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past presnt and futer of dyslidema ttt.pdf
1. THE PAST, PRESENT AND
FUTURE OF LIPID
MANAGEMENT
DR. GREG SEARLES
MEDICINE GRAND ROUNDS
AUGUST 30, 2017
1
2. FACULTY/PRESENTER DISCLOSURE
FACULTY: DR. GREG SEARLES
PROGRAM NAME: MEDICINE GRAND ROUNDS 2017
RELATIONSHIPS WITH COMMERCIAL INTERESTS:
• GRANTS/RESEARCH SUPPORT: NA
• SPEAKING ENGAGEMENTS/HONORARIA: PFIZER, BI, BAYER,
SERVIER, AMGEN, BMS
• ADVISORY BOARD/CONSULTING FEES: PFIZER, BAYER,
SANOFI, AMGEN, BI, ELI LILY
Conflict of Interest templates: Slide 1 of 3
3. OBJECTIVES
• 1. LEARN ABOUT CURRENT LIPID MANAGEMENT GUIDELINES
• 2. LEARN ABOUT OLD AND NEW DYSLIPIDEMIA TREATMENT
OPTIONS
• 3. LEARN WHERE OLDER AND NEW THERAPIES FIT IN
CLINICAL PRACTICE
3
6. LDL: the lower the better?
Every 1.0 mmol/L reduction in
LDL-C results in 23% reduction
in major coronary events and
21% reduction in major
vascular events
The greater the reduction
in LDL-C, the greater the
coronary artery disease
(CAD) risk reduction
Question:
target as low
as possible?
6
?
4.4
11.4
16.5 16.5 17.8
22
32.8
0
5
10
15
20
25
30
35
Risk of Cardiovascular Events by Categories of
Achieved LDL-C
LaRosa JC et al, N Engl J Med 2005; 352(14):1425-35; Boekhart et al, J AM Cardiol 2014; 64:485-94; Cannon CP et al, N Engl J Med 2015;372:2387-2397
Major
CV
Events
(%)
LDL-C mmol/L
TOC
7. 7
No
Pharmacotherapy
Low Risk
FRS <10%
Discuss Behavioural Modifications
2016 Canadian Cardiovascular Society
Dyslipidemia Guidelines
TOC
Primary Prevention Conditions
Intermediate Risk High Risk
FRS 10-19%
And
LDL-C ≥3.5 mmol/L
Or
Non-HDL-C ≥4.3 mmol/L
Or
ApoB ≥1.2 g/L
Or
Men ≥50 and women ≥60
with one additional risk
factor; low HDL-C,
impaired fasting glucose,
high waist circumference,
smoker, hypertension
FRS ≥20
Or
Alternative
method
Statin-Indicated Conditions
• Clinical
atherosclerosis
• Abdominal aortic
aneurysm
• Most diabetes
including:
•Age ≥40y
•Age ≥30y & 15y
duration (T1DM)
•Microvascular
disease
• Chronic kidney
disease
LDL-C
≥5mmol/L
(genetic
dyslipidemia)
Risk Assessment*, Stratification and Treatment Consideration
Anderson TJ et al, Canadian Journal of Cardiology 2016; doi: 10.1016/j.cjca.2016.07.510.
*Using Framingham Risk Score (FRS) or Cardiovascular Life Expectancy Model (CLEM) unless statin-indicated condition
8. 2016 Canadian Cardiovascular Society
Dyslipidemia Guidelines
8
TOC
Primary Prevention Conditions Statin-Indicated Conditions
Initiate Statin Treatment : Treat to Target Approach
LDL-C <2.0 mmol/L or >50% reduction or apoB <0.8 g/L or
non HDL-C <2.6 mmol/L
LDL-C >50%
reduction
Target achieved on maximally tolerated dose?
NO
Discuss add-on therapy with patient
NO NO
Add-
on
Add-on Therapy
Ezetimibe as 1st line
(BAS as alternative)
Ezetimibe as 1st line
(BAS as alternative)
PCSK9 inhibitors as 2nd line (add on to
other drugs)
Ezetimibe (or
BAS) or PCSK9
inhibitors
Add-
on
Add-
on
Monitor
Response to
statin Rx
Health behaviours
YES
No Add-on
Anderson TJ et al, Canadian Journal of Cardiology 2016; doi: 10.1016/j.cjca.2016.07.510.
(genetic dyslipidemia)
13. Many High-risk Canadian Patients
Treated With Statins Are Not at LDL-C Goal
1. Goodman SG et al, on behalf of the DYSIS Canadian Investigators. Can J Cardiol 2010;26(9):e330-e335.
2. Leiter LA et al , Can J Diabetes. 2013; 37: 82-89
45% 43%
Many high-risk* Canadian patients
treated with statins are not at LDL-C
Goal1 (≤ 2.0 mmo/L)
• N=2,436 patients, 1913 high risk patients
(DYSIS Study)
• 88% of patients received a ‘potent’ statin with
suboptimal dose; 14% of patients received
additional lipid-lowering agent
Canadian patients with diabetes are
NOT at LDL-C target2
(≤ 2.0 mmo/L)
• N=5,069
• 82% of patients were on a lipid-lowering agent
14
*High risk = coronary artery disease, peripheral arterial disease,
cerebrovascular disease, diabetes mellitus or Framingham 10-
year risk score ≥20%
TOC
16. 15 Years of Landmark Statin Trials
1994 4S
1995 WOSCOPS
1996 CARE
1998 AFCAPS/TexCAPS
LIPID
2001 MIRACL
2002 HPS
PROSPER
ALLHAT-LLT
2003 ASCOT-LLA
2004 PROVE IT
ALLIANCE
CARDS
A to Z
Primary Prevention
Secondary Prevention
MIRACL
ASCOT-LLA
CARDS
ALLIANCE
PROVE IT
TNT
IDEAL
Atorvastatin Trials
SPARCL
Primary Prevention
Secondary Prevention
1994 4S
1995 WOSCOPS
1996 CARE
1998 AFCAPS/TexCAPS
LIPID
2001 MIRACL
2002 HPS
PROSPER
ALLHAT-LLT
2003 ASCOT-LLA
2004 CARDS
ALLIANCE
PROVE IT
A to Z
2005 TNT
IDEAL
2006 SPARCL
2008 JUPITER
Second Wave of Trials
Focus on other high-risk groups
ACS, elderly, DM, HTN with risk factors
Comparisons beyond placebo
Vs usual care (ALLIANCE, ALL-HAT)
Active comparator (PROVE IT, A to Z)
Early Trials Proved Relative Risk Reduction
in Morbidity and Mortality vs Placebo
Intensive statin treatment in stable CHD patients
receiving contemporary therapy
Intensive statin treatment in patients with prior stroke or
TIA and without established prior CHD
Moderate statin therapy in patients with elevated CRP but
low to moderate LDL
17. Heart Protection Study (HPS)
• 20,536 patients in the UK at increased risk of CHD
death due to:
• MI or other coronary heart disease
• Occlusive disease of noncoronary arteries
• Diabetes mellitus or treated hypertension
• Age 40-80 years
• Total cholesterol >3.5 mmol/L
• Randomized to simvastatin 40 mg/day or placebo
and followed for 5 years
Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.
18. Vascular
Event
Total CHD
Total stroke
Revascularization
ANY OF ABOVE
Statin Placebo
(10,269) (10,267)
914 1234
456 613
926 1,185
2,042 2,606
(19.9%) (25.4%)
Risk Ratio and 95% Cl
Statin better Statin worse
0.4 0.6 0.8 1.0 1.2 1.4
24% SE 2.6
reduction
(2p<0.00001)
No. Events
Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.
HPS: Major Vascular Events
19. “Standard Therapy”
Pravastatin 40 mg
“Intensive Therapy”
Atorvastatin 80 mg
4,162 patients with an Acute Coronary Syndrome <10 days
Primary Endpoint: Death, MI, documented UA requiring hospitalization,
revascularization (>30 days after randomization), or stroke
PROVE IT - TIMI 22:
Study Design
Double-blind
Cannon CP, et al. N Engl J Med 2004;350:1495-1504.
ASA + Standard Medical Therapy
Duration: Mean 2 year follow-up (>925 events)
2x2 Factorial: Gatifloxacin vs. placebo
MI: myocardial infarction; UA: unstable angina.
20. PROVE-IT: Event Reduction by
6 Weeks
Hazard ratio = 0.75
p=0.0004
20
15
10
5
0
Atorvastatin 80 mg
Pravastatin 40 mg
Months following randomization
0 6 12 18 24 30
Ray K, et al. Am J Cardiol 2005;96:54F-60F.
%
event
reduction
Event
Reduction
Demonstrated
as Early as
30 Days
16% Relative
Risk Reduction
21. JUPITER: Primary Endpoint MI,
Stroke, UA/Revascularization, CV Death
Ridker P, et al. N Engl J Med 2008;359:2195-207.
UA: unstable angina; CV: cardiovascular.
25. Current Combination Therapy on
Top of Statins for LDL Lowering
BILE ACID
SEQUESTRANTS
• No evidence of cardiovascular benefit on top of statin
• May improve glycemia
EZETIMIBE
• Modest additional cardiovascular benefit as add-on to statin
(IMPROVE-IT)
FENOFIBRATE
• Does not generally lower LDL
• No evidence of benefit in recent large studies (FIELD, ACCORD
LIPID)
NIACIN
• Not well tolerated; may cause infection and bleeding
• No evidence of cardiovascular benefit on top of statin (HPS2-
THRIVE, AIM HIGH)
HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203–12
Keech A et al, Lancet 2005 Nov 26;366(9500):1849-61
ACCORD Study Group. N Engl J Med 2010;362:1563–74
Genest J et al, Can J Cardiol 2006; 22(10):863:868
26
TOC
Anderson TJ et al, Canadian Journal of Cardiology 2016; doi: 10.1016/j.cjca.2016.07.510.
27. Goals
IMPROVE-IT: First large trial evaluating clinical
efficacy of combination EZ/Simva vs. simvastatin
(i.e., the addition of ezetimibe to statin therapy):
➢ Does lowering LDL-C with the non-statin agent
ezetimibe reduce cardiac events?
➢ “Is (Even) Lower (Even) Better?”
(estimated mean LDL-C ~50 vs. 65mg/dL)
➢ Safety of ezetimibe
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
28. Patients stabilized post ACS ≤ 10 days:
LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)
Standard Medical & Interventional Therapy
Ezetimibe / Simvastatin
10 / 40 mg
Simvastatin
40 mg
Follow-up Visit Day 30, every 4 months
Duration: Minimum 2 ½-year follow-up (at least 5250 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
N=18,144
Uptitrated to
Simva 80 mg
if LDL-C > 79
(adapted per
FDA label 2011)
Study Design
*3.2mM
**2.6mM
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
90% power to detect
~9% difference
31. IMPROVE-IT vs. CTT:
Ezetimibe vs. Statin Benefit
CTT Collaboration.
Lancet 2005; 366:1267-78;
Lancet 2010;376:1670-81.
IMPROVE-IT
32. Safety — ITT
No statistically significant differences in cancer or
muscle- or gallbladder-related events
Simva
n=9077
%
EZ/Simva
n=9067
% p
ALT and/or AST≥3x ULN 2.3 2.5 0.43
Cholecystectomy 1.5 1.5 0.96
Gallbladder-related AEs 3.5 3.1 0.10
Rhabdomyolysis* 0.2 0.1 0.37
Myopathy* 0.1 0.2 0.32
Rhabdo, myopathy, myalgia with CK elevation* 0.6 0.6 0.64
Cancer* (7-yr KM %) 10.2 10.2 0.57
* Adjudicated by Clinical Events Committee % = n/N for the trial duration
33. Conclusions
IMPROVE-IT: First trial demonstrating incremental
clinical benefit when adding a non-statin agent
(ezetimibe) to statin therapy:
YES: Non-statin lowering LDL-C with ezetimibe
reduces cardiovascular events
YES: Even Lower is Even Better
(achieved mean LDL-C 53 vs. 70 mg/dL at 1 year)
YES: Confirms ezetimibe safety profile
Reaffirms the LDL hypothesis, that reducing
LDL-C prevents cardiovascular events
34. 2016 Canadian Cardiovascular Society
Dyslipidemia Guidelines
35
TOC
Primary Prevention Conditions Statin-Indicated Conditions
Initiate Statin Treatment : Treat to Target Approach
LDL-C <2.0 mmol/L or >50% reduction or apoB <0.8 g/L or
non HDL-C <2.6 mmol/L
LDL-C >50%
reduction
Target achieved on maximally tolerated dose?
NO
Discuss add-on therapy with patient
NO NO
Add-
on
Add-on Therapy
Ezetimibe as 1st line
(BAS as alternative)
Ezetimibe as 1st line
(BAS as alternative)
PCSK9 inhibitors as 2nd line (add on to
other drugs)
Ezetimibe (or
BAS) or PCSK9
inhibitors
Add-
on
Add-
on
Monitor
Response to
statin Rx
Health behaviours
YES
No Add-on
Anderson TJ et al, Canadian Journal of Cardiology 2016; doi: 10.1016/j.cjca.2016.07.510.
(genetic dyslipidemia)
35. Why We Need New
Lipid Lowering Agents
Statin monotherapy does not achieve targets in many patients
Existing 2nd line lipid lowering agents are sub-optimal
• Best evidence is for ezetimibe as a secondary agent but this achieves
only 15-20% additional LDL-C lowering and a proportionately small
augmentation of clinical benefit
• Niacin has limiting side effects and weak or worrisome outcome data
• No outcome data for resins as add on to statins
• Outcome data with fibrates as an adjunct has no benefit when added
to statin
36
HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203–12
Keech A et al, Lancet 2005 Nov 26;366(9500):1849-61
ACCORD Study Group. N Engl J Med 2010;362:1563–74
Genest J et al, Can J Cardiol 2006; 22(10):863:868
TOC
37. The Role of PCSK9
McKenney JM et al, J Clin Lipidology 2015;9:170-186
TOC
38. The Role of PCSK9 Inhibitors
McKenney JM et al, J Clin Lipidology 2015;9:170-186
TOC
39. Loss-of-Function PCSK9 Mutations Are Associated
with Low LDL-C and Low Prevalence of CHD Events
9.7%
PCSK9142x or PCSK9679X
No
12
8
4
0 1.2%
Coronary
Heart
Disease
(%)
88% reduction in the risk of CHD
events during 15-year follow-up
Yes
Cohen JC et al, N Engl J Med 2006;354:1264-72 40
• PCSK9 loss-of-function
mutations found in 1%
to 4% of population
1%-4%
• PCSK-9 loss of function
mutations associated
with 28% reduction in
mean LDL-C
28%
88%
TOC
40. Emerging Therapies in Lipid
Management: PCSK9 Inhibitors
Inhibit PCSK9 to
increase LDL
receptor levels,
increase removal of
LDL
Monoclonal antibodies:
• Alirocumab
• Bococizumab*
• Evolocumab
PCSK9: Proprotein Convertase Subtilisin Kexin Type
41
*Investigational Product, not approved by Health Canada
Praluent™ Product Monograph. April 2016; Repatha™ Product Monograph. September 2015
TOC
41. PCSK9i: Study Designs
42
• Alirocumab and evolocumab efficacy and safety were examined in
various populations:
FH Patients
Statin- Intolerant Patients
High CV Risk Patients
TOC
42. OSLER*: LDL Cholesterol
Sabatine MS et al, N Engl J Med. 2015 Apr 16;372(16):1500-9(suppl):1-21.
0.52
1.03
1.55
2.07
2.59
3.10
3.62
Median
LDL-C
mmol/L
1.89 mmol/L (95%CI 71-76%)
* Consisted of patients from evolocumab parent studies, randomized irrespective of study group
43
TOC
43. OSLER: Safety
* Neurocognitive events were delirium (including confusion), cognitive and attention
disorders and disturbances, dementia and amnesic conditions, disturbances in
thinking and perception, and mental impairment disorders.
44
Sabatine MS et al, N Engl J Med. 2015 Apr 16;372(16):1500-9(suppl):1-21.
TOC
46. ODYSSEY Long Term: Safety Analysis
*Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, nonfatal MI, fatal and nonfatal ischemic stroke, and unstable
angina requiring hospitalisation. “Unstable angina requiring hospitalisation” is limited to the UA events with definite evidence of
progression of the ischemic condition (strict criteria).
47
Robinson JG et al, N Engl J Med. 2015; 372:1489-1499 (suppl ): 1-76
TOC
58. Administration
• 1 injection SC q2wk,
Doses: 75 mg or 150 mg*
• Auto-injector
Alirocumab
Administration
● 1 injection SC q2wk,
Dose: 140 mg
● 3 injections SC q4wk
Total Dose: 420 mg
● Auto-injector
Evolocumab
Administration
ALIROCUMAB
ALIROCUMAB
59
*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
Praluent™ Product Monograph. April 2016; Repatha™ Product Monograph. September 2015
TOC
59. Prescribing Information
60
Indicated as an adjunct to diet and maximally
tolerated statin therapy in patients with FH or
clinical atherosclerotic CVD, who require additional
lowering of LDL-C
Subcutaneous injection
Alirocumab: 75 or 150 mg Q2W;
Evolocumab: 140 mg Q2W or
420 mg once monthly
Rotate injection site
Advise patient not to shake, heat up, freeze, or re-
use device
Missed dose should be injected as soon as possible
Alirocumab Product Monograph, April 2016; Evolocumab Product Monograph, September 2015.
TOC
60. Summary
61
1. Statins remain the basis for secondary prevention in patients with established or
identified CVD.
2. Many high risk patients are not achieving their LDL-C target despite optimal statin
therapy.
3. Recent evidence suggests that addition of a second lipid lowering agent, such as
ezetimibe, may be of benefit.
4. PCSK9 inhibitors represent a safe and effective addition to our armamentarium of
LDL-C lowering therapies. The clinical benefit of these agents is currently being
tested in CV outcome trials.
TOC
61. 2016 Canadian Cardiovascular Society
Dyslipidemia Guidelines
62
TOC
Primary Prevention Conditions Statin-Indicated Conditions
Initiate Statin Treatment : Treat to Target Approach
LDL-C <2.0 mmol/L or >50% reduction or apoB <0.8 g/L or
non HDL-C <2.6 mmol/L
LDL-C >50%
reduction
Target achieved on maximally tolerated dose?
NO
Discuss add-on therapy with patient
NO NO
Add-
on
Add-on Therapy
Ezetimibe as 1st line
(BAS as alternative)
Ezetimibe as 1st line
(BAS as alternative)
PCSK9 inhibitors as 2nd line (add on to
other drugs)
Ezetimibe (or
BAS) or PCSK9
inhibitors
Add-
on
Add-
on
Monitor
Response to
statin Rx
Health behaviours
YES
No Add-on
Anderson TJ et al, Canadian Journal of Cardiology 2016; doi: 10.1016/j.cjca.2016.07.510.
(genetic dyslipidemia)
62. Take home messages
• Lipid lowering drugs provide important reductions
in key clinical events
• Statins are cornerstone
• Diet and exercise encouraged for all
• For patients not to target
• PCSK9 inhibitor > ezetimibe if able o get coverage/afford
• For statin intolerant patients
• Same
63
64. Marais AD. Clin Biochem Rev. 2004;25:49-68; Mahley RW et al, In: Kronenberg: Williams Textbook of Endocrinology. 2008; Rader DJ et al, J Clin Invest. 2003;111:1795-1803;
Scandinavian Simvastatin Survival Study Group, 1995, Lancet; Genest J et al, Can J Cardiol 30 (2014) : 1471 – 1481.
65
A Closer Look at Familial Hypercholesterolemia
(FH) A Clinically Recognizable Genetic Disorder
Heritable,
autosomal co-
dominant disorder
caused by mutations
in the LDL-receptor
gene that results in
receptor absence or
malfunction
Decreased clearance
of LDL-C particles
from plasma
Increased
cardiovascular risk
by up to 20 fold and
early onset of CVD.
Most common
monogenic disorder
leading to premature
CHD and cardiac
death
TOC
65. Prevalence and Genetic Mutations
66
• Is one of the most common inherited
disorders and occurs at a prevalence of
approximately 1:200 to 1:500 people
• Yet frequently undiagnosed
Not a rare
condition
• > 1700 mutations
• LDLR mutation 1 in 80-270 in Quebec
• LDLR mutation 1 in 250 – 500 in rest of Canada
• ~ 84,000 patients in Canada: ~ 29,000 in
Quebec; ~ 55,000 rest of Canada
• Other mutations include in APOB and PCSK9
genes
Due to
LDL receptor
gene
mutations
Marais AD. Clin Biochem Rev. 2004;25:49-68; Rader DJ et al, J Clin Invest. 2003;111:1795-1803; Scandinavian Simvastatin Survival Study Group, 1995, Lancet;
Canadian Journal of Cardiology 2014 30, 1471-1481DOI: (10.1016/j.cjca.2014.09.028); A Guide to Familial Hypercholesterolemia (FH) for Healthcare Professionals:
www.FHCanada.net
TOC
66. +
CCS Position Statement on Familial Hypercholesterolemia
(FH): Diagnostic and Treatment Flow when FH is Suspected
Canadian Journal of Cardiology 2014 30, 1471-1481DOI: (10.1016/j.cjca.2014.09.028) 67
LDL Cholesterol > 5 mmol/L
Rule out secondary causes
Positive Family History
First degree relative with LDL
cholesterol > 5 mmol/L
OR
Early coronary heart disease (<65 years
in women, 55 years in men)
OR
Physical findings in patient
• Obstructive liver disease
• Hypothyroidism
• Nephrotic syndrome
• Anorexia
+
-
TOC
67. HeFH Clinical Features
68
Xanthelasmas
Arcus Corneus
Xanthomas
Xanthomas
Canadian Journal of Cardiology 2014 30, 1471-1481DOI:(10.1016/j.cjca.2014.09.028)
Mose J et al. Medscape. Familial hypercholesterolemia. Updated July 10 2016.
TOC
These clinical features are not
common in clinical practice since
patients are on statin
68. FH Resources
The Canadian FH Registry
www.FHCanada.net
www.fhpatientcanada.org
69
Physicians’ Guide available on www.FHCanada.net
Patient Information Guide available on www.FHCanada.net
TOC
