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
13
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
14
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
26
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
27
27
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.