Canadian Lipid Guidelines, a Century of Cholesterol and PCSK9inh

Transcription

1 Canadian Lipid Guidelines, a Century of Cholesterol and PCSK9inh Jacques Genest MD Cardiovascular Research Laboratories McGill University Health Center McGill Refresher Course Dec 5, 2016

2 Disclosure J. Genest MD 2016 Advisory Board, Speaker s Bureau, Consultant, Grants, Clinical Trials Merck * Pfizer Novartis * AMGEN * Cerenis * Sanofi/Regeneron * Lilly Valeant Aegerion * Ascati Stock ownership: none; Off label use: none * Scientific Advisory Relevant disclosure: JUPITER, IMPROVE-IT, CANTOS, CAPREE steering Committees; REVEAL, ACCELERATE, AMG145, Lilly Clinical Trials.

3 2016 CCS Lipid Guidelines Treatment Algorithm

4 Major Changes Since 2012 Guidelines 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 Risk assessment with modified Framingham Risk Score to determine risk category Shared decision making Retention of treatment targets for those on therapy Statins remain drugs of choice New recommendation for non-statin drugs Mediterranean, DASH or Portfolio diet

5 Primary and Secondary Lipoprotein Determinants Recommendations Non HDL-C or apob represent atherogenic lipoproteins Strong Recommendation, High Quality Evidence Values and preferences As clinicians are most familiar with LDL-C we continue to recommend its use as the primary target, but anticipate a shift to preferential use of non-hdl-c or apo B in the future.

6 Treatment based on risk (1) Strong Recommendation, High-Quality Evidence

7 Treatment based on risk (2) Conditional Recommendation, Moderate-Quality Evidence Strong Recommendation, Moderate-Quality Evidence

8 Treatment based on risk (3) Strong Recommendation, Moderate-Quality Evidence

9 Targets 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 tested a specific strategy of dosing statin to achieve a pre-specified LDL-C target However, evidence to date suggests that lower is better

10 Targets HR for Major CV Events ( ) On-Statin LDL-C Levels and Risk for Major Cardiovascular Events Percent of Patients ( %) Achieved On-statin LDL Levels Meta-analysis of 8 statin trials (n=38,153) >40% did not reach LDL-C target (<1.8 mmol/l) on high dose statin Boekholdt SM, et al. J Am Coll Cardiol. 2014;64(5):484

11 Targets LDL-C remains the primary target in the guidelines. The rationale to maintain LDL-C as the primary target is that nearly all studies have measured LDL-C as the primary indicator of response to therapy. Non-HDL-C and apob should continue to be considered alternate targets to LDL-C Both non-hdl-c as well as apo B have similar or higher predictive value for cardiovascular risk, including for reduction of additional events after statin treatment, when compared with LDL-C.

12 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) Apo B 0.8 g/l Non HDL-C 2.6 mmol/l 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 2 mmol/l or 50% decrease in LDL-C (Strong, Moderate) Apo B 0.8 g/l Non HDL-C 2.6 mmol/l Low FRS <10% ØLDL-C 5.0 mmol/l ØFamilial hypercholesterolemia (Strong, Moderate) 50% reduction in LDL-C (Strong, Moderate)

13 Adherence Osteberg L. Adherence to Medication. NEJM 2005;353:487

14 Adherence: Predictors Osteberg L. Adherence to Medication. NEJM 2005;353:487

15 Adherence: Solutions

16 Non-Statin drugs Readily Available Ezetimibe Resins Niacin Fibrates Limited Access PCSK9 inhibitors (ASCVD, FH) Lomitapide (HoFH) Mipomersen* (HoFH) LDL-C apheresis (FH, high risk/recurrent CVE)

17 Non-Statin drugs: Ezetimibe 50 Reduction in Rate of Major Vascular Events (%) IMPROVE-IT 0 a b c d e f g h i j k l m n The magnitude of CV event reduction afforded by the addition of ezetimibe was consistent with that seen in previous statin trials for a Similar reduction in LDL C Reduction in LDL Cholesterol (mmol/liter) Figure 2. Plot of the IMPROVE-IT Trial Data and Statin Trials for Change in Low-Density Lipoprotein (LDL) Cholesterol versus Clinical Benefit.

18 Non-Statin drugs: Resins Cholestyramine LRC-CPPT (1984) CVD reduction Colestipol Colesevalam LDL-C reduction 18-25% We suggest that bile acid sequestrants be considered for LDL-C lowering in high risk patients who remain above target despite statin +/- ezetimibe therapy (Conditional recommendation, low quality evidence)

19 Non-Statin drugs: Fibrates We do not recommend the addition of fibrates to statin therapy for cardiovascular disease prevention in patients who have achieved LDL-C targets (Strong recommendation, high quality evidence). Values and preferences: In sub-group analysis, patients with elevated triglycerides and low HDL-C may benefit from fibrate therapy.

20 Non-Statin drugs: Niacin We do not recommend the addition of niacin to statin therapy for cardiovascular disease prevention in patients who have achieved LDL-C targets. Strong Recommendation, High quality evidence Values and Preferences: It remains unclear whether niacin offers CV benefits in other patient groups (LDL-C above target or low HDL-C or high TG. The decision to use niacin in such patients must be balanced against the adverse effect profile of niacin documented in large clinical trials.

21 Non-Statin drugs: PCSK9i PCSK9 inhibitors (evolocumab, alirocumab) to lower LDL-C for patients with heterozygous FH whose LDL-C remains above target despite maximally tolerated statin therapy (Conditional recommendation, moderate quality evidence). We suggest that Evolocumab be added to background therapy in patients with homozygous familial hypercholesterolemia and continued if LDL-C lowering is documented (Conditional recommendation, moderate quality evidence).

22 Non-Statin drugs: PCSK9i 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).

23 Cell 2015:161;

24 Severe Hypercholesterolemia LDL-C, Familial Hypercholesterolemia Mutation Status, and Risk for CAD Amit V. Khera, Hong-Hee Won, Gina M. Peloso, Sekar Kathiresan, on behalf the Myocardial Infarction Genetics and CHARGE Consortia

25 Franz Hals (1683) Portrait of a sixty year old woman holding a book

26 Pedigree of a family with familial hypercholesterolaemia. The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

27 FH is a Condition of Highly Elevated LDL-C mmol/l 200 mg/dl 400 mg/dl 500 mg/dl Severe Hypercholesterolemia

28 Definition of FH Simon-Broome (UK) Dutch criteria (Netherlands) (MedPed (US)) (Japanese Atherosclerosis Society) Canadian Definition Based on Age and LDL-C levels LDL-C and DNA, Family Hx, Xanthomas Point system (Definite, possible, probable)

29 FH: Simon-Broome Criteria Widely used definition. Knowledge of family required

30 FH: Dutch Lipid Clinics Criteria Point system, cutaneous manifestations important

31 Early Diagnosis: Key Signs and Symptoms High LDL-C (>5.0 mmol/l) (200 mg/dl) Patient or Family History Early CV disease Persistently Elevated LDL-C Patient or Family Markers Xanthomata Xanthelasma Arcus corneae

32 Familial Hypercholesterolemia

33 Comparisons of HeFH Clinical Signs at first visit: 1979 vs 2000 and (n = 371) Frequency (%) (n = 270) 2012 (n=268) 10 0 Xanthelasma Corneal arci Tendinous xanthomas Gagne C, Quebec, Canada data

34 LDL-C 95% Percentile 6.00 Comparison in 95th percentile of LDL between males and females cohort: GDML lab data th percentile of LDL (mmol/l) Female Male 0.00 N=3,336,000 patients Age Group in 5-year segment

35 *LDL-C 5.0 mmol/l (>40 yo) + DNA Mutation Xanthomas LDL >8.5 mmol/l Yes No Definite FH 1 st degree relative with LDL-C Or ASCVD or 1 st degree relative with early onset ACVD Yes No Probable FH (Consider DNA testing) Hypercholesterolemia (Consider DNA testing)

36 Meta-analysis of Familial Hypercholesterolemia Prevalence /250 Leo E Akioyamen; Genest J; Tu J. Submitted 2016

37 Sensibiliser la population sur l HF : Site Web Canadian Registry for Familial Hypercholesterolemia

38 Canadian Guidelines for FH (2014)

39 Clinical Importance: CAD Risk is Substantially Higher in FH Mutation Carriers with LDL 190! OR#for#CAD# (95%CI)# LDL# #190#mg/dl## # FH#Mutation# #(N#=#1,264)# 6.0! (5.2# #6.9)# FH#Mutation#+#(N#=#73)# 22.3! (10.7# #53.2)# LDL#<#130#&#FH#Mutation# ## Reference# Logistic Regression in Myocardial Infarction Genetics Consortium Studies Covariates: Gender, Study, 5 principal components of ancestry

40 Clinical Importance: For a Given Observed LDL, FH Mutation Carriers are at Increased Coronary Risk 5 Familial Hypercholesterolemia Mutation No 25.8 ( ) ( ) Ref 2.2 ( ) 1.8 ( ) 3.8 ( ) 2.9 ( ) 5.6 ( ) Mean LDL 203 mg/dl 5.2 ( ) 7.7 ( ) Mean LDL 205 mg/dl

41 Implications for Clinical Medicine Routine Lipid Testing Sequencing FH Genes Differential Treatment 35 M LDL 167 FH Mutation Negative 35 M LDL 167 FH Mutation Positive Lifestyle Changes Early Pharmacotherapy Cascade Screening

42 Methods: FH Mutation Prevalence in MIGen Mutation Prevalence by Gene Myocardial Infarction Genetics Consortium Controls: 48 of 8,577 (0.6%) Cases: 116* of 5,540 (2.1%) *One homozygous carrier

43 Evidence-Based Medicine vs. Precision and Personalized Medicine Evidence-Based Med. 95% 99.99% Prevalence Precision-Based Med. Lipoprotein Level U/L

44 LDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a function of the age of initiation of statin therapy. Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273 The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

45 Kaplan Meier curve estimates of cumulative CHD-free survival among individuals with familial hypercholesterolaemia according to statin treatment (P < for difference). Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273 The Author Published by Oxford University Press on behalf of the European Society of Cardiology.

46 PCSK9

47 PCSK9: A Canadian Discovery Nature Genetics 34, (2003) Dr. Nabil Seidah IRCM

48 Proprotein Convertase Subtilisin/Kexin Type 9 Bacillus amyloliquefaciens saccharomyces cerevisiae Homo sapiens Evolutionary Conservation: Must be important

49 PCSK9 LDL-R A: LDL-R pathway in absence of PCSK9 LDL Degradation Lysosome Endosome apob B: Intracellular PCSK9 route PCSK9 pre-pcsk9 C: Extracellular PCSK9 route Mature PCSK9 ER TGN

50 PCSK9 as a Target Cohen JC, et al. NEJM 2006;354:1264

51 LDLR

52 Antibody technology has evolved over past decades e.g. Abciximab e.g. Bococizumab Red = mouse Blue = human Immunogenicity Highly Immunogenic Chimeric, Still very immunogenic Can be time-consuming to create e.g. Evolocumab and Alirocumab repeated dosing possible Fully Mouse 1 st generation Chimeric 2 nd generation Humanized 3 rd generation Fully Human 4 th generation Nomenclature: Prefix (Pharma) C (Cardiovascular) UMAB 52

53 Clinical Data

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58 ODYSSEY Long-Term: Alirocumab Plus Statin Achieved a 62% Reduction in LDL-C over Placebo+Statin at 24 weeks mmol/l 3.17 mmol/l 0.8% 3.6% Median LDL-C (mmol/l) % reduction, P<0.001 Absolute reduction: 1.2 mmol/l 1.25 mmol/l -61.0% 1.50 mmol/l -52.4% 0.60 Alirocumab + statin therapy at maximum tolerated dose ± other LLT (150 mg q2w) Placebo + statin therapy at maximum tolerated dose ± other LLT No. of patients with data available Week Placebo Alirocumab Robinson J, et al. N Engl J Med. 2015;372(16):

59 ODYSSEY Long-Term: Reduction in the Rate of Cardiovascular Events- Post-hoc Analysis Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event* 0.06 Cumulative probability of event Safety Analysis Cox model analysis HR % CI: 0.26 to 0.82 P<0.01 Alirocumab + max-tolerated statin ± other LLT (150 mg q2w) Placebo + max-tolerated statin ± other LLT 54% RRR 0.00 No. at Risk Placebo Weeks Alirocumab *Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalization. LLT, lipid-lowering therapy 52 weeks for all patients continuing treatment, incl. 607 patients who completed W78 visit Robinson J, et al. N Engl J Med. 2015;372(16):

60 Ratio of LDL Lowering to CV Event Reduction with PCSK9 Inhibitors Holds True to the LDL Hypothesis 70% 60% Proportional reduction in event rate (SE) 50% 40% 30% 20% 10% IMPROVE-IT ODYSSEY Long-Term OSLER 0% -10% Reduction in LDL cholesterol (mmol/l) Waters DD. HsuePY. Circ Res. 2015;16:

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63 Anti-drug antibodies (ADA): the challenge Immunogenicity: The potential for an antigen to induce an immune response Immunogenicity against therapeutic proteins that are not in the normal human repertoire is a normal immune response. Reaction to neo-antigens Proteins are non-human Fusion proteins create new epitopes Unusual glycosylation Anti-drug antibody formation Antibody Fab (Neutralizing) Anti-PSCK9 Antibody Fc

64 PCSK9 Outcome Trials Alirocumab Evolocumab Bococizumab Trial ODYSSEY Outcomes (secondary prevention) FOURIER (secondary prevention) SPIRE1 (secondary prevention) SPIRE2 (primary prevention) No of patients 18,600 27,500 17,000 10,600 Dosage s/c, Q2W s/c, Q2W or Q4W s/c, Q2W s/c, Q2W Start date Oct 2012 Jan 2013 Oct 2013 Oct 2013 Expected End date Primary endpoint Mar 2018 Q1 Feb 2017? 2018 Aug 2017 Aug 2017 CHD death non-fatal MI fatal and non-fatal ischemic stroke high risk UA requiring hospitalization CV death MI Stroke hospitalization for UA coronary revascularization CV death non-fatal MI non-fatal stroke hospitalization for UA needing urgent revascularization CV death non-fatal MI non fatal stroke hospitalization for UA needing urgent revascularization Duration Up to Month 64 Up to 5 years Up to Month 60 Up to Month 60 Population Patients 4 to 52 wks post ACS LDL-C 70 (1.8) History of clinically evident CVD: MI, stroke or symptomatic PAD and 1 major RF or 2 minor RFs LDL-C 70 (1.8) or High risk patients LDL-C 70 (1.8) and <100 (2.6) or High risk subjects LDL-C 100 (2.6) or 46,100 patients

65 PCSK9 mab: Whom, When? Numbers (Guess) HoFH FH + CAD FH Goal 10,000 10,000 CAD* Goal 250,000 Hi Risk Goal >250,000 CAD* Approx 1.5 M CDN

66 Conclusions v LDL-C (and Remnant cholesterol) is causal in atherosclerosis v Lowering non-hdl-c with statins decreases cardiovascular events, CV deaths and total mortality v Non-statin drugs may provide additional benefit v PCSK9 inhibitors lower LDL-C. They are indicated in FH and ASCVD patients not at goal. Cost is a major limitation

67 Back-up Slides (in case someone asks )

68 PCSK9 and Diabetes

69 Background: Statin Treatment and Increased Risk of T2DM CI, confidence interval; OR, odds ratio; T2DM, type 2 diabetes mellitus. Case = developed T2DM. Non-case = did not develop T2DM. Swerdlow DI, et al. Lancet. 2015;385:

70 Efficacy and Safety of Alirocumab: Pooled Analyses of 1051 Individuals with Diabetes Mellitus from Five Placebo-Controlled Phase 3 Studies of at least 52 weeks duration Henry N Ginsberg 1, Michel Farnier 2, Jennifer G Robinson 3, Christopher P Cannon 4, Naveed Sattar 5, Marie T Baccara-Dinet 6, Christelle Lorenzato 7, Maja Bujas-Bobanovic 8, Michael J Louie 9, Helen M Colhoun 10 1 Columbia University, New York, NY; 2 Point Medical, Dijon, France; 3 University of Iowa, Iowa City, IA; 4 Harvard Clinical Res Inst, Boston, MA; 5 University of Glasgow, Glasgow, UK; 6 Sanofi, Montpellier, France; 7 Sanofi, Chilly-Mazarin, France; 8 Sanofi, Paris, France; 9 Regeneron Pharmaceuticals, Tarrytown, NY; 10 University of Dundee, Dundee, UK. This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.

71 Mean Fasting Plasma Glucose Over Time (Safety Population) Alirocumab with DM Placebo with DM Alirocumab without DM Placebo without DM 10 Alirocumab 75/150 mg Q2W 10 Alirocumab 150 mg Q2W Mean (SE) FPG, mmol/l Week Week mg Q2W increased to 150 mg Q2W at W12 if LDL-C levels at Week 8 were 70 mg/dl (1.81 mmol/l). FPG, fasting plasma glucose.

72 Mean HbA 1c Over Time (Safety Population) Alirocumab with DM Placebo with DM Alirocumab without DM Placebo without DM Mean (SE) HbA1c, % 10 Alirocumab 75/150 mg Q2W 10 Alirocumab 150 mg Q2W Week Week mg Q2W increased to 150 mg Q2W at Week 12 if LDL-C levels at Week 8 were 70 mg/dl (1.81 mmol/l). HbA1c, glycated hemoglobin.

73 Evaluation of the One-Year Efficacy, Safety and Glycaemic Effects of Evolocumab (AMG 145) in 4,802 Subjects With, at High Risk for, or at Low Risk for, Diabetes Mellitus Naveed Sattar, 1 David Preiss, 1 Dirk Blom, 2 C. Stephen Djedjos, 3 Mary Elliott, 4 Andrea Pellacani, 3 Scott M Wasserman, 3 Michael Koren, 5 Rury Holman 6 1 BHF Cardiovascular Research Centre, University of Glasgow, UK; 2 Division of Lipidology, Department of Medicine, University of Cape Town, South Africa; 3 Amgen Inc., Thousand Oaks, CA, USA; 4 Amgen Limited, Cambridge, UK; 5 Jacksonville Center for Clinical Research, Jacksonville, FL, USA; 6 Diabetes Trials Unit, OCDEM, University of Oxford, UK European Association for the Study of Diabetes Stockholm, Sweden 17 September, 2015 Session OP 27

74 Results: Median Fasting Plasma Glucose Over One Year* Median Glucose, mmol/l *48 weeks of open-label treatment Error bars represent SE of the median SoC, standard of care; T2DM, type 2 diabetes mellitus 74

75 Results: Median HbA 1c Over One Year* Median HbA 1c, % *48 weeks of open-label treatment Error bars represent SE of the median HbA 1c, glycated haemoglobin; SoC, standard of care; T2DM, type 2 diabetes mellitus 75

76 Conclusion In patients with T2DM, or people at high or low risk of T2DM, one year of treatment with evolocumab or alirocumab: markedly reduced LDL-C in all groups showed encouraging safety showed no measurable effect on glycaemic parameters including new-onset T2DM vs SoC alone Clinical trials are ongoing to examine the effects of evolocumab on patients with T2DM, and on the incidence of new-onset T2DM 76

77 CETPinh

78 Familial Hypercholesterolemia 1- How would you define Familial Hypercholesterolemia (FH)? 2- What are the common genes responsible for FH? 3- What is the prevalence of FH in Canada? 4- What is the risk of CVD in patients with a LDL-C > 5 mmol/l? 5- What is the risk of CVD in patients with a LDL-C > 5 mmol/l and a LDL-receptor mutation? 6- How would you treat a patient with FH?