Lipids: new drugs, new trials, new guidelines

Lipids: new drugs, new trials, new guidelines Milan Gupta, MD, FRCPC, FCCS State of the Heart Co-Chair Associate Clinical Professor of Medicine, McMaster University Assistant Professor of Medicine, University of Toronto Medical Director, Canadian Collaborative Research Network Brampton, ON

Lipids: New Drugs, New Trials, New Guidelines Milan Gupta, MD Department of Medicine University of Toronto, McMaster University Canadian Collaborative Research Network www.ccrnmd.com

Disclosures Honoraria / Research Abbott, Aegerion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Merck, Miraculins, Novartis, Novo-Nordisk, Pfizer, Roche, sanofi-aventis, Servier, Valeant Primary panel member - 2016 CCS lipid guidelines

Overview The primacy of LDL cholesterol as a risk factor New mechanisms for LDL lowering The 2016 CCS lipid guidelines

PCSK Family of Proteins

CTTC meta-analysis of statin trials

Lessons from the CTTC meta-analysis Statins lower risk to the same relative degree independent of baseline risk and baseline LDL-C The absolute risk benefit with statins is greatest in the highest risk patients High intensity vs. lower intensity statin therapy further lowers risk No RCT has tested a specific strategy of dosing statin to achieve a pre-specified LDL-C target However, evidence suggests that treatment at lower and lower levels, leading to lower and lower achieved LDL-C levels, supports a "lower is better" philosophy 1. Cholesterol Treatment Trialists (CTT) Collaboration. Lancet. 2010;376:1670-1681. 2. Cholesterol Treatment Trialists (CTT) Collaborators. Lancet. 2005;366:1267-1278.

Intensive LDL-C Lowering Promotes Plaque Regression LDL-C Levels and Atherosclerosis Progression in IVUS Studies 1,2 Median Change in PAV (%) 2 1 0 1 ASTEROID Rosuvastatin REVERSAL Atorvastatin STRADIVARIUS Placebo SATURN 2 Rosuvastatin PRECISE-IVUS (ACS) Atorvastatin+Ezetimibe 3 1.0 1.6 2.1 2.6 Average On-Treatment LDL-C (mmol/l) 3.1 On treatment duration ranged from 10 to 24 months Puri R et al. Am Heart J. 176:83-92; Kenichi T et al J Am Coll Cardiol. 2015: 66:495-507. CAMELOT Placebo ILLUSTRATE Atorvastatin PRECISE-IVUS (ACS) Atorvastatin SATURN Atorvastatin REVERSAL Pravastatin

Patients with Genetically Lower LDL have Correspondingly Better CV Event Reduction Proportional Risk Reduction (SE) log scale 20% 10 % ABCG5/8 rs4299376 HMGCR rs1291 PCS 6 K9 rs247940 9 NPC1L rs21738 1 6 LDLR rs222867 1 PCSK9 rs1120651 0 HMGCR LDL-C NPC1L1 Score LDL-C Score Genetically Lower LDL-C NPC1L1 LDL-C Score HMGCR LDL-C Score LDLR rs651172 Combined 0 NPC1L1 & HMGCR LDL-C Score A to Z SEAR CH PCSK9 46L rs1159114 7 Pharmacologically Lower LDL-C GISSI -P IMPROVE- IT ALLHAT- LLT 0.003.005.078.104.130.155.181.207.233.259.285.311.330.363.389.389.440.466.492. 518. 544 Ference BA, et al. J Am Coll Cardiol. 2015;65(15):1552-1561 Lower LDL-C (mmol/l)

IMPROVE-IT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke Hazard Ratio, 0.936 (95% CI, 0.89-0.99) p=0.016 Simvastatin: 34.7% - 2742 events Mean LDL-C = 1.8 mmol/l NNT*= 50 Event Rate (%) Simvastatin/Ezetimibe: 32.7% - 2572 events Mean LDL-C = 1.4 mmol/l Time since randomization (years) * NNT = Number Needed to Treat Cannon CP et al. N Engl J Med 2015;372:2387-2397.

Overview The primacy of LDL cholesterol as a risk factor New mechanisms for LDL-lowering The 2016 CCS lipid guidelines

DYSIS Canada - LDL-C Levels in High Risk* Patients 2,436 participants from across Canada of whom 1,913 were considered high risk* LDL-C <2.0 mmol/l On a potent statin with suboptimal dose On an additional lipid-lowering agent 12% 14% 55% 45% 88% 86% Yes No *coronary artery disease, peripheral arterial disease, cerebrovascular disease, diabetes mellitus or Framingham 10-year risk score 20%. Goodman SG et al. Can J Cardiol 2010;26:e330-e335. 13

Barriers to LDL-C Management Over reliance on diet Use of insufficient starting doses Inability to reach more aggressive targets even with high dose statin Lack of follow-up for uptitration Complacency with sub-optimal cholesterol values achieved Confusion around recommended lipid targets Fear of sideeffects of statins Inertia Patient Non- Adherence Media / Dr. Google 14

Serum LDL-Cholesterol Binds to LDL-Receptors. Following Internalization, LDL is Degraded and the Receptor Recycled 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.

PCSK Family of Proteins

Efficacy of PCSK9 Inhibitors

Adverse Event Profiles of PCSK9i ODYSSEY Long Term study OSLER 1 and 2* Alirocumab (N=1550) Placebo (N=788) Evolocumab + standard of care (N=2976) Standard of care alone (N=1489) Adverse Events (%) Adverse Events (%) Adverse Events (%) Any 81% 82.5% 69.2% 64.8% Serious 18.7% 19.5% 7.5% 7.5% Leading to discontinuation of PCSK9i 7.2% 5.8% 2.4% n/a Injection-site reactions 5.9% 4.2% 4.3% n/a Muscle-related 5.4% 2.9% 6.4% 6.0% Neurocognitive 1.2% 0.5% 0.9% 0.3% Laboratory results (%) Laboratory results (%) Laboratory results (%) ALT or AST >3 ULN 1.8% & 1.4% 2.1% & 2.3% 1.0% 1.2% Creatine kinase >5 ULN 3.7% 4.9% 0.6% 1.1% * Pooled analysis from extension studies approximately 1 year of therapy; Adapted from 1. ODYSSEY LONG TERM Investigators. N Engl J Med. 2015 ;372:1489-99. 2. Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. N Engl J Med. 2015;372:1500-9.;

OSLER: Reduced Cardiovascular Event Rates Amongst Individuals Receiving Evolocumab* 3 Composite Endpoint: Death, MI, UA hospitalization coronary revasc, stroke, TIA, or CHF hospitalization Cumulative Incidence (%) 2 1 HR 0.47 95% CI 0.28-0.78 P=0.003 Evolocumab plus standard of care (N=2976) [29 events] Standard of care alone (N=1489) [31 events] 2.18% 0.95% 0 0 30 60 90 120 150 180 210 240 270 300 330 365 Days since Randomization *Pre-specified exploratory analysis from open-label extension studies OSLER 1 and 2 of adjudicated cardiovascular events. Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. N Engl J Med. 2015;372:1500-9.

ODYSSEY Long-Term: Reduced Cardiovascular Event Rates amongst Patients Receiving Alirocumab (Post-hoc Analysis) 0.06 Alirocumab [150 mg q2w] + maximally tolerated statin ± other LLT (27 events*; N=1550) Placebo + maximally tolerated statin ± other LLT (26 events*; N=788) Cumulative probability of event 0.04 0.02 0 No. patients at risk Placebo Alirocumab 0 12 24 36 52 64 78 86 788 1550 HR = 0.52 (95% C.I 0.31 to 0.90) Nominal P value = 0.02 Mean treatment duration: 70 weeks 776 1533 731 1445 Time (weeks) 700 1392 670 1342 653 1306 644 1266 597 1170 *, adjudicated major adverse cardiovascular events in post hoc analysis LLT, lipid-lowering therapy Robinson JG et al. N Engl J Med. 2015 ;372:1489-99.

ACCELERATE: Evacetrapib vs. placebo Cumulative Event Rate (%) 20 15 10 5 0 Cumulative Incidence of Primary Efficacy Endpoint Evacetrapib, 774 events (12.8%) Placebo, 768 events (12.7%) HR=1.01 95% CI, 0.91-1.12 P=0.85 0 6 12 18 24 30 36 N=12,092 high vascular risk individuals randomized to either evacetrapib 130 mg or placebo Follow-up 1.5 years Compared with placebo, evacetrapib was associated with 37% drop in LDL-C (2.2 mmol/l vs 1.4 mmol/l) 130% rise in HDL-C (2.7 mmol/l vs 1.2 mmol/l) MACE was similar in the two arms evacetrapib: 12.8%, placebo, 12.7%; HR=1.01; 95% CI, 0.91-1.12 Months Following Randomization HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular events. Nicholls SJ et al. Joint ACC/JAMA Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2016; Chicago, IL, USA.

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 Familial Hypercholesterolemia; PAD: peripheral-artery disease; T2DM: type 2 diabetes mellitus. clinicaltrials.gov accessed August 25, 2015.

Overview The primacy of LDL cholesterol as a risk factor New mechanism for LDL lowering The 2016 CCS lipid guidelines

Lipid Guidelines

Major Changes Since 2012 Guidelines 26 Change Lipid screening for both men and women 40 years of age Inclusion of screening for women with a history of hypertensive diseases of pregnancy Non-fasting lipid determination recommendation LDL-C as primary, non-hdl-c or apob as alternative targets Detailed review of the impact of nutritional components on lipids and CV events Broader treatment recommendations for those in intermediate risk category Retention of treatment targets for those on therapy Statins remain drugs of choice New recommendation for non-statin drugs LDL-C low density lipoprotein cholesterol; apo B apolipoprotein B; CKD chronic kidney disease; DASH Dietary Approaches to Stop Hypertension 26

How to Screen 27 Recommendations We recommend non-fasting lipid and lipoprotein testing which can be performed in adults in whom screening is indicated as part of a comprehensive risk assessment to reduce CVD events. Strong Recommendation, High Quality Evidence We suggest that for individuals with a history of triglyceride levels > 4.5 mmol/l that lipid and lipoprotein levels be measured fasting Conditional Recommendation, Low Quality Evidence Practical tip: Compared to fasting lipid values, there will be minimal change with non HDL-C, a slight decrease in LDL-C and small increase in triglyceride concentrations when individuals do not fast. 27

Intermediate-Risk Population Inclusion Criteria (Target Risk 1.0%/yr) Women 60 yrs, men 55 yrs with at least one additional Risk Factor Increased WHR Smoking Low HDL-C Dysglycemia Mild renal dysfunction Family history of CHD Exclusion Criteria: CVD or indication(s) or contraindication(s) to study drugs No strict BP or LDL-C criteria for entry Uncertainty principle 5

CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure Cumulative Hazard Rates 0.0 0.02 0.04 0.06 0.08 0.10 HR (95% CI) = 0.75 (0.64-0.88) P-value = 0.0004 Placebo Rosuvastatin Rosuva Placebo 0 1 2 3 4 Years 5 6 7 6361 6241 6039 2122 6344 6192 5970 2073 23

2016 CCS Lipid Guidelines Statin Indicated Conditions (those who will benefit the most): Clinical atherosclerosis* Abdominal aortic aneurysm Most diabetes mellitus CKD (age >50 years) LDL-C 5.0 mmol/l Treatment Targets: LDL-C consistently <2.0 mmol/l or >50% reduction Consider <1.8 mmol/l in patients with clinical atherosclerosis Apo B 0.80 g/l or non-hdl-c 2.6 mmol/l can be considered as alternative treatment targets *Clinical atherosclerosis, i.e. previous MI, or coronary revascularization by PCI or CABG surgery, other arterial revascularization procedures, angina pectoris, cerebrovascular disease including TIA, or peripheral arterial disease (claudication and/or ABI <0.9). Anderson TJ et al. Canadian Cardiovascular Society Guidelines for the management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult, Canadian Journal of Cardiology (2016), doi: 10.1016/ j.cjca.2016.07.510

Non Statin Drugs for ASCVD Prevention We recommend ezetimibe as second-line therapy to lower LDL-C in patients with clinical cardiovascular disease if targets are not reached on maximally tolerated statin therapy. (Strong Recommendation, High Quality evidence) www.ccs.ca Dyslipidemia Guidelines

Recommendations for PCSK9i in FH and ASCVD We suggest the use of PCSK9 inhibitors (evolocumab, alirocumab) to lower LDL-C for patients with heterozygous familial hypercholesterolemia whose LDL-C remains above target despite maximally tolerated statin therapy (Conditional recommendation, moderate quality evidence) We suggest that PCSK9 inhibitors be considered to lower LDL-C for patients with atherosclerotic cardiovascular disease in those not at LDL-C goal despite maximally tolerated statin +/- ezetimibe therapy (Conditional recommendation, moderate quality evidence) www.ccs.ca Dyslipidemia Guidelines

SUMMARY 1. The primacy of LDL cholesterol as a risk factor and a target of therapy is firmly established. 2. Statins remain the foundation of lipid-related risk reduction. However, many patients are unable to reach target on statin monotherapy. 3. The 2016 lipid guidelines recommend the use of non-fasting lipid levels for screening, expand the indications for statin therapy in intermediate risk patients, and call for more aggressive LDLlowering in ASCVD, including the use of non-statin drugs.