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.

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.

2

1

0

–1

–2

–3

Med

ian

Cha

nge

in P

AV (%

)

Average On-Treatment LDL-C (mmol/L) 1.0 1.6 2.1 2.6 3.1

REVERSAL Pravastatin

REVERSAL Atorvastatin

CAMELOT Placebo

STRADIVARIUS Placebo

ILLUSTRATE Atorvastatin

SATURN Atorvastatin

SATURN Rosuvastatin

ASTEROID Rosuvastatin

PRECISE-IVUS (ACS) Atorvastatin

PRECISE-IVUS (ACS) Atorvastatin+Ezetimibe

LDL-C Levels and Atherosclerosis Progression in IVUS Studies1,2

Intensive LDL-C Lowering Promotes Plaque Regression

Patients with Genetically Lower LDL have Correspondingly Better CV Event Reduction

10%

20% NPC1L1 LDL-C Score HMGCR

LDL-C Score

0 .003 .005 .078 .104 .130 .155 .181 .207 .233 .259 .285 .311 .330 .363 .389 .389 .440 .466 .492 .518

Lower LDL-C (mmol/L)

Ference BA, et al. J Am Coll Cardiol. 2015;65(15):1552-1561

.544

Prop

ortio

nal R

isk

Red

uctio

n (S

E) l

og

scal

e

PCSK9 46L rs11591147

ALLHAT-LLT

SEARCH

Pharmacologically Lower LDL-C

A to Z

Genetically Lower LDL-C

GISSI-P

IMPROVE-IT

Combined NPC1L1 & HMGCR LDL-C Score

LDLR rs6511720

LDLR rs2228671

PCSK9 rs11206510

ABCG5/8 rs4299376 HMGCR rs12916 PCS

K9 rs2479409 NPC1L

1 rs217386

HMGCR LDL-C Score NPC1L1 LDL-C

Score

IMPROVE-IT

Cannon CP et al. N Engl J Med 2015;372:2387-2397.

Simvastatin: 34.7% - 2742 events Mean LDL-C = 1.8 mmol/L

Simvastatin/Ezetimibe: 32.7% - 2572 events Mean LDL-C = 1.4 mmol/L

NNT*= 50

Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke

Eve

nt R

ate

(%)

Hazard Ratio, 0.936 (95% CI, 0.89-0.99) p=0.016

* NNT = Number Needed to Treat Time since randomization (years)

Overview

•  The primacy of LDL cholesterol as a risk factor

•  New mechanisms for LDL-lowering

•  The 2016 CCS lipid guidelines

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DYSIS Canada - LDL-C Levels in High Risk* Patients

*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.

2,436 participants from across Canada of whom 1,913 were considered high risk*

LDL-C <2.0 mmol/L

55% 45%

On a ‘potent’ statin with suboptimal dose

88%

12%

On an additional lipid-lowering agent

86%

14%

Yes No

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

Media / “Dr. Google”

Lack of follow-up for uptitration

Complacency with sub-optimal

cholesterol values achieved

Confusion around recommended

lipid targets

Fear of side-effects of statins Inertia Patient Non-

Adherence

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Qian YW, et al. J Lipid Res. 2007;48:1488-1498; Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177.

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

LDL

LDL-R

Endocytosis

LDL-R Recycling Endosome

LDL Degradation

LDL

LDL-R

Endocytosis

Endosome

PCSK9

PCSK9 Self-procession

Hepatocyte

Plasma

© 2013 Amgen Canada Inc. All rights reserved.

Golgi Apparatus

Endoplasmic Reticulum

(ER) Nucleus LDL, LDL-R and PCSK9 Degradation

PCSK Family of Proteins

Efficacy of PCSK9 Inhibitors

Adverse Event Profiles of PCSK9i

*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.;

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%

OSLER: Reduced Cardiovascular Event Rates Amongst Individuals Receiving Evolocumab*

*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.

3

2

1

0

0 30 60 90 120 150 180 210 240 270 300 330 365

Cum

ulat

ive

Inci

denc

e (%

)

Days since Randomization

Evolocumab plus standard of care (N=2976) [29 events] Standard of care alone (N=1489) [31 events]

Composite Endpoint: Death, MI, UA → hospitalization coronary revasc, stroke, TIA, or CHF → hospitalization

HR 0.47 95% CI 0.28-0.78 P=0.003

2.18%

0.95%

ODYSSEY Long-Term: Reduced Cardiovascular Event Rates amongst Patients Receiving Alirocumab (Post-hoc Analysis)

*, 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.

Time (weeks) No. patients

at risk

0.06

0.04

0.02

0

0 12 24 36 52 64 78 86

Cum

ulat

ive

prob

abili

ty o

f eve

nt

788 1550

776 1533

731 1445

700 1392

670 1342

653 1306

644 1266

597 1170

Placebo Alirocumab

HR = 0.52 (95% C.I 0.31 to 0.90) Nominal P value = 0.02 Mean treatment duration: 70 weeks

Alirocumab [150 mg q2w] + maximally tolerated statin ± other LLT (27 events*; N=1550)

Placebo + maximally tolerated statin ± other LLT (26 events*; N=788)

ACCELERATE: Evacetrapib vs. placebo

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.

•  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

20

15

10

5

0

Cum

ulat

ive

Eve

nt R

ate

(%)

Months Following Randomization 0 6 12 18 24 30 36

HR=1.01 95% CI, 0.91-1.12 P=0.85

Evacetrapib, 774 events (12.8%) Placebo, 768 events (12.7%)

Cumulative Incidence of Primary Efficacy Endpoint

Outcome Trials with PCSK9 Inhibitors

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.

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

Overview

•  The primacy of LDL cholesterol as a risk factor

•  New mechanism for LDL lowering

•  The 2016 CCS lipid guidelines

Lipid Guidelines

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26

Major Changes Since 2012 Guidelines

LDL-C – low density lipoprotein cholesterol; apo B – apolipoprotein B; CKD – chronic kidney disease; DASH – Dietary Approaches to Stop Hypertension

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

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How to Screen

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.

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 •  Dysglycemia

•  Smoking •  Mild renal dysfunction

•  Low HDL-C •  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

Years

Cum

ulat

ive

Haz

ard

Rat

es

0.0

0.02

0.

04

0.06

0.

08

0.10

0 1 2 3 4 5 6 7

Placebo

Rosuvastatin

HR (95% CI) = 0.75 (0.64-0.88) P-value = 0.0004

6361 6241 6039 2122 6344 6192 5970 2073

Rosuva Placebo

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

.

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

*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)

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

Dyslipidemia Guidelines www.ccs.ca

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)

Non Statin Drugs for ASCVD Prevention

Dyslipidemia Guidelines www.ccs.ca

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)

Recommendations for PCSK9i in FH and ASCVD

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 LDL-lowering in ASCVD, including the use of non-statin drugs.