Hyperlipidemia Guidelines: What s New in 2015? Eva Lonn, MD, MSc Professor of Medicine

Hyperlipidemia Guidelines: What s New in 2015? Eva Lonn, MD, MSc Professor of Medicine

The new england journal of medicine Original Article Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes Christopher P. Cannon, M.D., Michael A. Blazing, M.D., Robert P. Giugliano, M.D., Amy McCagg, B.S., Jennifer A. White, M.S., Pierre Theroux, M.D., Harald Darius, M.D., Basil S. Lewis, M.D., Ton Oude Ophuis, M.D., Ph.D., J. Wouter Jukema, M.D., Ph.D., Gaetano M. De Ferrari, M.D., Witold Ruzyllo, M.D., Paul De Lucca, Ph.D., KyungAh Im, Ph.D., Erin A. Bohula, M.D., D.Phil., Craig Reist, Ph.D., Stephen D. Wiviott, M.D., Andrew M. Tershakovec, M.D., M.P.H., Thomas A. Musliner, M.D., Eugene Braunwald, M.D., and Robert M. Califf, M.D., for the IMPROVE-IT Investigators* This article was published on June 3, 2015, at NEJM.org. N Engl J Med 2015;372:2387-97. DOI: 10.1056/NEJMoa1410489

Study Design Patients stabilized post ACS 10 days: LDL-C 50 125*mg/dL (or 50 100**mg/dL if prior lipid-lowering Rx) *3.2mM **2.6mM N=18,144 Standard Medical & Interventional Therapy Simvastatin 40 mg Uptitrated to Simva 80 mg if LDL-C > 79 (adapted per FDA label 2011) Ezetimibe / Simvastatin 10 / 40 mg Follow-up Visit Day 30, every 4 months 90% power to detect ~9% difference Duration: Minimum 2 ½-year follow-up (at least 5250 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization ( 30 days after randomization), or stroke Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

LDL-C and Lipid Changes 1 Yr Mean LDL-C TC TG HDL hscrp Simva 69.9 145.1 137.1 48.1 3.8 EZ/Simva 53.2 125.8 120.4 48.7 3.3 Δ in mg/dl -16.7-19.3-16.7 +0.6-0.5 Median Time avg 69.5 vs. 53.7 mg/dl

Primary Endpoint ITT 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

Individual Cardiovascular Endpoints and CVD/MI/Stroke HR Simva* EZ/Simva* p-value All-cause death 0.99 15.3 15.4 0.782 CVD 1.00 6.8 6.9 0.997 CHD 0.96 5.8 5.7 0.499 MI 0.87 14.8 13.1 0.002 Stroke 0.86 4.8 4.2 0.052 Ischemic stroke 0.79 4.1 3.4 0.008 Cor revasc 30d 0.95 23.4 21.8 0.107 UA 1.06 1.9 2.1 0.618 CVD/MI/stroke 0.90 22.2 20.4 0.003 0.6 1.0 1.4 Ezetimibe/Simva Better Simva Better *7-year event rates (%)

CV Death, Non-fatal MI, or Non-fatal Stroke HR 0.90 CI (0.84, 0.97) p=0.003 NNT= 56 Simva 22.2% 1704 events EZ/Simva 20.4% 1544 events 7-year event rates

50 Reduction in Rate of Major Vascular Events (%) 40 30 20 10 IMPROVE-IT 0 a b c d e f g h i j k l m n 10 0.5 1.0 1.5 2.0 Reduction in LDL Cholesterol (mmol/liter)

Conclusions IMPROVE-IT: First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy: YES: Non-statin lowering LDL-C with ezetimibe reduces cardiovascular events YES: Even Lower is Even Better (achieved mean LDL-C 53 vs. 70 mg/dl at 1 year) YES: Confirms ezetimibe safety profile Reaffirms the LDL hypothesis, that reducing LDL-C prevents cardiovascular events Results could be considered for future guidelines

PCSK9 Inhibitors are here Recent FDA and EMEA approval of evolocumab and alirocumab for the treatment of high risk patients who have not achieved adequate LDL-C lowering on maximum tolerated therapy

Serum In the Presence LDL-Cholesterol of PCSK9, Binds the to LDL-R LDL-Receptors. Is Degraded Following and Does Not Cycle Back to Cell Internalization, LDLSurface is Degraded and the Receptor Recycled Discovered in Canada Plasma LDL PCSK9 LDL LDL-R LDL-R Endocytosis Hepatocyte Endocytosis LDL-R Recycling Endosome PCSK9 Self-procession Endosome Golgi Apparatus LDL Degradation LDL, LDL-R and PCSK9 Degradation Nucleus Qian YW, et al. J Lipid Res. 2007;48:1488-1498; Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177. Endoplasmic Reticulum (ER) 2013 Amgen Canada Inc. All rights reserved.

Monoclonal Blocking PCSK9 Antibody Activity binds Inhibits to PCSK9 and inhibits Intracellular Binding to the Degradation LDL-Receptor of LDL-R PCSK9 MAb Plasma LDL LDL-R LDL-R Recycling Endocytosis Endosome Hepatocyte PCSK9 Self-procession Lyosome Golgi Apparatus LDL Degradation Nucleus Endoplasmic Reticulum (ER) 2013 Amgen Canada Inc. All rights reserved. Qian YW, et al. J Lipid Res. 2007;48:1488-1498; Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177.

Loss-of-function Mutations in PCSK9 Are Associated with Lower Serum LDL-C and Lower Incidence of CHD 30 No Mutation (N=3,278) 50 th Percentile 20 12 Frequency (%) 10 8 PCSK9 0 loss-of-function mutations found in 1% to 4% of 0 1.3 2.6 3.9 5.2 6.5 7.8 population Associated with Loss of function mutation PCSK9 142X or PCSK9 679X (N=85) 30 20 10 28% reduction in mean LDL-C 88% reduction in lifetime risk of CHD* Coronary Heart Disease (%) 4 0 No Yes PCSK9 142X or PCSK9 679X 0 0 1.3 2.6 3.9 5.2 6.5 7.8 Plasma LDL-C in Black Subjects (mmol/l) *(P = 0.008 for the reduction; hazard ratio, 0.11; 95% CI, 0.02 to 0.81; P = 0.03) Cohen JC, et al. N Engl J Med. 2006;354:1264-1272.

PROFICIO Program Evaluates Reduction in LDL-C, Atherosclerosis, and CV Risk with Evolocumab Combo-therapy with statin Phase 2 Phase 3 LAPLACE (N = 629) LAPLACE-2 (N = 1,896) Mono-therapy MENDEL (N = 406) MENDEL-2 (N = 614) Statin-intolerant GAUSS (N = 157) GAUSS2 (N = 329) GAUSS3 (N = 100) HeFH with LDLR mutations HoFH with mutations in both LDLR alleles Long-term safety and efficacy Open-label extension Plaque imaging study Secondary prevention RUTHERFORD (N = 167) TESLA (N < 67) OSLER (N = 1,324) RUTHERFORD-2 (N = 307) TESLA/TAUSSIG (N < 250) DESCARTES (N = 901) OSLER-2 (N > 3,800) GLAGOV (N = 950) FOURIER (N = 22,500) Clinicaltrials.gov; Koren MJ, et al. Lancet. 2012;380:1995-2006; Guigliano RP, et al. Lancet. 2012;380:2007-17; Sullivan D, et al. JAMA. 2012;308:2497-506; Raal FJ, et al. Circulation. 2012;26:2408-17.

Co-primary Endpoint: Consistent, Clinically Equivalent LDL-C Reduction Mean Percent Change from Baseline in LDL-C at Week 10/12 10 0-10 -20-30 -40-50 -60-70 10-10 -30-50 Combination Therapy ( 115) Monotherapy ( 114) 10-10 -30-50 Q2W QM -70 Q2W QM HeFH ( 117) Statin-intolerant ( 116) 10-10 -30-50 -70 Q2W QM -70 Q2W QM Placebo Week 10 and 12 Evo Week 10 and 12 Ezetimibe Week 10 and 12 Note: p<0.001 for all comparison versus placebo or ezetimibe

Alirocumab: ODYSSEY Phase II/III Program Overview PII Primary/secondary Prevention N = 77; 12 weeks Primary Hypercholesterolemia N = 92; 8 weeks HeFH population Add-on to max tolerated statin (+/- other LMT) HC in high CV risk population HC in high CV risk population (+/- other LMT)* Additional populations ODYSSEY MONO Patient on no background LMT N = 100; 6 months PIII ODYSSEY FH I N = 471; 18 months ODYSSEY FH II N = 250; 18 months ODYSSEY HIGH FH N = 105; 18 months ODYSSEY LONG TERM N = 2,100; 18 months ODYSSEY COMBO I N = 306; 12 months ODYSSEY COMBO II N = 660; 24 months ODYSSEY CHOICE I N = 700; 12 months ODYSSEY ALTERNATIVE Patients with defined statin intolerance N = 660; 24 months ODYSSEY CHOICE II Patients with hypercholesterolemia on non-statin LMT or diet N = 200; 6 months ODYSSEY OPTIONS I Patients not at goal with moderate dose atorvastatin N = 350; 6 months LMT= lipid modifying therapy * For the ODYSSEYCOMBO II other LMT not allowed at entry Clinicaltrials.gov ODYSSEY OUTCOMES N = 18,000 ODYSSEY OPTIONS II Patients not at goal with moderate dose rosuvastatin N = 300; 6 months

Alirocumab (PCSK9i mab): Phase III LDL-C Lowering Summary % change from baseline in reflexive LDL-C 10 0-10 -20-30 -40-50 -60 Monotherapy* Q2W n=52-54.1% EZE n=51-17.2% 26.9% had dose increase at W12 FH I FH II (HeFH, Combo with Statin) 9.1% 2.8% N=163 N=322 48.8% 48.7% 43.4% had dose increase at W12 COMBO II* (Combo with Statin) Alirocumab 75 mg with potential to 150 mg Q2W SC, except for LONG TERM:Alirocumab 150 mg Q2W SC *Ezetimibe comparator N=81 N=166 38.6% had dose increase at W12 N=467 50.6% 18.4% had dose increase at W12 N=240 20.7% 38.6% had dose increase at W12 LONG TERM (HeFH or high-risk, Combo with Statin) 0.8% N=780 Placebo Alirocumab Ezetimibe 61.0% Kastelein JJP, et al. Presented at ESC Sept 2014 (FH I & FH II); Roth EM, et al. Int J Cardiol. 2014 Sep;176(1):55-61 (MONOTHERAPY); Cannon CP, et al. Presented at ESC Sept 2014 (COMBO II); Robinson JG, et al. Presented at ESC Sept 2014 (LONG TERM).

Robinson JG et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1501031 18

ODYSSEY LONG TERM Study Design HeFH or High CV-risk patients On max-tolerated statin ± other lipid-lowering therapy LDL-C 1.81 mmol/l [70 mg/dl] Assessments R W0 n=1553 n=788 W4 W8 W12 Double-blind treatment (18 months) Alirocumab 150 mg Q2W SC (single 1-mL injection using prefilled syringe for self-administration) Placebo Q2W SC W16 W24 W36 W52 W64 W78 Follow-up (8 weeks) Primary efficacy endpoint Pre-specified analysis Efficacy: All Patients uo to W52 Safety: Baseline-W78 All patients 73% completed the study (both treatment arms) 99.9% were included in the safety analysis (both treatment arms) ClinicalTrials.gov identifier: NCT01507831.

LDL-C Over Time

Mean Kaplan-Meier treatment Estimates for Time to First Adjudicated Major CV Event duration: 80 weeks No. at Risk Placebo Alirocumab 21 Post-hoc Adjudicated Cardiovascular TEAEs Safety Analysis (at least 52 weeks for all patients in ongoing study) Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit) Cumulative probability of event 0.06 0.05 0.04 0.03 0.02 0.01 0.00 0 788 1550 Placebo + max-tolerated statin ± other LLT Alirocumab + max-tolerated statin ± other LLT Cox Cox model model analysis: analysis: HR=0.46 HR=0.52 (95% (95% CI: CI: 0.26 0.31 to to 0.82) 0.90) Nominal Nominal p-value p-value = <0.01 0.02 12 776 1534 24 731 1446 Mean treatment Duration: duration: 80 65 weeks Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy Robinson JG et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1501031 36 703 1393 48 682 1352 60 667 1335 72 321 642 84 127 252 Weeks

Cardiovascular Outcomes 3 Composite Endpoint: Death, MI, UA hosp, coronary revasc, stroke, TIA, or CHF hosp Cumulative Incidence (%) 2 1 HR 0.47 95% CI 0.28-0.78 P=0.003 Standard of care alone (N=1489) 2.18% 0.95% 0 Evolocumab plus standard of care (N=2976) 0 30 60 90 120 150 180 210 240 270 300 330 365 Days since Randomization

Ongoing Outcome Trials with PCSK9 Inhibitors Study FOURIER ODYSSEY OUTCOMES SPIRE-1 Treatment Evolocumab 420 mg Q4W or 140 mg Q2W with atorvastatin Background: EZE allowed Alirocumab 75 mg Q2W (up titrated to 150 mg Q2W if LDL > 1.3 mmol/l; down titrated if LDL < 0.65mmol/L) Background: optimized lipid lowering therapy Bococizumab 150 mg Q2W Background: Lipid lowering therapy Population Recent MI or stroke (< last 6 months) OR Recent history ( 5 years) MI or stroke and either a history of T2DM or, if not diabetic, additional risks factors Patients hospitalized for ACS (<12 months before randomization) Patients at high risk of a CV event # patients 22,500 18,000 12,000 LDL-C for eligibility LDL-C 1.8 mmol/l (or non- NonHDL-C 2.6 mmol/l) after 4 week stabilization with atorva ± EZE 1.8 mol/l LDL C 1.8 and < 2.6 mmol/l Est. study completion February 2018 January 2018 August 2017 EZE = ezetimibe Source: clinicaltrials.gov

Changes in Lipid Guidelines and Cholesterol Targets Have Typically Followed Shortly after Clinical Trials 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 KEY TRIALS CANADIAN GUIDELINES HPS ASCOT PROVE-IT TIMI 22 CCS < 2.5 mmol/l and TC:HDL-C <4.0 TNT CTTC CCS < 2 mmol/l or 50% Reduction CTTC (14 trials) CCS < 2 mmol/l or 50% Reduction CTTC (27 trials) JUPITER CCS < 2 mmol/l or 50% Reduction US GUIDELINES EU GUIDELINES NCEP ATP III, AHA/ACC 2.6 mmol/l ESC 2 nd Task Force 2.6 mmol/l NCEP ATP III Revised AHA/ACC 2.6mmol/L 2.6mmol/L 1.8mmol/L 1.8mmol/L Optional Optional ESC 3 rd Task Force 2.6mmol/L (2.1 mmol/l if feasible) AHA/ACC 2.6mmol/L 1.8mmol/L Optional ESC 4 th Task Force 1.8mmol/L or 50% Reduction AHA/ACC Sources: clinicaltrials.gov; Canadian Cardiovascular Society (ccs.ca); National Cholesterol Education Program USA (nhlbi.nih.gov); European Society of Cardiology (escardio.org).

LDL-C Remains the Primary Target with Emerging Role for Non-HDL-C and ApoB as Alternate Targets Risk Level Initiate Therapy If Primary Target LDL-C Alternate Target High FRS 20% Consider treatment in all (Strong, High) 2 mmol/l or 50% decrease in LDL-C (Strong, High) ApoB 0.8 g/l Non HDL-C 2.6 mmol/ L (Strong, High) Intermediate FRS 10%-19% LDL-C 3.5 mmol/l (Strong, Moderate) For LDL-C < 3.5 consider if: Apo B 1.2 g/l or Non-HDL-C 4.3 mmol/l (Strong, Moderate) 2 mmol/l or 50% decrease in LDL-C (Strong, Moderate) ApoB 0.8 g/l Non HDL-C 2.6 mmol/l (Strong, Moderate) Low FRS < 10% LDL-C 5.0 mmol/l Familial hypercholesterolemia (Strong, Moderate) 50% decrease in LDL-C (Strong, Moderate) Strong, High: Strong Recommendation, High-quality Evidence Strong, Moderate: Strong Recommendation, Moderate-quality Evidence Anderson TJ, Grégoire J, et al. 2012 Update of CCS Dyslipidemia Guidelines. Can J Cardiol. 2013;29:151 167.

Comparison of Guidelines: More Similar than Different CCS EAS/ESC AHA/ACC Risk Assessment Tool Modified Framingham Risk Score (FRS) Systematic COronary Risk Evaluation (SCORE) Pooled Cohort Atherosclerotic CV Disease (ASCVD) Risk Estimator Estimates 10-year risk of developing cardiovascular disease using: Age Gender Total cholesterol HDL-C Smoking Systolic blood pressure On medication for high BP Diabetes Estimates 10-year risk of first fatal atherosclerotic event using: Age Gender Total cholesterol HDL-C Smoking Systolic blood pressure Diabetes Predicts 10-year risk for a first atherosclerotic cardiovascular disease (ASCVD) event using: Age Gender Total cholesterol HDL-C Smoking Systolic blood pressure On medication for high BP Diabetes Race Other Risk Estimations Cardiovascular age Lifetime risk Total (fatal+non-fatal) Cardiovascular disease Lifetime risk CKD or High Risk Hypertension Treat with statins Treat with statins No specific recommendations Includes global CVD (coronary and cerebrovascular disease and CHF) Estimates hard CHD (coronary death or MI) Anderson TJ, Grégoire J, et al. 2012 Update of CCS Dyslipidemia Guidelines. Can J Cardiol. 2013;29:151 167; Stone NJ, et al. 2013 ACC/AHA Guideline. Circulation. 2014; 29(25 Suppl 2):S1-S45; Reiner Ž et al. ESC/EAS Guidelines for the management of dyslipidaemias. Atherosclerosis. 217S (2011);S1-S44, doi:10.1016/j.atherosclerosis.2011.06.012.

Stay Tuned New CCS Guidelines October 2015 CCC