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 CHD event 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 Relative risk reduction 22% CVE (p < 0.001) 0.10 major Atorvastatin 10 mg LDL-C 101 mg/dL 0.05 Atorvastatin 80 mg LDL-C 77 mg/dL Proportion of patients experiencing experiencing a 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 25 Pravastatin 40 mg 20 LDL-C 95 mg/dL Atorvastatin 80 mg 15 LDL-C 62 mg/dL 10 16% RRR % patients % patients event 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 TNT-Primary efficacy outcome measure: major cardiovascular events 0.15 Relative risk reduction 22% CVE (p < 0.001) 0.10 major Atorvastatin 10 mg LDL-C 101 mg/dL 0.05 Atorvastatin 80 mg LDL-C 77 mg/dL Proportion of patients experiencing experiencing a 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 25 Pravastatin 40 mg 20 LDL-C 95 mg/dL Atorvastatin 80 mg 15 LDL-C 62 mg/dL 10 16% RRR % patients % patients event 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.