controversies and advances that may change …pdfs,slides,etc/mancini.pdfmay change canadian lipid...

Controversies and Advances that May Change Canadian Lipid

Guidelines Soon

G. B. John Mancini, MD, FRCPC, FACP, FACC Professor of Medicine, University of British Columbia

Director of Research, UBC Division of Cardiology Director, Cardiovascular Imaging Research Core

Laboratory (CIRCL)

DISCLOSURES: HONORARIA AND CONSULTANCY ROLES WITH AMGEN, SANOFI, REGENERON, MERCK NIH CLINICAL TRIAL: ISCHEMIA (OMT VS REVASCULARIZATION) PRIMARY PANEL OF CCS DYSLIPIDEMIA GUIDELINES LEAD OF CANADIAN STATIN INTOLERANCE WORKING GROUP

Objectives

• To understand current indications for lipid treatment based on risk assessment and implications for use of new risk assessment approaches

• To understand the rationale for treating to LDL-C targets and why these may be lowered in the future

• To understand an emerging rank order of preferred lipid lowering agents for concomitant LDL-C and CV risk reduction

• To introduce new mechanisms for lipid lowering currently undergoing clinical research

ACC/AHA Dyslipidemia Guideline

Keaney JF. NEJM 28NOV2013

Are the ACC/AHA Guidelines on the Treatment of Blood Cholesterol a Game

Changer? A Perspective from the CCS Dyslipidemia Panel

Anderson et al. CJC 2014; 30: 377-380

Statin Benefit Groups Identified Without Calculators: “The 5 No Brainers”

• Clinically obvious CVD

• Severe LDL-C > 5 (likely genetic, high lifetime risk)

• DM (high lifetime risk):

– > 40yo

– > 30yo + 15yrs duration (eg 30 yo, onset age 15)

– complicated by microvascular disease

• Pre-dialysis CKD (not part of FRS but high CV risk):

– eGFR < 45

– ACR > 30

– eGFR < 60 + ACR > 3

• High Risk Hypertension (3 of the following: male, >55, smoking, TC:HDL > 6, Fam Hx premature CHD, LVH, abnormal ECG, microalbuminuria)

Comparison of Cardiovascular Risk Assessment Algorithms to Determine Eligibility for Statin Therapy: Implications for

Practice in Canada G. B. John Mancini MD, Arnold Ryomoto, BSc. CJC 2014; 30: 661-6

Risk Algorithms Percentage of

Male Patient

Profiles in Low

Risk Category

Percentage of

Female Patient

Profiles in Low

Risk Category

Identification of

Statin-eligible

Patients Based on

Calculator

Reynold’s Risk

Score

62.4 – 63.4% 93.4 – 94.5% Most

Conservative

Adult Treatment

Panel III

26.9 – 27.3% 89.3 – 90.1%

Pooled Cohort

Equation (white)

22.9 – 23.5% 63.3 – 64.0%

Pooled Cohort

Equation (black)

11.2 – 11.5% 32.4 – 34.7%

SCORE (low risk

population)

7.1 – 7.3% 47.3 – 47.9%

Framingham Risk

Score

4.3 – 4.6% 29.4 – 29.7%

SCORE (high risk

population)

0.8 – 0.9% 28.0 – 28.5% Least

Conservative

“Old FRS”

“Global FRS”

PCE ≥ 7.5% LDL-C > 1.7 mmol/L = treatment. This threshold is already below target!

Look at other lipid parameters. Consider secondary tests.

Trials Risk Level (5 year)

Median LDL-C

22 Placebo Controlled Trials

< 5% 3.43

≥ 5 - < 10% 3.68

≥ 10% - < 20% 3.61

≥ 20% - < 30% 3.72

≥ 30% 3.92

Overall Median LDL-C 3.70

5 More vs Less Statin Trials

≥ 10% - < 20% 2.37

≥ 20% - < 30% 2.59

≥ 30% 2.81

Overall Median LDL-C 2.53

Lancet 2012; 380: 581–90

Secondary Considerations or Novel Biomarkers

• ACC/AHA guidelines acknowledge that not all patients with PCE risk > 7.5% may warrant or accept therapy

• Secondary considerations include:

– Family History of CVD, suspicion of genetic dyslipidemia, CACS, hs-CRP, ABI, elevated lifetime risk

• Not terribly different than CCS but

– excludes carotid US (may be useful in women; essential in young as CACS seldom helpful)

– Does not consider value of apoB or non-HDL or Lp(a) to detect atherogenic dyslipidemia

Objectives





Plaque Regression Can Occur in Response to Intensive LDL-C Lowering

1. Adapted from Sipahi I, et al. Cleve Clin J Med. 2006;10:937-944; 2. Nissen SE, et al. JAMA. 2006:295:1556-156.

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

Regression in plaque volume associated with

LDL-C <1.9 mmol/L, r2=0.95; P<0.0011

1.8

1.2

0

-0.6

-1.2

1.6 1.8 2.1 2.3 2.6 2.8 3.1

Mean LDL-C (mmol/)L

Me

dia

n C

ha

nge

in P

erc

en

t

Ath

ero

ma V

olu

me (

%)

1.3

ASTEROID (statin)

0.6 REVERSAL (statin)

REVERSAL (statin)

A-PLUS (placebo)

ACTIVATE (placebo)

CAMELOT (placebo)

r2 = 0.95 P < 0.001

Statin RCT’s with Dose Titration: 4S, AFCAPS, GREACE • 4S: LDL-C < 3.8; AFCAPS: < 2.8 mM; GREACE: < 2.6

mM

• Advantages: – personalized dose of statin (not more/not less in context of

prevailing targets)

– takes into account variability of response and circumstances when baseline LDL-C is unknown

– allows non-judgmental discussion of adherence to both drug and lifestyle elements of therapy

– facilitates management of intolerance

– allows rational use of secondary/emerging agents

• Disadvantages: – optimal target is a “moving target”

– patients with “low” baseline LDL-C might be denied benefits of therapy

– requires more LDL testing

Relationship Between LDL-C Reduction and Coronary Events for Secondary and Primary Prevention

Studies

Updated from: LaRosa JC, et al. N Engl J Med 2005; 352(14):1425-35; Pencina et al NEJM 2014

20

0

10

Co

ron

ary

even

t ra

te (

%)

25

LDL cholesterol (mmol/L)

Major Statin Trials

5

15

1.3

TNT

2.84 2.3 1.8 3.36 4.91 4.39 3.87 5.43

4S

IDEAL

CARE Lipid

HPS-P

AFCAPS

ASCOT

WOS

JUPITER

Secondary Prevention

Primary Prevention

4S: highest risk, mod. intensity statin

JUPITER: lowest risk, high intensity statin

IMPROVE-IT: EZE add-on

Support of the LDL HYPOTHESIS using SAFE Interventions: Linear Relationship Between Reduction of CV

Events and LDL-C Reduction Independent of Method (Diet, Bile Acid Sequestrants, Surgery, Statins etc)

Robinson JG, et al. J Am Coll Cardiol 2005; 46(10):1855-62.

80

-20

40

No

n-f

ata

l M

I a

nd

CH

D d

ea

th R

RR

(%

)

100

LDL-C reduction (%)

20

60

25 20 15 35 30 40

0

45 50

JUPITER

London

Oslo

MRC

Los Angeles

Upjohn

LRC

NHLBI

POSCH

4S

WOSCOPS

CARE

LIPID

AF/TexCAPS

HPS

ALERT

PROSPER

ASCOT-LLA

CARDS

SHARP: Simva + EZE

• Neither guideline endorses poly-pharmacy except when “warranted.”

• Getting to “target” is not endorsed by the ACC/AHA but ensuring “expected fall of 30 – 50%” is endorsed (this is essentially a “target”).

• Measuring LDL-C also identifies patients whose residual LDL-C-related CV risk might be improved by rational use of existing, safe agents or emerging secondary agents

• Statin intolerance and role of secondary agents is acknowledged by both.

Boekholdt et al: JACC 2014; 64: 485

< 2.0 mmol/L

Wiviott et al: PROVE-IT JACC 2005;46: 1411

JUPITER: Rates (per 100 person-years) of treatment-emergent adverse events by attained

LDL-C Placebo Rosuvastatin

All LDL-C not <50 LDL-C<50

n 8150 8154 4000 4154

Rate Rate p Rate p Rate p

Peripheral neuropathy 0.22 0.21 0.82 0.21 0.93 0.20 0.76

Memory impairment 0.18 0.18 1.00 0.25 0.23 0.12 0.22

Insomnia 1.13 1.23 0.39 1.24 0.48 1.22 0.52

Depression 1.20 1.03 0.12 1.23 0.86 0.85 <0.01

Anxiety 0.87 0.72 0.11 0.78 0.42 0.67 0.07

P values vs placebo from proportional hazard models

Objectives





LDL-C and Lipid Changes M

ean

LD

L-C

(m

mo

l/L

)

1.0

1.25

1.5

1.75

2.0

2.25

2.5

QE R 1 4 8 12 16 24 36 48 60 72 84 96

Time since randomization (months) Number at risk:

1 Yr Mean LDL-C TC TG HDL hsCRP

Simva 1.81 3.75 1.55 1.24 3.8 mg/dl

EZ/Simva 1.38 3.25 1.36 1.26 3.3 mg/dl

Δ in mmol/L -0.43 -0.50 -0.19 +0.2 -0.5mg/dl

Median Time avg

1.8 vs. 1.4 mmol/L

Primary Endpoint — ITT

Simva — 34.7%

2742 events

EZ/Simva — 32.7%

2572 events

HR 0.936 CI (0.887, 0.988)

p=0.016

Cardiovascular death, MI, documented unstable angina requiring

rehospitalization, coronary revascularization (≥30 days), or stroke

7-year event rates

NNT= 50

IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit

CTT Collaboration.

Lancet 2005; 366:1267-78;

Lancet 2010;376:1670-81.

IMPROVE-IT

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

Non Statin Alternatives as Adjuncts Current Options

1. Suchy D, et al. Pharmacol Rep. 2011;63:1335-48; 2. MedlinePlus, NIH USA. Accessed May 30, 2014; 3. Ruparelia N, et al. Curr Opin

Cardiol. 2011;26:66–70; 4. Cziraky MJ, et al. J Manag Care Pharm. 2008;14(8 Suppl):S3-28; 5. Creider JC, et al. Nat. Rev. Endocrinol.

2012;8:517–528;

6. AIM-HIGH Investigators. N Engl J Med. 2011;365:2255-6; 7. HPS2-Thrive Collaboration Group. Eur Heart J. 2013;34(17):1279-91;

8. Tenebaum A, Fishman EZ. Cardiovasc Diabetol. 2012;11:125; 9. Moutzouri E, et al. Vasc Health Risk Manag. 2010;6:525-39; 10. Corsini A,

et al. Eur J Cardiovasc Prev Rehabil. 2009;16(1):1-9.

Add-on Therapy LDL-C Lowering Other Lipid

Effects

Outcome Data

(Add-On to statin) Side Effects2

Ezetimibe1 15 – 20%

IMPROVE-IT

(vs statin)

SHARP (vs

placebo)

URTI,

headache,

myalgia

Niacin3-5 5 - 20% ↑ HDL by 30%

↓ TG by 40% No benefit as add-on to statin6,7

Flushing/pruritus,

GI side effects

Fibrates8,9 5 – 20%

↑ HDL-C (10-50%)

↓ TG (20-50%)

No benefit as add-on to statin

GI side effects,

myalgia

Bile Acid

Sequestrants10 15 – 20% Limited GI side effects,

myalgia

2o

3o

Objectives





Four Mechanisms for Reducing LDL-C

Lilly SM, Rader DJ. Curr Opin Lipid. 2007;18:650–655; Shinkai H. Vasc Health Risk Manag. 2012;8:323-331.

CETP Mediates Transfer of Cholesterol

Shinkai H. Vasc Health Risk Manag. 2012;8:323-331. CETP = Cholesteryl Ester Transfer Protein

HDL VLDL

Plasma

LDL-R

Golgi

Apparatus

Endoplasmic

Reticulum (ER)

Nucleus

Hepatocyte

© 2013 Amgen Canada Inc. All rights reserved.

LDL

Free

Cholesterol

Cholesterol

Ester (CE)

Free

Cholesterol

Cholesterol

Ester (CE)

CETP Inhibitors Prevent Transfer of Cholesterol, Increases HDL

Shinkai H. Vasc Health Risk Manag. 2012;8:323-331. CETP = Cholesteryl Ester Transfer Protein

HDL VLDL


LDL

CETP Inhibition

Plasma

LDL-R

Golgi

Apparatus

Endoplasmic

Reticulum (ER)

Nucleus

Hepatocyte

CETP Inhibitors: Impact on LDL-C and HDL-C

CETP = Cholesteryl Ester Transfer Protein

Clinicaltrials.gov; Shinkai H. Vasc Health Risk Manag. 2012;8:323–331; Cannon CP, et al. N Engl J Med. 2010;363:2406-15; Gotto AM Jr, et al.

J Cardiovasc Pharmacol Ther. 2014 Apr 14. ;Nicholls SJ, et al. JAMA. 2011;306(19):2099-2109; Schwartz GG, et al, dal-OUTCOMES

Investigators. N Engl J Med. 2012;367(22):2089-99.

Anacetrapib Evacetrapib Dalcetrapib Torcetrapib

Effect on CETP Complete inhibition No data Modulation

(selective inhibition) Complete inhibition

HDL Increase

24- weeks: 138%

2-yr extension: 153% 12- weeks: 129% 31% 72%

LDL Decrease 24- weeks: 40%

2-yr extension: 40% 12- weeks: 36% No change 25%

Clinical Status

Phase III

DEFINE

DEFINE-extension

Phase III

REVEAL (outcome)

Phase II

Primary prevention

Phase III

ACCELERATE

(outcome)

Discontinued - lack of

clinical outcome

benefit

dal-OUTCOMES

Discontinued -

increases in CV

events and total

mortality

ILLUMINATE

In the Presence of PCSK9, the LDL-R Is Degraded and Does Not Cycle Back to Cell Surface

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


Golgi

Apparatus

Endoplasmic

Reticulum

(ER) Nucleus LDL, LDL-R and

PCSK9 Degradation

Blocking PCSK9 Activity Inhibits Intracellular Degradation of LDL-R

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

Monoclonal Antibody binds to PCSK9 and inhibits Binding to the LDL-Receptor

PCSK9

Self-procession

PCSK9 MAb

LDL-R

Endocytosis

Endosome

LDL

Degradation

LDL-R

Recycling

Lyosome

LDL

Hepatocyte

Plasma


Golgi

Apparatus

Endoplasmic

Reticulum

(ER) Nucleus

1. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438.

2. Dubuc G, et al. Arterioscler Thromb Vasc Biol. 2004;24:1454-1459.

Statin Influence on LDL-C Metabolism and PCSK9

STATIN

Acetyl-CoA + acetoacetyl-CoA

HMG-CoA reductase

Plasma

Nucleus Endoplasmic

Reticulum (ER)

Hepatocyte

SREB* Activation

LDL-R Expression

PCSK9 Expression

LDL-R PCSK9 Protein

LDL Protein at Cell Surface

LDL

PCSK9 Secretion

Cholesterol

Biosynthetic Rate

Cholesterol

Internatization

Hepatocyte Cholesterol

Content

HMG-CoA

Mevalonate

Isopententyl-PP

Cholesterol

Decreases in Hepatic Cholesterol Content Increases LDL-R and Plasma PCSK9

* P < 0.05 versus baseline and placebo baseline and endpoint

1. Amgen, data on file.

2. Careskey HE, Davis RA, et al. J Lipid Res. 2008;49:394–398.

LDL-R and PCSK9 Expression Are Both Upregulated When

Intracellular Cholesterol Levels Are Low

25

50

75

Baseline Endpoint

Placebo Atorvastatin

(40 mg)

*

Baseline Endpoint P

CS

K9

(m

g/m

L)

Alirocumab Maintained Consistent

LDL-C Reductions over 52 Weeks

39

39

53

67

81

95

109

123

137

151

1

1.5

2

2.5

3

3.5

4

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Week

3.1 mmol/L

118.9 mg/dL

1.3 mmol/L

48.3 mg/dL

3.2 mmol/L

123.0 mg/dL

1.4 mmol/L

53.1 mg/dL

mg

/dL

Placebo

Alirocumab

LD

L-C

, L

S m

ean

(S

E),

mm

ol/

L

Achieved LDL-C Over Time All patients on background of maximally-tolerated statin ±other lipid-lowering therapy

Intent-to-treat (ITT) analysis

1174

2318

1160

2294

1098

2171

1057

2087

1026

2030

862

1713

349

698

127

252

84 72 60 48 36 24 12 0

0.06

0.05

0.03

0.02

0.01

0.00

0.04

40

Post-hoc Adjudicated Cardiovascular TEAEs†

Pooled from Phase 3 Placebo-controlled Trials

Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Pooled Safety Analysis from five Phase 3 placebo-controlled trials (N=3459)

(at least 52 weeks for all patients continuing treatment)

Cu

mu

lati

ve p

rob

ab

ilit

y o

f even

t Placebo + max-tolerated statin ± other LLT

Alirocumab + max-tolerated statin ± other LLT

Cox model analysis:

HR=0.65 (95% CI: 0.40 to 1.08)

Nominal p-value = 0.0985

Weeks No. at Risk

Placebo

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

Mean baseline LDL-C (mg/dL):

Alirocumab:126.0 to 129.1; placebo, 125.4 to 129.9

Mean percent change in LDL-C from baseline to W24:

Alirocumab, 48.6 to 60.4%; placebo, 4.3 to 0.5%

Mean on-treatment LDL-C difference: 70.5 to 72.6 mg/dL

Conclusions

• 2012 Canadian Dyslipidemia Guidelines provide a solid rationale for clinicians and are being updated currently

• The concept of treating to target will be discussed and a lower LDL-C target may emerge

• Current evidence supports statin as the primary therapy and ezetimibe as the most obvious adjunct for concomitant LDL-C and CV risk reduction

• New agents based on new mechanisms for lipid lowering show promising efficacy and safety in ongoing trials

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