Managing lipids: Integrating novel insights with gold standard therapies Philip Barter School of Medical Sciences University of New South Wales Sydney, Australia
Disclosures 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.
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) • Smoking • Elevated LDL-C • Elevated triglyceride-rich lipoproteins • Reduced HDL-C • Elevated blood pressure • Diabetes • Abdominal obesity
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.
Relationship of CVD events to LDL-C reduction achieved in statin clinical trials CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81.
And the lower the achieved level of LDL-C, the lower the risk of having an event
Secondary Prevention Statin Trials Achieved LDL-C Levels vs Events 30 4S-Plac % with CHD event 4S-Sim 20 LIPID-Plac LIPID-Pra CARE-Plac CARE-Pra IDEAL-Ator HPS-Plac IDEAL-Sim 10 TNT-Ator10 HPS-Sim TNT-Ator80 0 70 90 110 130 150 170 190 210 LDL-C ( mg/dL)
TNT-Primary efficacy outcome measure: major cardiovascular events 0.15 experiencing a major CVE Relative risk reduction 22% Proportion of patients (p < 0.001) 0.10 Atorvastatin 10 mg LDL-C 101 mg/dL 0.05 Atorvastatin 80 mg LDL-C 77 mg/dL 0 0 1 2 3 4 5 6 Time (years) LaRosa JC, et al . N Eng J Med. 2005;352
PROVE-IT: All-cause mortality or major CV events in all randomised subjects 30 % patients with event 25 Pravastatin 40 mg LDL-C 95 mg/dL 20 Atorvastatin 80 mg 15 LDL-C 62 mg/dL 10 16% RRR P =0.005 5 0 0 3 6 9 12 15 18 21 24 27 30 Months of follow-up Cannon CP, et al. N Engl J Med. 2004;350:1495
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
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
Effects of adding ezetimibe to a statin Ezetimibe lowers LDL-C an additional 19%-23% compared with statin alone 140 LDL-C (mg/dL) at study end 120 19% 21% 100 23% Statin alone 23% 80 Statin + EZE 60 40 20 0 Lova Prava Simva Atorva Co-admin Co-admin Co-admin Co-admin 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.
IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial Ezetimibe 10 mg + simvastatin 40-80 mg 18 000 patients • Men and Simvastatin 40-80 mg women • Aged 18 years • High-risk ACS Continue until 5250 subjects have a primary Primary End Point event. Minimum 2.5-year Composite of CV death, major coronary follow-up events, and stroke Study completed in 2014 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
Relationship of CVD events to LDL-C reduction achieved in statin clinical trials IMPROVE-IT CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81.
New agents to lower of LDL-C PCSK9 inhibitors
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
Plasma LDL Particle LDL Receptor LDL Receptor LDL Receptor recycles LDL Receptor LDL Particle c c c c c c c c Endoplasmic reticulum Liver cell Lysosome
Statins reduce the plasma level of LDL-C by increasing the number of LDL receptors on the cell surface
What about PCSK9
Plasma LDL Particle PCSK9 LDL Receptor unable to dissociate from complex and does not recycle LDL Receptor PCSK9 c c c c c c c c Endoplasmic reticulum Liver cell Lysosome
So, PCSK9 decreases the number of LDL receptors on the cell surface and thus increases the concentration of LDL-C in plasma
PCSK9: Human genetic studies 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 of the PCSK9 gene are associated with a low level of LDL-C and a decreased ASCVD risk
CHD in people with PCSK9 deficiency 12 CHD (%) 8 P=0.008 4 0 No Yes PCSK9 142x PCSK9 679x or Cohen JC. N Engl J Med. 2006;354:1264 ‐ 72
So, inhibiting PCSK9 is a logical strategy to reduce the level of LDL-C whether or not the patient is on a statin
Approaches to PCSK9 inhibition Anti-PCSK9 monoclonal antibodies
Plasma LDL Particle PCSK9 LDL Receptor unable to dissociate from complex and does not recycle LDL Receptor PCSK9 c c c c c c c c Endoplasmic reticulum Liver cell Lysosome
Anti-PCSK9 Plasma LDL antibody Particle PCSK9 LDL Receptor LDL Receptor recycles LDL Receptor LDL Particle PCSK9 c c c c c c c c Endoplasmic reticulum Liver cell Lysosome
Treatment with anti PCSK9 monoclonal antibodies to inhibit PCSK9 reduces the level of LDL-C by more than 50 % whether given as monotherapy or 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
Human Clinical Trials with Fibrates Fibrate Trial Positive • WHO: clofibrate No • HHS: gemfibrozil Yes • VA-HIT: gemfibrozil Yes • BIP: bezafibrate No • FIELD: fenofibrate No • ACCORD: fenofibrate No
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 70 60 CHD events/1000 P 50 40 P 30 P 20 10 0 TG ≤ 200 Total TG > 200 population mg/dl mg/dl Manninen et al, Circulation, 1992
Helsinki Heart Study: effects of baseline TG on response to treatment 70 60 CHD events/1000 P 50 40 P 34% 30 P G 20 10 0 TG ≤ 200 Total TG > 200 population mg/dl mg/dl Manninen et al, Circulation, 1992
Helsinki Heart Study: effects of baseline TG on response to treatment 70 60 CHD events/1000 P 50 40 P 34% 30 20% 56% P G G G 20 10 0 TG ≤ 200 Total TG > 200 population mg/dl mg/dl Manninen et al, Circulation, 1992
Helsinki Heart Study: combined effects of BMI and dyslipidemia on CHD events 80 P CHD events/1000 70 60 50 40 P 34% 30 G 20 10 0 Total BMI > 26 kg/m2 plus population TG>200, HDL-C<40) Tenkanen et al, Circulation, 1995
Helsinki Heart Study: combined effects of BMI and dyslipidemia on CHD events 80 P CHD events/1000 70 60 50 40 P 34% 30 G 78% 20 G 10 0 Total BMI > 26 kg/m2 plus population TG>200, HDL-C<40) Tenkanen et al, Circulation, 1995
BIP Study: effects of baseline TG on response to treatment 20 CHD events/1000 P 9% P B 10 0 Total TG > 200 population mg/dl BIP Study Group, Circulation, 2000;102:21-7
BIP Study: effects of baseline TG on response to treatment 20 CHD events/1000 P 9% 39% P B 10 B 0 Total TG > 200 population mg/dl BIP Study Group, Circulation, 2000;102:21-7
FIELD Study: effects of baseline TG on CHD Events P 15 CVD events % P 10 5 0 Normal TG, High TG, normal HDL-C low HDL-C Scott et al. Diabetes Care 32:493 – 498, 2009
FIELD Study: effects of baseline TG on response to treatment P 15 6% CVD events % P F 10 5 0 Normal TG, High TG, normal HDL-C low HDL-C Scott et al. Diabetes Care 32:493 – 498, 2009
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