Evolving concepts in management of patients at increased CV risk Philip Barter, MD Sydney, Australia Evolving concepts in management of patients at increased CV risk?
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. Major risk factors for Atherosclerotic Cardiovascular Disease (ASCVD) • Age • Gender • Smoking • Elevated LDL-C • Elevated triglyceride-rich lipoproteins • Reduced HDL-C • Elevated blood pressure • Diabetes • Abdominal obesity Modifiable risk factors for ASCVD
• Smoking • Elevated LDL-C • Elevated triglyceride-rich lipoproteins • Reduced HDL-C • Elevated blood pressure • Diabetes • Abdominal obesity Modifiable risk factors for ASCVD
• Smoking • Elevated LDL-C • Elevated triglyceride-rich lipoproteins • Reduced HDL-C • Elevated blood pressure • Diabetes • Abdominal obesity Treatment with statins has been shown in many trials to reduce the risk of having an atherosclerotic cardiovascular event In these statin trials, 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
4S-Sim 20 LIPID-Plac LIPID-Pra CARE-Pra CARE-Plac IDEAL-Ator 10 IDEAL-Sim HPS-Plac HPS-Sim TNT-Ator10
% with with % event CHD TNT-Ator80 0 70 90 110 130 150 170 190 210 LDL-C (mg/dL) LaRosa JC, Proportion of patients experiencing a major CVE 0.05 0.10 0.15 TNT et al et 0 . 0 N Eng J Med.Eng J N - Primary major Atorvastatin mg 10 LDL 1 Relative risk reduction Relative 2005;352 - C c 101 mg/ efficacy ardiovascular 2 (p < 0.001) Time (years) dL 3 o Atorvastatin mg Atorvastatin 80 utcome LDL 4 e - 22 C vents 77 mg/dL % m 5 easure 6 : PROVE-IT: All-cause mortality or major CV events in all randomised subjects
30
25 Pravastatin 40 mg 20 LDL-C 95 mg/dL Atorvastatin 80 mg 15 LDL-C 62 mg/dL
10 16% RRR % patients event patients % with 5 P=0.005
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 LaRosa JC, Proportion of patients experiencing a major CVE 0.05 0.10 0.15 TNT et al et 0 . 0 N Eng J Med.Eng J N - Primary major Atorvastatin mg 10 LDL 1 Relative risk reduction Relative 2005;352 - C c 101 mg/ efficacy ardiovascular 2 (p < 0.001) Time (years) dL 3 o Atorvastatin mg Atorvastatin 80 utcome LDL 4 e - 22 C vents 77 mg/dL % m 5 easure 6 : PROVE-IT: All-cause mortality or major CV events in all randomised subjects
30
25 Pravastatin 40 mg 20 LDL-C 95 mg/dL Atorvastatin 80 mg 15 LDL-C 62 mg/dL
10 16% RRR % patients event patients % with 5 P=0.005
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, there is a persisting residual risk even when the level of LDL- C is reduced to 1.5 mmol/L (60 mg/dL) How can this residual risk be reduced? Modifiable risk factors for ASCVD
• Smoking • Elevated LDL-C • Elevated triglyceride-rich lipoproteins • Reduced HDL-C • Elevated blood pressure • Diabetes • Abdominal obesity Many people with clinically manifest ASCVD 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 Ezetimibe Effects of adding ezetimibe to a statin
Ezetimibe lowers LDL-C an additional 19%-23% compared with statin alone
140
120 21% 19%
100 23% 23% Statin alone 80
60 Statin + EZE
40 C (mg/dL) at study end study at (mg/dL) C
- 20
LDL 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 events, and stroke follow-up 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
• CETP inhibitors
• ACL inhibitors
• MTP inhibitors
• Inhibition of apoB synthesis New agents to lower of LDL-C
• PCSK9 inhibitors
• CETP inhibitors
• ACL inhibitors
• MTP inhibitors
• Inhibition of apoB synthesis Removal of LDL from plasma Plasma LDL Receptor
LDL Receptor
Endoplasmic reticulum Liver cell LDL Plasma LDL Particle Receptor
LDL Receptor
Endoplasmic reticulum Liver cell LDL Plasma LDL Particle Receptor
LDL Receptor
Endoplasmic reticulum Liver cell LDL Plasma LDL Particle Receptor
LDL Receptor LDL Particle
c c c c c c c Endoplasmic c reticulum Liver cell Lysosome LDL Plasma LDL Particle Receptor LDL Receptor
LDL Receptor recycles
LDL Receptor LDL Particle
c c c c c c c Endoplasmic c reticulum Liver cell Lysosome Regulation of the LDL receptor
Intracellular cholesterol decreased
SREBP-2 activated
Synthesis of LDL receptor increased SREBP-2 also increases PCSK9
Intracellular cholesterol decreased
SREBP-2 activated
Synthesis of LDL Synthesis of receptor increased PCSK9 increased Plasma
PCSK9
LDL Receptor PCSK9
Endoplasmic reticulum Liver cell LDL Plasma Particle PCSK9
LDL Receptor PCSK9
Endoplasmic reticulum Liver cell LDL Plasma Particle PCSK9
LDL Receptor unable to dissociate from complex and does not recycle LDL Receptor PCSK9
c c c c c c c Endoplasmic c reticulum Liver cell Lysosome PCSK9: Lessons from human genetic studies Human genetic studies
Gain of function mutations of the PCSK9 gene represent a rare cause of familial hypercholesterolaemia and increased ASCVD risk 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
8 P=0.008
CHD CHD (%) 4
0 No Yes PCSK9142x or PCSK9679x
Cohen JC. N Engl J Med. 2006;354:1264‐72 Statins increase PCSK9 Statins increase PCSK9
Treatment with a statin
Intracellular cholesterol decreased
SREBP-2 activated
Synthesis of LDL Synthesis of receptor increased PCSK9 increased This statin-induced increase in synthesis of PCSK9 opposes the ability of statins to increase the number of cell surface LDL receptors and thus prevents statins from maximally reducing the level of LDL-C Inhibition of PCSK9 will therefore enhance the ability of statins to increase the number of LDL receptors on the cell surface and, as a consequence, maximise the statin-induced reduction in LDL-C Approaches to PCSK9 inhibition
• Anti-PCSK9 monoclonal antibodies
• Small interfering RNAs (siRNAs) to inhibit the synthesis of PCSK9 Approaches to PCSK9 inhibition
• Anti-PCSK9 monoclonal antibodies
• Small interfering RNAs (siRNAs) to inhibit the synthesis of PCSK9 LDL Plasma LDL Particle Receptor PCSK9
LDL Receptor unable to dissociate from complex and does not recycle LDL Receptor PCSK9
c c c c c c c Endoplasmic c reticulum Liver cell Lysosome Anti-PCSK9 antibody Plasma
PCSK9
LDL Receptor PCSK9
Endoplasmic reticulum Liver cell Anti-PCSK9 antibody LDL Plasma Particle
PCSK9 LDL Receptor
LDL Receptor recycles
LDL Receptor LDL PCSK9 Particle
c c c c c c c Endoplasmic c reticulum Liver cell Lysosome New agents to lower of LDL-C
• PCSK9 inhibitors
• CETP inhibitors
• ACL inhibitors
• MTP inhibitors
• Inhibition of apoB synthesis Role of CETP in plasma cholesterol transport
Liver LDL-R CE CE SR-B1 SR-B1 VLDL/LDL FC CETP
CE Extrahepatic Tissues LCAT (including the artery wall HDL FC Free Cholesterol Bile Inhibition of CETP retains cholesterol in the non-atherogenic HDL fraction while reducing it in the potentially pro-atherogenic non-HDL fractions. CETP gene polymorphisms resulting in lower CETP activity are associated with a reduced risk of atherosclerotic cardiovascular disease Copenhagen City Heart Study
Johannsen et al JACC 2012; 60:2041 CETP and Atherosclerosis in Rabbits
Rabbits have high level of activity of CETP
Rabbits naturally highly susceptible to the development of atherosclerosis
Inhibition of CETP in rabbits decreases atherosclerosis in all models studied
Sugano et al. J Biol Chem.1998;273:5033. Rittershaus et al. ATVB. 2000;20:2106. Okamoto et al. Nature. 2000;406:203. Morehouse et al. J Lipid Res. 2007;48:1263. CETP inhibitors:
• Reduce LDL cholesterol
• Increase HDL cholesterol by 30-180%,
• Reduce Lp(a) by up to 37%
• Increase HDL-mediated efflux of cholesterol from macrophages But
There are now three large, randomised clinical trials in humans in which treatment with torcetrapib, dalcetrapib or evacetrapib did not reduced the risk of having a clinical cardiovascular event The future of CETP inhibition will depend on what is found in the ongoing REVEAL trial with anacetrapib REVEAL trial Randomized Evaluation of the Effects of Anacetrapib through Lipid- modification
Anacetrapib 100 mg 30,000 patients Atovastatin to aged > 50 with achieve LDL-C with occlusive target arterial disease Placebo Sites in North America, Europe and Asia 4 year follow-up
Primary End Point Coronary death, myocardial infarction or Planned completion coronary revascularization in 2017 New agents to lower of LDL-C
• PCSK9 inhibitors
• CETP inhibitors
• ACL inhibitors
• MTP inhibitors
• Inhibition of apoB synthesis ATP-Citrate Lyase (ACL)
Citrate + coenzyme A (CoA) ACL Acetyl-CoA + Oxaloacetate
HMG-CoA HMG-CoA-reductase Mevalonic Acid Cholesterol Inhibition of ACL
Citrate + coenzyme A (CoA)
ETC-1002 ACL Acetyl-CoA + Oxaloacetate
HMG-CoA
Statins HMG-CoA-reductase Mevalonic Acid Cholesterol ETC 1002
• Well tolerated
• Effective lowering of LDL-C and non-HDL-C Effect of ETC 1002 in patients unable to tolerate statins
Thompson et al. J Clin Lipidol 2015. 9:295 New agents to lower of LDL-C
• PCSK9 inhibitors
• CETP inhibitors
• ACL inhibitors
• MTP inhibitors
• Inhibition of apoB synthesis LDL formation VLDL
TG VLDL B MTP CE plus lipid B B TG CE
ApoB synthesis
B TG CE
LDL Lomitapide is an oral inhibitor of MTP
Treatment with lomitapide reduces LDL-C by 40 – 50% in all people studied, including those without any functioning LDL receptors as in homozygous FH
Cuchel et al. Lancet. 2013; 381:40 New agents to lower of LDL-C
• PCSK9 inhibitors
• CETP inhibitors
• ACL inhibitors
• MTP inhibitors
• Inhibition of apoB synthesis LDL formation VLDL
TG VLDL B MTP CE plus lipid B B TG CE
ApoB synthesis
B TG CE
LDL Mipomersen
Mipomersen is an antisense oligonucleotide (ASO) developed to inhibit synthesis of apoB-100 in the liver
Reduces the concentration of apoB- containing lipoproteins even when there are no LDL receptors and is thus effective even in homozygous FH Benefits of early (or lifelong) low levels of LDL-C as distinct from lowering LDL-C later in life
Lessons from genetics Genetic causes of lower LDL-C and the risk of CHD
Ference et al JACC 2012; 60:2631 Genetic causes of lower LDL-C and the risk of CHD
Ference et al JACC 2012; 60:2631 These genetic studies provide strong evidence that CHD risk reduction will be much greater if low levels of LDL-C are achieved and maintained from early life Lp(a)
Genetic studies have clearly identified Lp(a) as a causal risk factor for developing ASCVD
Inhibitors of both PCSK9 and CETP reduce the plasma level of Lp(a) by about 30%
Lp(a) ASOs are currently in development ApoC-III
• ApoC-III is a pro-inflammatory protein that also increases the concentration of triglyceride-rich lipoproteins and their atherogenic catabolic remnants. • An elevated level of apoC-III in apoB-containing lipoproteins is an independent predictor of the risk of having an ASCVD event. • Over-expression of human apoC-III in transgenic mice increases the concentration of plasma triglyceride and also increase susceptibility to atherosclerosis. ApoC-III
ApoC3 gene variants associated with loss of function of apoC-III are associated with a significantly reduced risk of having coronary heart disease event. Antisense inhibition of ApoC-III synthesis.
An antisense inhibitor of APOC3 mRNA has been developed and shown to: • reduce the plasma levels of apoC-III • reduce plasma TG • increase HDL-C
Gaudet et al. New Eng J Med 2015 373:438 Summary
• Reduction in LDL-C with statins reduces SASCVD risk
• Many people remain at high risk despite treatment with statins
• A number of new agents are being developed to reduce this residual risk
• The earlier in life the LDL-C is reduced, the greater the reduction in lifetime ASCVD risk