insights with gold standard therapies Philip Barter School of - - PowerPoint PPT Presentation

Managing lipids: Integrating novel insights with gold standard therapies

Philip Barter School of Medical Sciences University of New South Wales Sydney, Australia

Received honorariums for participating as a consultant or as a member of advisory boards for AMGEN, AstraZeneca, CSL-Behring, Lilly, Merck, Novartis, Pfizer and Sanofi and for giving lectures for AMGEN, AstraZeneca, Merck and Pfizer.

Disclosures

• Smoking
• Elevated LDL-C
• Elevated triglyceride-rich lipoproteins
• Reduced HDL-C
• Elevated blood pressure
• Diabetes
• Abdominal obesity

Modifiable risk factors for Atherosclerotic Cardiovascular Disease (ASCVD)

• Smoking
• Elevated LDL-C
• Elevated triglyceride-rich lipoproteins
• Reduced HDL-C
• Elevated blood pressure
• Diabetes
• Abdominal obesity

Modifiable risk factors for Atherosclerotic Cardiovascular Disease (ASCVD)

Treatment with statins reduces the risk of having an atherosclerotic cardiovascular event

The more the LDL-C is reduced, the greater is the reduction in risk of having an event.

CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81.

Relationship of CVD events to LDL-C reduction achieved in statin clinical trials

And the lower the achieved level of LDL-C, the lower the risk of having an event

10 20 30

CARE-Pra LIPID-Pra 4S-Sim CARE-Plac LIPID-Plac 4S-Plac

Secondary Prevention Statin Trials

Achieved LDL-C Levels vs Events

210 90 110 130 150 170 190

LDL-C (mg/dL) % with CHD event

70

TNT-Ator10 TNT-Ator80 HPS-Plac HPS-Sim IDEAL-Sim IDEAL-Ator

Proportion of patients experiencing a major CVE

0.05 0.10 0.15

Atorvastatin 80 mg

1 2 3 4 5 6 Time (years)

Relative risk reduction 22% (p < 0.001)

TNT-Primary efficacy outcome measure: major cardiovascular events

LaRosa JC, et al. N Eng J Med. 2005;352

LDL-C 77 mg/dL

Atorvastatin 10 mg

LDL-C 101 mg/dL

PROVE-IT: All-cause mortality or major CV events in all randomised subjects

3 18 21 24 27 30 6 9 12 15

Months of follow-up Atorvastatin 80 mg 16% RRR P=0.005

30 25 20 15 10 5

% patients with event

Cannon CP, et al. N Engl J Med. 2004;350:1495

LDL-C 62 mg/dL

Pravastatin 40 mg

LDL-C 95 mg/dL

So, it has been proven beyond all reasonable doubt that lowering LDL-C with statins reduces ASCVD risk and the greater the lowering of LDL-C, the greater the risk reduction of both CHD and ischemic stroke

So, all high risk people should be treated with a statin to reduce the risk of having an ASCVD event

Even though people with end- stage kidney disease appear to get little benefit, those with severe (but not end stage) have ASCVD risk reduced by LDL- lowering therapy

But, many people at high ASCVD risk still have LDL-C levels that are unacceptably high even when taking statins.

Options to achieve greater reductions in LDL-C levels in high risk patients

Change to a higher dose of a more potent statin

Options to achieve greater reductions in LDL-C levels in high risk patients

Change to a higher dose of a more potent statin Add another agent Statin plus Ezetimibe Statin plus a PCSK9 inhibitor

Options to achieve greater reductions in LDL-C levels in high risk patients

Lova Co-admin Prava Co-admin Simva Co-admin Atorva Co-admin

Effects of adding ezetimibe to a statin

20 40 60 80 100 120 140

Statin alone Statin + EZE

LDL-C (mg/dL) at study end

19% 23% 23% 21% Lipka L, et al. J Am Coll Cardiol (Suppl). 2002. Melani L, et al. J Am Coll Cardiol (Suppl). 2002. Davidson M, et al. J Am Coll Cardiol (Suppl). 2002. Ballantyne C, et al. J Am Coll Cardiol (Suppl). 2002. Bays H, et

• al. J Am Coll Cardiol (Suppl). 2002.

Ezetimibe lowers LDL-C an additional 19%-23% compared with statin alone

IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial

Ezetimibe 10 mg + simvastatin 40-80 mg Simvastatin 40-80 mg 18 000 patients

• Men and

women

• Aged 18 years
• High-risk ACS

Continue until 5250 subjects have a primary

• event. Minimum 2.5-year

follow-up Study completed in 2014

Primary End Point

• Composite of CV death, major coronary

events, and stroke

Cannon et al. N Engl J Med. 2015;372:2387

Cannon et al. N Engl J Med. 2015;372:2387

Cannon et al. N Engl J Med. 2015;372:2387

Cannon et al. N Engl J Med. 2015;372:2387

Cannon et al. N Engl J Med. 2015;372:2387

CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81.

Relationship of CVD events to LDL-C reduction achieved in statin clinical trials

IMPROVE-IT

PCSK9 inhibitors New agents to lower of LDL-C

PCSK9 inhibitors reduce the plasma level of LDL-C by increasing the number of LDL receptors on the cell surface

Role of LDL receptor in the removal of LDL from plasma

c c c c c c c c

Endoplasmic reticulum LDL Receptor LDL Particle LDL Receptor

Liver cell

Lysosome LDL Particle LDL Receptor recycles

Plasma

LDL Receptor

Statins reduce the plasma level

• f LDL-C by increasing the

number of LDL receptors on the cell surface

What about PCSK9

c c c c c c c c

Endoplasmic reticulum LDL Receptor LDL Particle Lysosome PCSK9 LDL Receptor unable to dissociate from complex and does not recycle PCSK9

Liver cell Plasma

So, PCSK9 decreases the number of LDL receptors on the cell surface and thus increases the concentration of LDL-C in plasma

Gain of function mutations of the PCSK9 gene represent a rare cause of familial hypercholesterolaemia and increased ASCVD risk

PCSK9: Human genetic studies

In contrast, loss of function mutations

• f the PCSK9 gene are associated with

a low level of LDL-C and a decreased ASCVD risk

PCSK9: Human genetic studies

Cohen JC. N Engl J Med. 2006;354:1264‐72

CHD in people with PCSK9 deficiency

CHD (%)

12 8 4 P=0.008 No PCSK9142x PCSK9679x

• r

Yes

So, inhibiting PCSK9 is a logical strategy to reduce the level of LDL-C whether or not the patient is on a statin

Anti-PCSK9 monoclonal antibodies

Approaches to PCSK9 inhibition

c c c c c c c c

Endoplasmic reticulum LDL Receptor LDL Particle Lysosome PCSK9 LDL Receptor unable to dissociate from complex and does not recycle PCSK9

Liver cell Plasma

c c c c c c c c

Endoplasmic reticulum LDL Receptor LDL Particle LDL Receptor Lysosome PCSK9 Anti-PCSK9 antibody LDL Receptor recycles PCSK9

Liver cell Plasma

LDL Particle

Treatment with anti PCSK9 monoclonal antibodies to inhibit PCSK9 reduces the level of LDL-C by more than 50 % whether given as monotherapy

• r in people already taking

statins

Modifiable risk factors for ASCVD

• Smoking
• Elevated LDL-C
• Elevated triglyceride-rich lipoproteins
• Reduced HDL-C
• Elevated blood pressure
• Diabetes
• Abdominal obesity

Fibrate Trial Positive

• WHO:

clofibrate No

• HHS:

gemfibrozil Yes

• VA-HIT:

gemfibrozil Yes

• BIP:

bezafibrate No

• FIELD:

fenofibrate No

• ACCORD:

fenofibrate No

Human Clinical Trials with Fibrates

But, in all of these trials treatment with a fibrate significantly reduced ASCVD events in people with elevated plasma triglyceride and low HDL-C.

Helsinki Heart Study: effects of baseline TG on CHD Events

P P P

10 20 30 40 50 60 70

CHD events/1000

Total population TG ≤ 200 mg/dl TG > 200 mg/dl

Manninen et al, Circulation, 1992

Helsinki Heart Study: effects of baseline TG on response to treatment

P P P G

34% Total population TG ≤ 200 mg/dl TG > 200 mg/dl 10 20 30 40 50 60 70

CHD events/1000

Manninen et al, Circulation, 1992

Helsinki Heart Study: effects of baseline TG on response to treatment

P P P G G G

34% 20% 56% Total population TG ≤ 200 mg/dl TG > 200 mg/dl 10 20 30 40 50 60 70

CHD events/1000

Manninen et al, Circulation, 1992

Tenkanen et al, Circulation, 1995

Helsinki Heart Study: combined effects of BMI and dyslipidemia on CHD events

70 10 20 30 40 50 60

CHD events/1000

P

80 Total population

P

BMI > 26 kg/m2 plus TG>200, HDL-C<40)

G

34%

Tenkanen et al, Circulation, 1995

Helsinki Heart Study: combined effects of BMI and dyslipidemia on CHD events

70 10 20 30 40 50 60

CHD events/1000

P

80 Total population

P

BMI > 26 kg/m2 plus TG>200, HDL-C<40)

G

34%

G

78%

Total population 10 20

P P B

9%

CHD events/1000

TG > 200 mg/dl

BIP Study: effects of baseline TG on response to treatment

BIP Study Group, Circulation, 2000;102:21-7

Total population 10 20

P P B B

9% 39%

CHD events/1000

TG > 200 mg/dl

BIP Study: effects of baseline TG on response to treatment

BIP Study Group, Circulation, 2000;102:21-7

5 10 15

CVD events %

P P

FIELD Study: effects of baseline TG on CHD Events

Scott et al. Diabetes Care 32:493–498, 2009

Normal TG, normal HDL-C High TG, low HDL-C

5 10 15

F

6%

CVD events %

P P

FIELD Study: effects of baseline TG on response to treatment

Scott et al. Diabetes Care 32:493–498, 2009

Normal TG, normal HDL-C High TG, low HDL-C

5 10 15

CVD events %

Normal TG, normal HDL-C

P F

27% High TG, low HDL-C

P

FIELD Study: effects of baseline TG on response to treatment

Scott et al. Diabetes Care 32:493–498, 2009

F

6%

Total population 10 20

P CHD events/1000

ACCORD Study: effects of baseline TG and HDL-C on response to treatment

P

TG > 204 HDL-C < 34 mg/dl

ACCORD Study Group N Engl J Med. 2010;362:1563-74.

Total population 10 20

P F

8%

CHD events/1000

ACCORD Study: effects of baseline TG and HDL-C on response to treatment

P

TG > 204 HDL-C < 34 mg/dl

ACCORD Study Group N Engl J Med. 2010;362:1563-74.

Total population 10 20

P P F F

8% 29%

CHD events/1000

TG > 204 HDL-C < 34 mg/dl

ACCORD Study: effects of baseline TG and HDL-C on response to treatment

ACCORD Study Group N Engl J Med. 2010;362:1563-74.

Conclusions from Fibrate Trials

There is a consistent finding in all of the fibrate trials that treatment with a fibrate reduces the risk of having an ASCVD events in people with high TG and low HDL-C, whether or not they are treated with a statin

Conclusions

• Statins reduce LDL-C and reduce CVD risk
• In many people the LDL-C remains too

high despite treatment with statins

• New LDL-lowering agents (including

inhibitors of PCSK9) have been developed

• Fibrates should be considered in high risk

people with elevated TG and low HDL-C