Cholesterol, guidelines, targets and new medications

Transcription

1 Cholesterol, guidelines, targets and new medications Alexis Baass MD, MSc, FRCPC, DABCL, FNLA Medical Biochemist and Lipidologist MUHC Clinical Researcher and Lipidologist IRCM

2 Disclaimers Grants/Research Support Amgen, Pfizer, Sanofi, Regeneron, Merck, Astra Zeneca, Ionis, Leducq Foundation Speakers Bureau/Honoraria Amgen, Sanofi, Aegerion Stock Ownership None Off Label Use None

3 Objectives Understand the relationship between cholesterol and ASCVD risk Reaffirm the importance of statin therapy Review the Canadian Lipid Guidelines Interpret the data concerning PCSK9 inhibitors

4 Outline Cholesterol Background: Association with ASCVD risk Importance of Statin Therapy CCS Lipid Guidelines New Medications PCSK9 inhibitors

5 Cholesterol

6 How did we get from here...

7 To here???

8 Cholesterol : Observational Studies Epidemiologic Data Serum Cholesterol Levels and CHD MRFIT trial: age-adjusted CHD death rate and serum cholesterol in 361,662 US men (aged years) Each 1% Increase in Total Cholesterol Level is associated with a 2% Increase in CHD Risk Martin MJ, et al. Lancet 1986;2:

9 Cholesterol : Statin RCT More intense LDL-C lowering associated with greater reduction of coronary heart disease events Updated from: LaRosa JC, et al. N Engl J Med 2005; 352(14): ; Pencina et al NEJM 2014

10 LDL-C and Atherosclerosis in IVUS* Studies Interventional Studies Have Shown Linear Relationship Between LDL-C, and Atherosclerosis Progression Median Chamge in percent Atheroma Volume (%) E GLAGOV (PCSK9i) ASTEROID (statin) REVERSAL (statin) A-PLUS (placebo) REVERSAL (statin) ACTIVATE (placebo) CAMELOT (placebo) Mean LDL-C (mmol/l) * Intravascular Ultrasound (IVUS) Adapted from Sipahi I, et al. Cleve Clin J Med. 2006;10: and Nissen SE, et al. JAMA; 2006:295: ; Nissen SE, et al. Advance online publication. JAMA doi: /jama

11 The LDL Hypothesis Linear Relationship Between Reduction of CV Events and LDL-C Reduction Independent of Method (Diet, Bile Acid Sequestrants, Surgery and Statins) Non-fatal MI and CHD death RRR (%) LDL-C reduction (%) Robinson JG, et al. J Am Coll Cardiol 2005; 46(10):

12 CCS Lipid Guidelines

13 Adherence to Guidelines Despite Guideline Targets Many High-risk Canadian Patients Treated with Statins Are Not at LDL-C Goal 45% Canadian high-risk patients are NOT at LDL-C target 1* ( 2 mmol/l) 88% of patients received a potent statin with suboptimal dose Only 14% of patients received additional lipid-lowering agent 43% Canadian patients with diabetes are NOT at LDL-C target 2 ( 2 mmol/l) 82% of patients were on a lipid-lowering agent *High risk = coronary artery disease, peripheral arterial disease, cerebrovascular disease, diabetes mellitus or Framingham 10-year risk score 20%. DYSIS Study 2,436 patients, 1913 high risk patients. N = 5, Goodman SG, et al. on behalf of the DYSIS Canadian Investigators. Can J Cardiol. 2010;26(9):e330-e Leiter LD, et al. Can J Diabetes. 2013;37:82-89.

14 Adherence to Therapy Adherence: Predictor of Serum Cholesterol Response 1 : 4.6 mmol/l achievable in adherent* patient vs. 5.1 mmol/l in non-adherent patient, P<0.001 Adherence: Reduction in all cause Mortality 2 : 32% risk reduction with adherence** (P=0.015) over those with lower adherence * Defined as 80% adherence; ** Defined as 75% adherence 1. BatalHA, et al. BMC Health ServRes. 2007;7: The West of Scotland Coronary Prevention Study Group. Eur Heart J. 1997;18:

15 Non-adherence to Statin Therapy Uncertainty Uncertain about benefits or importance of statin Lack of clinician follow-up Unclear on instructions Concerned about possible drug interactions Adverse Events Concerns or experiences with immediate AEs Concerned about long-term AEs Concern about generic statin over brand-name Other Lack of convenience to take medication Forgot to take medication Inconvenient to wait for prescription fill/refill Media disinformation about statin therapy Vicki F, et al. Perm J. 2010;14(1):4-10.

16 Who to Screen

17 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 (10%) and small increase in triglyceride (20%) concentrations when individuals do not fast.

18 When to start statins Category Consider Initiating pharmacotherapy if: Target NNT Primary Prevention High (FRS 20%) Intermediate (FRS 10-19%) LDL-C <2.0 mmol/l or >50% Statin Indicated Conditions** LDL-C 3.5 mmol/l or Non-HDL-C 4.3 mmol/l or Apo B 1.2 g/l or Men 50 & women 60 yrs and 1 CV risk factor Clinical atherosclerosis* (CAD, CVD, PAD) Abdominal aortic aneurysm Or Apo B <0.8 g/l Or 20 Diabetes mellitus: 40 yrs, or >15 yrs duration & age 30 yrs (DM 1), or microvascular disease CKD (age 50 yrs): egfr < 60 ml/min/1.73 m 2, or ACR >3 mg/mmol non-hdl-c <2.6 mmol/l LDL-C 5.0 mmol/l >50% in LDL-C * consider LDL-C < 1.8 mmol/l for subjects with ACS within last 3 months;** statins indicated as initial therapy

19 Non-statins 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). We recommend that niacin not be added to statin therapy for CVD prevention in patients who have achieved LDL-C targets (Strong Recommendation, High Quality Evidence). We recommend that fibrates not be added to statin therapy for CVD event prevention in patients who have achieved LDL-C targets (Strong Recommendation, High Quality Evidence). 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). 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 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). 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). Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016 (In-Press). DOI: /j.cjca

20 Novel Medications

21 What is PCSK9? PCSK9: Proprotein Convertase Subtilisin Kexin type 9 Discovered by Dr. Nabil Seidah in Montreal Certain mutations in PCSK9 are associated with familial hypercholesterolemia PCSK9 main function is to bind the LDL receptor and regulate it s recycling Dr. Nabil Seidah IRCM

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

23 Loss-of-function Mutations in PCSK9 30 No Mutation (N=3,278) 50 th Percentile PCSK9 8 0 loss-of-function mutations found in 1% to 4% of population Frequency (%) Associated with Loss of function mutation 28% PCSK9 142X reduction or PCSK9 679X in mean LDL-C (N=85) 3088% reduction in lifetime risk of CHD* Coronary Heart Disease (%) No Yes PCSK9 142X or PCSK9 679X Plasma LDL-C in Black Subjects (mmol/l) *(P = 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:

24 Evolocumab: Fourier Trial

25 Baseline Characteristics Characteristic Value Age, years, mean (SD) 63 (9) Male sex (%) 75 Type of cardiovascular disease (%) Myocardial infarction 81 Stroke (non-hemorrhagic) 19 Symptomatic PAD 13 Cardiovascular risk factor (%) Hypertension 80 Diabetes mellitus 37 Current cigarette use 28 Median time from most recent event ~3 yrs Pooled data; no differences between treatment arms

26 Baseline Characteristics Characteristic Value Statin use (%)* High-intensity 69 Moderate-intensity 30 Ezetimibe use (%) 5 Median lipid measures (IQR) mg/dl LDL-C 92 (80-109) Total cholesterol 168 ( ) HDL-C 44 (37-53) Triglycerides 133 ( ) 2.4 mmol/l 3.3 mmol/l 1.1 mmol/l 1.5 mmol/l *Per protocol, patients were to be on atorva 20 mg/d or equivalent. 1% were on low intensity or intensity data were missing. Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines. Pooled data; no differences between treatment arms

27 LDL-C 1.45 mmol/l (95% CI ) (Median 0.78 mmol/l IQR, mmol/l

28 Primary endpoint CV death, MI, stroke, hosp. for UA, or coronary revasc

29 Secondary endpoint CV death, MI or stroke (MACE)

30 Types of CV Outcomes Endpoint Evolocumab (N=13,784) Placebo (N=13,780) 3-yr Kaplan-Meier rate HR (95% CI) CV death, MI, or stroke ( ) Cardiovascular death ( ) Death due to acute MI ( ) Death due to stroke ( ) Other CV death ( ) MI ( ) Stroke ( )

31 More Intensive LDL-C Lowering & CV Death Trial Year More Intensive Rx Arm No clear benefit on CV mortality # of CV Deaths Less Intensive Rx Arm HR (95% CI) PROVE-IT TIMI ( ) A2Z ( ) TNT ( ) IDEAL ( ) SEARCH ( ) IMPROVE-IT ( ) Summary ( ) NEJM 2004;350: JAMA 2004;292: NEJM 2005;352: JAMA 2005;294: Lancet 2010;376: NEJM 2015;372: More intensive therapy better Less intensive therapy better

32 Subgroups

33 Lower LDL-C Is Better Patients divided by quartile of baseline LDL-C and by treatment arm P< Q4 Q3 Q3 Q4 Q1 Q2 Q1 Q2 Placebo Evolocumab

34 Landmark Analysis

35 Fourier: Comparison to Statin Trials

36 Safety Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%) Any Serious Allergic reaction Injection-site reaction Treatment-related and led to d/c of study drug Muscle-related Cataract Diabetes (new-onset) Neurocognitive Laboratory results (%) Binding Ab 0.3 n/a Neutralizing Ab none n/a New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC

37 Summary LDL-C by 59% Consistent throughout duration of trial Median achieved LDL-C of 0.78 mmol/l IQR, mmol/l CV outcomes in patients already on statin therapy 20% MACE (CV death, MI, or stroke) Consistent benefit in all subgroups Long-term benefits consistent w/ statins per mmol/l LDL-C Safe and well-tolerated Similar rates of AEs, incl DM & neurocog events w/ EvoMab & pbo Rates of EvoMab discontinuation low and no greater than pbo No neutralizing antibodies developed

38 PCSK9 inhibitors in Canada Both Repatha and Praluent have been approved by Health Canada Familial Hypercholesterolemia 1. Patient has a confirmed diagnosis of HeFH 2. Patient is unable to reach the target LDL-C level specified in current guidelines 3. Patient is currently receiving optimally tolerated standard of care (maximally tolerated statins (MTS) with or without ezetimibe Secondary prevention 1. Patient is unable to reach the target LDL-C level specified in current guidelines 2. Patient is currently receiving optimally tolerated standard of care (MTS with or without ezetimibe)

39 Administration Alirocumab Administration 1 injection SC q2wk, Doses: 75 mg or 150 mg Auto-injector ALIROCUMAB ALIROCUMAB *As per the product monograph, measure LDL-C levels within 4 to 8 weeks of initiation or titration to assess response and adjust dose if needed Evolocumab Administration 1 injection SC q2wk, Dose: 140 mg 3 injections SC q4wk Total Dose: 420 mg Auto-injector Patient Support Programs available for both: MyPraluent Coach and Repatha Ready

40 Future Lipid Lowering Therapies Inclisiran: Targeting PCSK9 by small interfering RNA therapy AKCEA-APO(a)-L Rx : Targeting Apo(a) by antisense RNA therapy AKCEA-APOCIII-L Rx : Targeting ApoCIII by antisense RNA therapy Evinacumab: Targeting ANGPTL3 by a monoclonal antibody

41 Conclusions LDL-C is an important causal factor of ASCVD Statins are underused and undertitrated in Canada Statins remain the first line of therapy for ASCVD reduction Novel therapies such as PCSK9 can be used as an add on therapy to statins in select patients.

42 Questions?