ldl-cholesterol – lower is better

04/16 CARD-1063303-0004Date of preparation May 2014

LDL-Cholesterol – Lower is Better

Reducing CHD in high risk patients


Contents

1. Contents Slide2. Presentation summary3. Title slide: LDL-Cholesterol – Lower is Better: Reducing CHD in high risk patients4. OPTIONAL SLIDE #1: Cardiovascular disease and cholesterol: Key facts5. Identifying ‘higher risk’ patients6. Why treat high risk patients?7. The impact of lowering LDL-C: Lower is better – however you achieve it8. Beneficial CV risk reduction with lowering LDL-C – however you achieve it9. OPTIONAL SLIDE #2: What does NICE advise for high risk patients?10. What are your options?11. Title slide: Treatment options: What the trials say12. OPTIONAL SLIDE #3: Trial overview13. Lowering LDL-C: Treatment options14. ALTERNATIVE VERSION TO SLIDE #12: Lowering LDL-C: Treatment options 15. Treating high risk patients: What are your choices?16. NICE recommendations for treatment with ezetimibe 17. OPTIONAL SLIDE #4: Safety data for ezetimibe 18. What NICE says... Patients with Type 2 diabetes19. What NICE says... Patients with Familial Hypercholesterolaemia 20. In summary: Treating higher risk patients21. OPTIONAL SLIDE #5 Additional Slides


Presentation summary

1. Cholesterol and CVD, leading cause of death and high cost

2. Reducing LDL-C levels significantly reduces the risk of CHD

3. Treatment strategies for the cohort of high risk patients

4. Review evidence, clinical trials, clinical practice and NICE Guidance to manage this difficult group of patients


Cardiovascular disease and cholesterol: Key facts

• CVD is the leading cause of death in England and Wales1

• The annual cost of managing CVD exceeds £30 billion2

• Over 80% of premature CVD is avoidable2,3

• Reducing CVD risk by 1% over 10 years would prevent 25,000 new cases of CVD4

• Reducing total cholesterol levels by 5% would save the NHS £80 million per annum4

• LDL-C is a key modifiable CVD risk factor1

• NICE targets for secondary prevention of CVD (high risk patients): TC < 4 mmol/L or LDL-C < 2 mmol/L1

• More than 50% of patients will not achieve their target lipid levels on statin therapy alone1

1. NICE Clinical Guideline 67. May 2008. Reissued March 2010, 2. British Heart Foundation. Modelling the UK burden of cardiovascular disease to 2020. September 2008. Available at: http://www.bhf.org.uk/plugins/PublicationsSearchResults/DownloadFile.aspx?docid=ad18e5a0-7da6-4c7c-8142-f68f27cde451 [Accessed on 21 January 2014], 3. WHO. Cardiovascular diseases. Available at: http://www.euro.who.int/en/what-we-do/health-topics/noncommunicable-diseases/cardiovascular-diseases/facts-and-figures [Accessed on 21 January 2014], 4. Barton P et al. BMJ 2011 Jul 28; 343:d4044.

04/16 CARD-1063303-0004Date of preparation: May 2014

Identifying ‘higher risk’ patients

Who are the higher risk patients?• There is a population of patients

who are difficult to treat and at increased risk of CVD:– Patients with Type 2 diabetes and

established CVD who need to achieve a total cholesterol or an LDL-C of < 4mmol/L and < 2mmol/L, respectively2,3

– Those with familial hypercholesterolaemia requiring > 50% reduction in LDL-C4

1. Trusler D. BMJ 2011; 343: d4350, 2. NICE Clinical Guideline 67. May 2008. Reissued March 2010, Reproduced with permission 3. NICE Clinical Guideline 87. May 2009. Reproduced with permission 4. NICE Clinical Guideline 71 August 2008. Reproduced with permission.


Why treat high risk patients?

• Patients with T2DM die from complications of their disease• > 70% of patients with T2DM die from cardiovascular causes1

• Patients at high risk of cardiovascular disease have the most to gain from risk factor modification2

• Intensive LDL-C reduction results in significant reductions in cardiovascular morbidity and mortality3

• A 1 mmol/L reduction in LDL-C results in a 22% reduction in the risk of major vascular events4

• The opportunity to improve cardiovascular outcomes by treating atherogenic dyslipidaemia in diabetes (or diabetic patients) should not be missed3

1. Laakso M. Diabetes Care 2010; 33(2): 442–449, 2. SIGN97. Feb 2007 Available at: http://www.sign.ac.uk/pdf/sign97.pdf [Accessed on 22 January 2014], 3. Nesto RW. Clinical Diabetes 2008; 26(1): 8–13, 4. Cholesterol Treatment Trialists’ (CTT) Collaboration. The Lancet 2010; 376(9753): 1670–1681.


The impact of lowering LDL-C: Lower is better – however you achieve it

• For every 1 mmol/L reduction in LDL-C there is a 22% reduction in the risk of major vascular events at 1 year1

• There is a proportional relationship between lowering LDL-C and reducing 5-year non-fatal MI and CHD death risk – irrespective of how LDL-C is lowered2

1 mmol/L

22%

1. Cholesterol Treatment Trialists’ (CTT) Collaboration. The Lancet 2010; 376(9753): 1670–1681, 2. Robinson JG et al. J Am Coll Cardiol 2005; 46(10): 1855–1862.


POSCH

4S

WOSCOPS

CARE

LIPID

AF/TexCAPS

100

80

60

40

20

0

-20

15 20 25 30 4035

LDL-C reduction (%)

Non

fata

l myo

card

ial i

nfar

ction

and

CHD

dea

thEs

timat

ed re

lativ

e ris

k re

ducti

on (%

)

Oslo

MRC

Los Angeles

Upjohn

LRC

NHLBI

HPS

ALERT

PROSPER

ASCOT-LLA

CARDS

The London and Sydney trials are not shown, but were included in the analysis

Relative risk reduction95% probability intervalSlope=1

Adapted from Robinson JG et al. J Am Coll Cardiol 2005;46(10):1855–1862

Meta-analysis of data from 19 trials with 81,859 participants1

Beneficial CV risk reduction with lowering LDL-C – however you achieve it

• Data from 5 diet, 3 bile acid sequestrant and 10 statin trials• Data from 1 surgery trial

1. Robinson JG et al. J Am Coll Cardiol 2005; 46(10): 1855–1862.


• What guidance is available for lowering cholesterol?– Diabetes NICE CG871, FH NICE CG712, Lipids NICE CG673

• Which of these guidelines relate to high risk patients?– Diabetes NICE CG87

• Initiate simvastatin 40 mg, increasing to 80 mg* unlessTC < 4mmol/L or LDL-C < 2mmol/L

• Consider intensifying therapy with statin or ezetimibe if existing or new CVD or increased albumin excretion rate

– FH NICE CG71• High intensity statin to achieve a recommended LDL-C reduction of 50% from baseline.

Ezetimibe co-administered with a statin (if) target lipid levels are not controlled after dose titration of initial statin, or because titration is limited by intolerance to initial statin

What does NICE advise for high risk patients?

NICE Recommended

Levels:LDL-C: 2.0 mmol/L

orTC: 4.0 mmol/L

*MHRA (May 2010) reported increased risk of myopathy with high-dose (80 mg) simvastatin and advised: “Consider only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.”4

1. NICE Clinical Guideline 87. May 2009. Reproduced with permission. 2. NICE Clinical Guideline 71. August 2008 Reproduced with permission. 3. NICE Clinical Guideline 67. May 2008. Reissued March 2010. Reproduced with permission. 4. MHRA. Drug Safety Update. May 2010. Available at: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169 [Accessed on 21 January 2014].

Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated


What are your options?

• Lifestyle• Statin• Fibrate• Resin, fish oil, nicotinic acid*• Cholesterol absorption inhibitor

*No longer available as a modified release medicine in the EU. Instant release available as a supplement in health shops.


Treatment options

What the trials say



Therapy 5 mg 10 mg 20 mg 40 mg 80 mg

Rosuvastatin 38-45% in LDL-C.1,2 43-52% in LDL-C.1,2,3 48-55% in LDL-C.1,2,3 53-63% in LDL-C.1,2,3

Atorvastatin 37% in LDL-C.1,3 43% in LDL-C.1,3 48-49% in LDL-C.1,3 51-55% in LDL-C.1,3

Simvastatin 27-30% in LDL-C.1,3,4 32-38% in LDL-C.1,3,4 37-41% in LDL-C.1,3,4 42-47% in LDL-C.1,3,4

Pravastatin 20 % in LDL-C.1,3 23-24 % in LDL-C.1,3,5 29-34% in LDL-C.1,3,6

Statin + ezetimibe

31% in LDL-C eze 10 + atorva 20 mg

vs. 11% in LDL-C

atorva 40 mg.7

27% in LDL-C eze 10 + atorva 40 mg

vs.11% in LDL-C

atorva 80 mg.8

46% in LDL-C eze 10 + simva 10 mg

vs. 35% in LDL-C

simva 20 mg.9


vs. 42% in LDL-C

simva 40 mg.9


vs. 46% in LDL-C

simva 80 mg*.9

61% in LDL-C eze 10 + simva 80 mg*

vs. 46% in LDL-C

simva 80 mg*.9

Statin + Anion exchange resin

42% in LDL-C colesevelam 3.8 mg + simva 10 mg

vs. 26% in LDL-C simva 10 mg

vs.16% in LDL-C colesevelam

3.8 mg.10

42% in LDL-C colesevelam 2.3 mg + simva 20 mg

vs. 34% in LDL-C simva 20 mg

vs.8% in LDL-C colesevelam

2.3 g.10

1. Law MR et al. BMJ 2003; 326(7404); 1423–1427, 2. Crestor Summary of Product Characteristics, 3. Jones PH et al. Am J Cardiol 2003; 93: 152–160, 4. Zocor Summary of Product Characteristics, 5. Lipostat Summary of Product Characteristics, 6. Shepherd J et al. The Lancet 2002; 360(9346): 1623–1630, 7. Conard SE et al. Am J Cardiol 2008; 102: 1489–1494, 8. Leiter LA et al. Am J Cardiol 2008; 102(11): 1495–1501, 9. Goldberg AC et al. Mayo Clin Proc. 2004; 79: 620–629, 10.Knapp HH et al. Am J Med 2001; 110(5): 352–360.

All reductions are from baseline as specified in the relevant studies.

LDL-C lowering efficacy of lipid lowering therapies


Treatment option % LDL-C reduction from treated baseline

Doubling statin

Switching statin

Adding ezetimibe

Lowering LDL-C: Treatment options

6%1,2

8%1

23.2%1

1. NICE Technology Appraisal Guidance 132, November 2007, 2. Knopp RH. N Engl J Med 1999; 341: 498–511.


Lowering LDL-C: Treatment options

Treatment option5

0

-5

-10

-15

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Treated baseline

% L

DL-C

redu

ction

from

bas

elin

e

Graphical version of previous slide

Doubling statin

Switching statin

Adding ezetimibe

% LDL-C reduction from treated baseline

6%1,2

8%1

23.2%1

1. NICE Technology Appraisal Guidance 132, November 2007, 2. Knopp RH. N Engl J Med 1999; 341: 498–511.



Risk factors NICE-recommended treatmentType 2 diabetes (T2DM) 1,2 Initiate patient on simvastatin 40 mg

T2DM, 1–3 months after initiation, if on assessment LDL-C > 2 mmol/L or total cholesterol > 4 mmol/L, or other CVD risk factors develop2

Intensify statin therapy to simvastatin 80 mg*

T2DM: If there is existing CVD, increased albumin excretion or inadequate lipid level control 2

Intensify statin therapy; or considerstatin + ezetimibe

Secondary prevention of CVD1Initiate simvastatin 40 mg (or a lower dose if potential drug interactions or 40 mg is contraindicated)

Secondary prevention CVD if lipid levels are LDL-C > 2 mmol/L or total cholesterol > 4 mmol/L1

Intensify statin therapy to simvastatin 80 mg* (or switch to drug of similar efficacy) if lipid targets not met

Acute Coronary Syndrome (ACS)1 Treat with higher intensity statin

Familial Hypercholesterolaemia3

Combined statin + ezetimibe

Ezetimibe monotherapy if patient cannot tolerate statins

Treating high-risk patients: What are your choices?

1. NICE Clinical Guideline 67. May 2008. Reissued March 2010, 2. NICE Clinical Guideline 87. May 2009 , 3. NICE Clinical Guideline 71. August 2008, 4.MHRA. Drug Safety Update. May 2010. Available at: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169 [Accessed on 21 January 2013].

Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated


• Ezetimibe is recommended, as an option, in combination with a statin, when:– Serum total or LDL-C concentration is not appropriately controlled

• either after appropriate dose titration of initial statin or• because dose titration is limited by intolerance to the initial statin therapy

– You are considering switching from the initial statin therapy

• Ezetimibe monotherapy is recommended, as an option, in adults with primary hypercholesterolaemia– who are intolerant to statins, or who are contraindicated for statin therapy

NICE recommendations for treatment with ezetimibe1

“The Committee agreed that there is sufficient evidence to link reductions in LDL cholesterol concentrations induced by treatment with ezetimibe with future reductions in cardiovascular events.”* 1

1. NICE Technology Appraisal Guidance 132. November 2007. Reproduced with permission.

*Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated


Safety data for ezetimibe1

AEs in clinical studies of up to 112 weeks duration

Ezetimibe monotherapy (n=2,396) vs. placebo (n=1,159)

Ezetimibe co-administered with a statin (n=11,308) vs. statin alone (n=9,361)

Common (≥ 1/100 to < 1/10)

Abdominal pain, diarrhoea, flatulence, fatigue

ALT and/or AST increased, headache, myalgia

Uncommon (≥ 1/1,000 to < 1/100)

ALT and/or AST increased, blood CPK increased, GGT increased, liver function test abnormal, cough, dyspepsia, gastro-oesophageal reflux disease, nausea, arthralgia, muscle spasms, neck pain, decreased appetite, hot flush, hypertension, chest pain, pain

Paraesthesia, dry mouth, gastritis, pruritus, rash, urticaria, back pain, muscular weakness, pain in extremity, asthenia, oedema peripheral

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; GGT, gamma-glutamyltransferase Importantly, evidence from 13 randomised, blinded clinical trials in which ezetimibe and simvastatin were administered in combination either as separate or combined tablets (n=4,558) suggests that ezetimibe does not enhance nor aggravate the known muscle effects of simvastatin when compared to simvastatin monotherapy (n=2,563).2

1. Ezetrol 10 mg Tablets Summary of Product Characteristics, 2. Davidson MH et al. Am J Cardiol 2006; 97(2): 223–228.


What NICE says… Patients with Type 2 Diabetes

“Consider intensifying cholesterol-lowering therapy (with a more effective statin or ezetimibe in line with NICE guidance) if there is existing or newly diagnosed cardiovascular disease, or if there is an increased albumin excretion rate, to achieve a total cholesterol level below 4.0 mmol/litre (and HDL cholesterol not exceeding 1.4 mmol/litre) or an LDL cholesterol level below 2.0 mmol/litre.”

National Institute for Health and Care Excellence. Type 2 Diabetes. Clinical Guideline 87 July 2011. London:NICE. Available from http://guidance.nice.org.uk/CG87. Reproduced with permission


What NICE says…Patients with Familial Hypercholesterolaemia

“Ezetimibe, co-administered with initial statin therapy, is recommended as an option for the treatment of adults with heterozygous-familial hypercholesterolaemia who have been initiated on statin therapy when:• Serum total or LDL-C 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• Consideration is being given to changing from initial statin therapy to

an alternative statin.”

National Institute for Health and Care Excellence. FH. Clinical Guideline 71 August 2008. London: NICE. Available from http://guidance.nice.org.uk/CG71. Reproduced with permission


In summary: Treating higher risk patients

• In secondary prevention patients NICE recommends to consider increasing the statin to simvastatin 80mg, or a drug of similar efficacy and acquisition cost, if TC <4mmol/L or LDL-C<2mmol/L is not attained1

• The evidence indicates that a greater reduction in baseline LDL-C can be achieved by adding ezetimibe to a statin, than by increasing the statin dose,2 or by switching from simvastatin to atorvastatin3

• In patients with CVD, NICE recommends intensified treatment for hypercholesterolaemia.1 In these patients, ezetimibe added to a statin can help more patients achieve NICE-recommended lipid management levels

• Reduction in LDL-C, irrespective of how it is achieved, reduces the risk of CVD.4 NICE have accepted there is sufficient evidence to link LDL-C reduction via ezetimibe use with a reduction in future CV events*5

1. NICE Clinical Guideline 67. May 2008. Reissued March 2010. Reproduced with permission. 2. Conard SE et al. Am J Cardiol 2008; 102(11): 1489–1494, 3. McCormack T et al. Int J Clin Prac 2010; 64(8): 1052–1061, 4. Robinson JG, et al. J Am Coll Cardiol 2005; 46(10): 1855–1862, 5. NICE Technology Appraisal Guidance 132, November 2007. Reproduced with permission.

*Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated


Additional Slides


Leiter LA et al.

Efficacy and safety of ezetimibe added on to atorvastatin (40 mg) compared with up-titration of atorvastatin (to 80 mg) in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol 2008; 102 (11): 1495–1501.


Efficacy of adding ezetimibe to atorvastatin 40mg vs. up-titrating to atorvastatin 80mg

• Randomised, multi-centre, double-blind study• Criteria – hypercholesterolaemia and high risk of CHD• LDL-C ≥1.8mmol/L and ≤4.1mmol/L• Run-in – atorvastatin 40mg for at least 4 weeks• Treatment – up-titration to atorvastatin 80mg or addition of ezetimibe

10mg to atorvastatin 40mg for 6 weeks

Leiter LA et al. Efficacy and Safety of Ezetimibe Added on to Atorvastatin (40mg) Compared with Uptitration of Atorvastatin (to 80mg) in Hypercholesterolemic Patients at High Risk of Coronary Heart Disease Am J Cardiol 2008; 102: 1495–1501.


Efficacy of adding ezetimibe to atorvastatin 40mg vs. up-titrating to atorvastatin 80mg

0

-5

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-15

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-25

-30

Baseline

% ch

ange

in L

DL-C

from

trea

ted

base

line

at w

eek

6

Baseline LDL-C 2.3mmol/Lp<0.001 for treatment difference between arms

-11%

-27%

Atorvastatin 80mg (n=279)

Atorvastatin/ezetimibe 40/10mg (n=277)

Leiter LA et al. Am J Cardiol 2008; 102: 1495–1501.

Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet

been demonstrated


Tolerability of adding ezetimibe to atorvastatin 40mg vs. up-titrating to atorvastatin 80mg

• Tolerability profiles of both treatments generally similar and consistent with previous studies of similar duration

• Serious adverse event incidence low– None considered drug-related

• No myopathy or rhabdomyolysis• No significant differences in pre-specified AEs between groups

Leiter LA et al. Am J Cardiol 2008; 102: 1495–1501.


Jones PH et al.

STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin and pravastatin across doses. Am J cardiol 2003; 93: 152–160.


Comparison of the efficacy and safety of rosuvastatin vs. atorvastatin, simvastatin and pravastatin across doses (STELLAR trial)1

• Randomised, multi-centre, parallel group, open-label (n = 2431)• Patient criteria – hypercholesterolaemia i.e. LDL-C between 4.10 and < 6.42

mmol/l ( 160 and < 250 mg/dl)• Treatment duration – 6 weeks• Randomised treatments:

– rosuvastatin 10, 20, 40 or 80 mg*– atorvastatin 10, 20, 40 or 80 mg– simvastatin 10, 20, 40 or 80 mg†– pravastatin 10, 20, or 40 mg

1. Jones PH et al. Am J Cardiol 2003; 93: 152–160, 2. MHRA. Drug Safety Update. May 2010. Available at: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169 [Accessed on 21 January 2014].

* Rosuvastatin 80 mg is not licensed† MHRA (May 2010) reported increased risk of myopathy with high-dose (80 mg) simvastatin and advised: “Consider only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.”2


Pooled-dose analyses: rosuvastatin reduced mean LDL-C at 6 weeks more than atorvastatin, simvastatin and pravastatin

0

-5

-10

-15

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-25

-30

Baseline

Incr

ease

d m

ean

% re

ducti

ons i

n LD

L-C

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bas

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e at

W

eek

6 w

ith ro

suva

stati

n vs

. com

para

tor s

tatin

s

p <0.001 (for all 3 comparisons)

-8.2%

-12 to -18%

Reduction compared with atorvastatin 10–80 mg

Reduction compared with simvastatin 10 to 80 mg

-26%

Reduction compared with pravastatin 10 to 40 mg

Adapted from Jones PH et al. Am J Cardiol 2003; 93: 152–160


Safety: rosuvastatin vs. atorvastatin, simvastatin and pravastatin

• Drug tolerability was similar across treatments• Percentage of patients reporting AEs ranged from 40 – 56% across treatments;

most mild to moderate in intensity and dose-related• Most common AEs: pain (6%), pharyngitis (5%), myalgia (4%), headache (4%)• 29 serious adverse events reported• 2 patients died (1 received simvastatin 10 mg, 1 atorvastatin 40 mg); both

deaths due to CV disease – unrelated to treatment

Jones PH et al. Am J Cardiol 2003; 93: 152–160

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