithades oneyear ago. T hreem onthsago,hepresented w ithangina and adenovolesionofhisr CA notpresentone yearago. N ow hisl AD stentlesionhasalsorestenosed. Hehasbeenon20m gofcrestor,10m g ofzetia,w itht C 170,L DL -C 80,T G 150 andhgb A1C,6.5. Arew edoingasm uchasw ecandofor hislipids?
The LDL (lipid) hypothesis is the concept that excess LDL and other atherogenic lipoproteins are the predominant causal factors in the development of atherosclerosis. This hypothesis also assumes that reducing LDL, regardless of the means, should produce a corresponding reduction in cardiovascular events. Adapted from Jarcho JA, Keaney, J Jr, NEJM 2015; 372:2448
Cell Division Lipid R udolfvirchow 1856
Michael Brown Joseph Goldstein Regulation of Cholesterol Metabolism via LDL Receptor Nobel 1985
Details of the LDL Hypothesis VLDL Remnants LDL Chylo (Apo-B48) Remnants Atherogenic particles Deposition Oxidation Mɸ uptake foam cells Cellular proliferation Matrix production Inflammation Plaque rupture & erosion Thrombosis Primary factor Facilitating factors
Boekholdt SM et al, JACC 2014;64:485 Cardiovascular Risk vs. Statin Treatment-achieved LDL-C in 8 RCTs (N = 38,153) Achieved LDL-C (mg/dl)
Nikpay M et al, Nature Genetics 2015;47:1121-32 1000 Genomes-based Genome-wide Association Analysis of CHD (185K cases and controls, 6.7 M common and 2.7M rare variants) LDLR Confirmed traditional risk factors: LDL Lp(a) RLPs TG SBP PCSK9
Ference BA et al, JACC 2012;60:2631 Mendelian Randomization Analysis: Genetically Lower LDL-C (9 variants) vs. CHD Risk in 312,321 Subjects 30% CHD Risk Reduction rs11591147 20% rs4420638 rs646776 rs2228671 10% rs12916 0% 0 rs6511720 rs599839 rs1206510 rs4299376 5 10 LDL-C (mg/dl) Reduction 15
Ference BA et al, JACC 2012;60:2631 Early vs. Late Cholesterol Lowering for Reducing CHD Risk: Statin Trials vs. Mendelian Analysis (9 SNPs, 6 genes) in 312,321 Subjects 1.0 mmol/l 0.5 mmol/l 0.25 mmol/l 0.125 mmol/l Genetically lower Statin trials CHD Risk
Case Study: 86 yof,asym ptom aticw ithonno m eds,w antsherm am m ography results P M H:negative,nevertookm eds FH:Fatherhad early CHD,Vineberg,died at66 P.E.:BP 152/78,P 78,BM I24 N orm al L abs:t C 316,L DL -C 210,HDL -C 54,T G 258 ECG:W N L ClinicalCourse:lived to96,died of old age
9Rodrigues F et al, JAMA Cardiol 2016, Nov 9. Statin Hypothesis : Annual Mortality in 509,766 Older VA Patients with ASCVD by Statin Treatment 7% Annual Mortality 6% 5% 4% 3% 2% 1% 0% No Statin Low-intensity Statin M0d-intensity Statin High-Intensity Statin
LDL-C, IDL-C Triglycerides, RLPs NO Availability NF- CRP M, MMP-1, MMP-3, MMP-9 Platelet Activation TF LDL Receptors Endothelial F n Inflammation Clotting
Ridker et al, N Engl J Med Aug 27, 2017 CANTOS: Canakinumab (IL-1β inhibitor) 50, 150, and 300mg SC q3mo vs. Placebo in 10,061 Subjects with prior MI and CRP >2 on Lipid Lowering over 4 Years MI, CVA, CVD with Canakinumab 150mg vs. Pbo (Initial LDL-C 82 mg/dl)
N aturegenetics2003;534:154 N EnglJM ed 2006;354:1264-72 Sequence variations in PCSK9, low LDL, and protection against coronary heart disease CohenJC,Boerw inklee,m osley T H Jr,HobbsHH RESULTS: O fthe3363 blacksubjectsexam ined,2.6 percenthad nonsensem utationsinp CS K9;thesem utationsw ere associated w itha28 percentreduction inm eanl DL cholesteroland an88 percentreduction intheriskofchd (P =0.008 forthereduction;hazard ratio,0.11;95 percent confidenceinterval,0.02 to0.81;p =0.03).O fthe9524 w hitesubjectsexam ined,3.2 percenthad asequence variation inp CS K9 thatw asassociated w itha15 percent reduction inl DL cholesteroland a47 percentreduction in theriskofchd (hazard ratio,0.50;95 percentconfidence interval,0.32 to0.79;p =0.003). CONCLUSIONS: T hesedataindicatethatm oderatelifelongreduction inthe plasm alevelofl DL cholesterolisassociated w itha substantialreduction intheincidenceofcoronary events, eveninpopulationsw ithahigh prevalenceofnon-lipidrelated cardiovascularriskfactors.
LDL, IDL, RLPs B/E Receptor) Cholesterol HMG--CoA HMG CoA--R 17 (Sterol regulating elementelement-binding protein)
PCSK9 Regulation of LDL Receptor Expression Forillustrationpurposesonly 18
Cohen JC, et al. NEJM 2006; 354: 1264 72 Loss-of-Function PCSK9 Genetic Variants are Associated with LDL-C and CHD CHD 47% CHD 88% LDL-C 28% Black Subjects LDL-C 15% White Subjects
Hooper AJ et al, Atherosclerosis 2007;193:445
Sabatine MS et al, N Engl J Med 3/17/17
N EnglJM ed3/17/17 FOURIER Trial: Adverse Events
Ridker PM et al, N Engl J Med 3/17/17 Bococizumab in 27K Subjects with ASCVD, DM, or CKD with >1RF SPIRE 1 LDL-C >70 7 Months SPIRE 2 LDL-C >100 12 Months
CTT Collaboration. Lancet 2005; 366:1267; Lancet 2010;376:1670. Wiviott SD et al. JACC 2005;46:1411 Pedersen T et al, JAMA 2005;294:2437 Statin vs. Pbo, Statin vs. Statin, IMPROVE-IT, and FOURIER Trials: Relationship of LDL-C Lowering to CVE Reduction IMPROVE-IT (simva 40/80 + eze) PROVE-IT (prava 40 vs. atorva 80) TNT St FOURIER (atorva 10 vs. 80) (simva + evolocumab) Statin vs. Pbo
Hepatic Cell LDL-R PCSK9 PCSK9 EGF-A Domain Catalytic Site Monoclonal antibodies:fully and partly hum anm Ab (FDA-approved) Peptide mimics:p eptidesthatm im ictheegf-a dom ainofthel DL receptor Gene silencing:m R N A antisenseoligonucleotides Anti-cleavage (furin) compounds Anti-PCSK9 vaccine
Case Report A 67 y/odiabeticm anhaschd and anefof30% (AICD). Hehasbeenangina-freeafteranL AD stenosisw astreated w ithades oneyear ago. T hreem onthsago,hepresented w ithangina and adenovolesionofhisr CA notpresentone yearago. N ow hisl AD stentlesionhasalsorestenosed. Hehasbeenon20m gofcrestor,10m g ofzetia,w itht C 170,L DL -C 80,T G 150 and Hgb A1C,6.5. Arew edoingasm uchasw ecandofor hislipids?
ACC and NLA Guidelines on PCSK9-I Use
PCSK9 induces LDL receptor degradation mab PCSK9 inhibitors reduce LDL-C 50-70% in patients on/off statins and in HeFH Initial two-year data demonstrates a 20% reduction in major CVEs in CHD subjects on statins The early safety profile appears good Initial annual retail cost is $15K Other approaches to PCSK9 are ac vely being investigated