Contemporary management of Dyslipidemia Todd Anderson Feb 2018
Disclosure Statement Within the past two years: I have not had an affiliation (financial or otherwise) with a commercial organization that may have a direct or indirect connection to the content of my presentation. I have had an affiliation (financial or otherwise) with a commercial organization that may have a direct or indirect connection to the content of my presentation. Details below. Does your presentation describe the off-label use of a device, product, or drug that is approved for another purpose? No Yes If you answered YES, you must disclose this to the audience within your presentation Type of Relationship A - Consulting Fees/Honoraria B - Officer, Director, Or In Any Other Fiduciary Role C Clinical Trials D - Ownership/Partnership/Principal E - Intellectual Property Rights F - Other Financial Benefit Modest (less than $10K) Amgen, Sanofi, Bayer Organization Name Significant (greater than $10K) Merck, Amgen, Dal-cor www.ccs.ca
Approach to Risk Management Who, how when to screen How to evaluate risk When to initiate what treatment Monitoring and surveillance
Areas to consider guideline change Target levels of LDL-C Role of Combination therapy Risk assessment strategies
Category Primary prevention Statin indicated conditions Consider Initiating pharmaco-therapy if High FRS ( 20%) all Intermediate FRS (10-19%) LDL-C 3.5 mmol/l or Non-HDL 4.3 mmol/l or Apo B 1.2 g/l or Men 50 and women 60 yrs and one additional CVD RF Clinical atherosclerosis* Abdominal aortic aneurysm Diabetes mellitus >40 yrs 15 yrs duration for age >30 yrs (DM 1) Microvascular disease Chronic kidney disease (age 50 y) egfr < 60 ml/min/1.73 m 2 or ACR > 3 mg/mmol LDL-C 5. 0 mmol/l Target LDL-C < 2.0 mmol/l or > 50% Or Apo B < 0.8 g/l Or non-hdl-c < 2.6 mmol/l >50% in LDL-C FRS modified Framingham Risk Score; ACR albumin:creatinine ratio; * consider LDL- C < 1.8 mmol/l for subjects with ACS within last 3 months NNT 35 40 20
The Case for Lower is Better Biological plausibility Apo B lipoproteins linked to atherogenesis Epidemiology data Mendelian randomization On Rx LDL- C related to events CTT meta- analysis 22% reduction per 1 mmol/l IVUS trials Emerging randomized trial data with new meds www.ccs.ca
Biological Plausibility Statin effect is mediated entirely by change in LDL-C www.ccs.ca Labos et al. ATVB 2018;; ahead of press
CHD Reduction from Earlier LDL-C Lowering: Lifetime low LDL Lifetime lower LDL-C due to genetics resulted in a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life Association between 1mmol/L lower LDL-C and risk of CHD www.ccs.ca Ferrence BA, et al. J Am Coll Cardiol. 2012;60(25):2631-9.
Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction, by baseline LDL-C No. of events (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction More vs less statin <2.0 ³ 2,<2.5 ³ 2.5,<3.0 ³ 3,<3.5 ³ 3.5 Total 704 (17.9%) 1189 (18.4%) 1065 (20.1%) 517 (20.4%) 303 (23.9%) 3837 (19.4%) 795 (20.2%) 1317 (20.8%) 1203 (22.2%) 633 (25.8%) 398 (31.2%) 4416 (22.3%) 0.71 (0.52-0.98) 0.77 (0.64-0.94) 0.81 (0.67-0.97) 0.61 (0.46-0.81) 0.64 (0.47-0.86) 0.72 (0.66-0.78) Statin vs control <2.0 ³ 2,<2.5 ³ 2.5,<3.0 ³ 3,<3.5 ³ 3.5 Total 206 (9.0%) 339 (7.7%) 801 (8.2%) 1490 (10.8%) 4205 (12.6%) 7136 (11.0%) 217 (9.7%) 412 (9.1%) 1022 (10.5%) 1821 (13.3%) 5338 (15.9%) 8934 (13.8%) 0.87 (0.60-1.28) 0.77 (0.62-0.97) 0.76 (0.67-0.86) 0.77 (0.71-0.84) 0.80 (0.77-0.84) 0.79 (0.77-0.81) All trials <2.0 ³ 2,<2.5 ³ 2.5,<3.0 ³ 3,<3.5 ³ 3.5 Total 910 (14.7%) 1528 (14.0%) 1866 (12.4%) 2007 (12.3%) 4508 (13.0%) 10973 (13.0%) 1012 (16.4%) 1729 (15.9%) 2225 (14.7%) 2454 (15.2%) 5736 (16.5%) 13350 (15.8%) 0.78 (0.61-0.99) 0.77 (0.67-0.89) 0.77 (0.70-0.85) 0.76 (0.70-0.82) 0.80 (0.76-0.83) 0.78 (0.76-0.80) 99% or 95% CI 0.5 0.75 1 1.25 1.5 Statin/more better Control/less better
Primary Endpoint ITT (2014) Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke HR 0.936 CI (0.887, 0.988) p=0.016 Simva 34.7% 2742 events NNT= 50 EZ/Simva 32.7% 2572 events 7-year event rates
LDL Cholesterol 100 90 Placebo LDL Cholesterol (mg/dl) 80 70 60 50 40 30 20 10 59% mean reduction (95%CI 58-60), P<0.00001 Absolute reduction: 56 mg/dl (95%CI 55-57) Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School
Primary Endpoint CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 16% 14% 12% 10% 8% 6% 4% 2% Hazard ratio 0.85 14.6% (95% CI, 0.79-0.92) P<0.0001 Placebo 12.6% Evolocumab 0% 0 6 12 18 24 30 36 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization
PCSK9 Inhibition and Very low LDL- C www.ccs.ca Giugliano et al. Lancet Aug 28, 2017 25,982 Fourier patients 4 week LDL-C Positive outcomes down to 0.2 mmol/l
PCSK9 Inhibition and Very low LDL- C 25,982 Fourier patients 4 week LDL-C Positive outcomes down to 0.2 mmol/l Primary EP death, MI, revasc, www.ccs.ca Giugliano et al. Lancet Dyslipidemia Aug 28, 2017Guidelines hospitalization for UA
Ongoing Outcome Trials with PCSK9 Inhibitors Study FOURIER ODYSSEY OUTCOMES SPIRE- 1/ SPIRE- 2 Treatment Evolocumab: 420 mg QM or 140 mg Q2W Background: optimal lipid lowering therapy Alirocumab: 75 mg Q2W (up titrated to 150 mg Q2W if LDL >1.3 mmol/l;; down titrated if LDL <0.65 mmol/l) Background: optimized lipid lowering therapy Bococizumab: 150 mg Q2W Background: lipid lowering therapy Population MI or stroke ( last 4 weeks) OR PAD (plus Risk factors for CVD) Patients hospitalized for ACS (<12 months before randomization) Patients at high risk of a CV event # patients 27,500 18,000 SPIRE-1: 17,000 SPIRE-2: 9,000 LDL-C for eligibility LDL-C 1.8 mmol/l (or non- HDL-C 2.6 mmol/l) after 4 week stabilization with optimal lipid lowering therapy 1.8 mol/l or non-hdl-c 2.6 mmol/l SPIRE-1: LDL-C 1.8 and <2.6 mmol/l SPIRE-2: LDL-C 2.6 mmol/l or non-hdl-c 3.4 mmol/l Estimated study completion 2017 December 2017 SPIRE-1:June 2018 SPIRE-2: March 2018 ACS: acute coronary syndrome; CAD: coronary artery disease; CHD: coronary heart disease; CVD: coronary vascular disease; EZE: ezetimibe; FH:Familial Hypercholesterolemia; HeFH: Heterozygous Dyslipidemia Familial Hypercholesterolemia; Guidelines PAD: peripheral- artery disease; T2DM: type 2 diabetes mellitus. clinicaltrials.gov accessed August 25, 2015. www.ccs.ca
CETP Inhibition in CV disease www.ccs.ca Landry et al. NEJM;; Aug 24, 2017 30449 in TIMI 55/Reveal Study
www.ccs.ca
Targets ACC/AHA www.ccs.ca Lloyd-Jones JACC 2017
When to Consider Pharmacological Treatment in Risk Management Statin Indicated conditions www.ccs.ca
Targets American Association of Clinical Endocrinologists www.ccs.ca Jellinger et al. Endocrine Practice 2017;;23:supplement
Quantitative approach to non-statins Defined risk based on trials Used % reduction in LDL-C for various drugs to determine NNT in different scenarios CTT estimate of event reduction based on 22% per 1 mmol/l Very high risk CVD plus DM or CKD or FH, or recent ACS High risk CVD alone, or FH in primary prevention www.ccs.ca Robinson et al. JACC 2016;;68:2412
PCSK9 Inhibition cost effectiveness Annual event rate of 6.4%/yr www.ccs.ca Fonarow et al, JAMA Cardiology, August 2017
Areas to consider guideline change Target levels of LDL-C Lower target of 1.8 for ASCVD Elimination of target use indications for combination therapy > 50 % reduction and target of < 1.8 for ASCVD Role of Combination therapy Change in status of PCSK9 inhibitors Risk assessment strategies More categories of risk Different algorithms to determine risk instead of just FRS or statin indicated conditions www.ccs.ca