Role of ezetimibe in targeting residual risk Faculty Disclosure - - PowerPoint PPT Presentation

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Role of ezetimibe in targeting residual risk Faculty Disclosure - - PowerPoint PPT Presentation

Mar 15, 2023 108 likes •277 views

Beyond statins: Role of ezetimibe in targeting residual risk Faculty Disclosure Declaration of financial interests For the last 3 years and the subsequent 12 months: I I have received a research grant(s)/ in kind support A From current

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Beyond statins: Role of ezetimibe in targeting residual risk

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SLIDE 2

Faculty Disclosure

I I have received a research grant(s)/ in kind support

A From current sponsor(s) (MSD, Sanofi) YES B From any institution (Roche) YES

II I have been a speaker or participant in accredited CME/CPD

A From current sponsor(s) (MSD, Sanofi) YES B From any institution (Amgen) YES

III I have been a consultant/strategic advisor etc

A For current sponsor(s) (MSD, Sanofi) YES B For any institution (Pfizer, Amgen) YES

IV I am a holder of patent/shares/stock ownerships

A Related to presentation NO B Not related to presentation NO

Declaration of financial interests For the last 3 years and the subsequent 12 months:

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40 50 60 70 80

Clinical event horizon

Age (years)

30

Non-modifiable residual risk age, sex, genetics

Asymptomatic phase Plaque rupture

Statin Rx Statin Plus Rx

Fatty streak Unstable lesion Stable lesion

Total modifiable risk Modifiable residual risk

Targeting residual risk

After Packard CJ, Weintraub WS, Laufs U. Vascul Pharmacol. (2015); 71:37-9

ACS

Cholesterol lowering

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SLIDE 4

Impact of dual inhibition of cholesterol synthesis and absorption

50%

Chylomicron remnants

Dietary sources 1500 mg 500 mg Synthesis

x

25%

(1000 mg) (1000 mg) (900 mg)

500 mg LDL

Statin

x

Chol

Ezetimibe

Chol

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SLIDE 5

LDL-C and Lipid Changes

1 Yr Mean LDL-C TC TG HDL hsCRP Simva 69.9 145.1 137.1 48.1 3.8 EZ/Simva 53.2 125.8 120.4 48.7 3.3 Δ in mg/dL

  • 16.7
  • 19.3
  • 16.7

+0.6

  • 0.5

Median Time avg 69.5 vs. 53.7 mg/dL

Cannon et al. N Engl J Med. (2015) 372:2387-97

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HR Simva* EZ/Simva* p-value All-cause death 0.99 15.3 15.4 0.782 CVD 1.00 6.8 6.9 0.997 CHD 0.96 5.8 5.7 0.499 MI 0.87 14.8 13.1 0.002 Stroke 0.86 4.8 4.2 0.052 Ischemic stroke 0.79 4.1 3.4 0.008 Cor revasc ≥ 30d 0.95 23.4 21.8 0.107 UA 1.06 1.9 2.1 0.618 CVD/MI/stroke 0.90 22.2 20.4 0.003

Ezetimibe/Simva Better Simva Better

Individual Cardiovascular Endpoints and CVD/MI/Stroke

0.6 1.0 1.4

*7-year event rates (%)

Cannon et al. N Engl J Med. (2015) 372:2387-97

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Mendelian randomisation 2x2 ‘trial’ of LDL lowering

Referent (wild type) variants

Ference et al. Circulation. 2014;130; A19754

NPC1L1 gene variants HMGR gene variants Both NPC1L1 and HMGR variants LDLc 0.08mmol/l lower CHD events 6.5% decrease LDLc 0.09mmol/l lower CHD events 7.0% decrease LDLc 0.17mmol/l lower CHD events 13.7% decrease

Meta-analysis of 14 studies, 108,376 subjects, 10,464 CHD events

NPC1L1

absorption

HMGR

3-OH 3MG CoA mevalonate

synthesis

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SLIDE 8

Lessons from clinical trials

IMPROVE-IT total events analysis

Murphy et al. J Am Coll Cardiol (2016);67:353-61

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Long-term benefits of LDL lowering

WOSCOPS 20-year followup

CHD mortality

Placebo Pravastatin

All-cause mortality

Average age of cohort 55 65 75 y

5 10 15 20 25 30 35 40 45 2 4 6 8 10 12 14 16 18 20 22

Percentage with event Years since randomisation

Over entire period 13% risk reduction P<0.001 Over entire period 27% risk reduction P<0.001 Placebo Pravastatin 2 4 6 8 10 12 2 4 6 8 10 12 14 16 18 20 22

Percentage with event

Years since randomisation Original trial

Ford I et al. Circulation. (2016); 133:1073-80

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WOSCOPS at 20 years

In trial and post trial event rates

In trial event rates (1989-1995)

Placebo, number (%) with event Total n = 3023 Pravastatin, number (%) with event Total n = 3118 Adjusted Hazard Ratio (95% CI) P-value* 427 ( 14.13%) 372 ( 11.93%) 0.82 ( 0.71, 0.94) , 0.0054 480 ( 15.88%) 418 ( 13.41%) 0.82 ( 0.72, 0.93) , 0.0028 823 ( 27.92%) 739 ( 24.12%) 0.79 ( 0.70, 0.89) , 0.0002 1301 ( 46.05%) 1215 ( 41.51%) 0.81 ( 0.73, 0.90) , <0.0001 332 ( 10.61%) 329 ( 10.36%) 1.00 ( 0.82, 1.22) , 0.9856 Endpoint Placebo, number (%) with event Total n = 3293 Pravastatin, number (%) with event Total n = 3302 Adjusted Hazard Ratio (95% CI) P-value* Fatal or nonfatal MI 190 ( 5.77%) 115 ( 3.48%) 0.59 ( 0.47, 0.74) , <0.0001 CHD related death

  • r nonfatal MI

198 ( 6.01%) 119 ( 3.60%) 0.58 ( 0.47, 0.73) , <0.0001 CHD related death

  • r hospitalisation

273 ( 8.29%) 177 ( 5.36%) 0.58 ( 0.47, 0.72) , <0.0001 CV related death or hospitalisation 415 ( 12.60%) 329 ( 9.96%) 0.62 ( 0.52, 0.73) , <0.0001 Fatal or nonfatal stroke 40 ( 1.21%) 29 ( 0.88%) 0.56 ( 0.31, 1.03) , 0.0608

In trial Post trial

Ford I et al. Circulation. (2016); 133:1073-80

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CTTC Lancet (2005) 367;1267-78

Data from trials of:-

  • Statin vs placebo
  • More vs less intense

statin therapy.

  • Combination therapy

with ezetimibe

Regression line reveals:- 1.0 mmol/l fall in LDLc translates into a 22% decrease in risk

LDLc reduction (mmol/l) Relative risk reduction

Lessons from completed LDL lowering trials Risk reduction is related to LDL decrease

Cannon et al. N Engl J Med. (2015) 372:2387-97

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Understanding the broader impact of LDL lowering in IMPROVE-IT

  • 20%

40 80 120 160 4.1 3.3 1.7 1.3

mg/dl mmol/l

4 8 12 16

LDL cholesterol

Rx

CTTC regression

1 mmol/l drop in LDLc = 22% risk reduction

Absolute CV risk

% with CV event

CTTC Lancet ( Laufs et al EHJ (2014) CTTC Lancet (2010) 376;1670-81 Laufs et al EHJ (2014) Europ Heart J 35;1996-2000

  • 20%

IMPROVE-IT Real-world usage

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NICE - Lipid lowering with ezetimibe

Technology Appraisal Guidance - February 2016

  • Ezetimibe monotherapy is recommended as an option for treating

primary hypercholesterolaemia in adults in whom initial statin therapy is contraindicated or who cannot tolerate statin therapy.

  • Ezetimibe, co-administered with initial statin therapy, is

recommended as an option in adults who have started statin therapy when:

  • LDL cholesterol concentration is not appropriately controlled either after

appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin therapy and

  • a change from initial statin therapy to an alternative statin is being considered

NICE - Lipid modification in ACS – CG181: 2015

  • Aim for >40% reduction in non-HDLc
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Need for treatment options

But cardiologist Dr Aseem Malhotra said: 'I have no doubt millions of people taking statins in the UK will not benefit but are being put at risk of unnecessary harm.'

May 15th 2016

Concerns about statins were raised earlier this year by the Queen's former doctor, Sir Richard Thompson.

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Options in optimal LDL/ nonHDLc lowering

Patient not at goal for LDLc/ non-HDLc Further LDL reduction indicated clinically Increase statin dose ‘Rule of ‘6%’ Tolerability Side effects Combination therapy Statin + ezetimibe Statin + PCSK9 inhibitor (statin + CETP inhibitor - future)

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SLIDE 16

Summary

  • Recent evidence from clinical trials supports and

emphasises the benefits of more aggressive LDL lowering in secondary prevention.

  • New guidelines reinforce previous treatment goals

for very high risk, high risk and low to moderate risk categories of patients.

  • Treatment gaps persist linked possibly to perceived

tolerability of statins and discontinuity of care. Optional therapeutic strategies can be adopted.