CETP inhibition: pros and cons. Philip Barter The Heart Research Institute Sydney, Australia

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1 CETP inhibition: pros and cons Philip Barter The Heart Research Institute Sydney, Australia

2 Philip Barter Disclosures Received honorariums for lectures, consultancies or membership of advisory boards from: AstraZeneca, CSL, Merck, Novartis, Pfizer, Roche, Sanofi Aventis

3 Lipoprotein classes and atherosclerosis Chylomicrons, VLDL, and their catabolic remnants Pro-atherogenic LDL HDL Anti-atherogenic

4 A case can be made that strategies designed to reduce the risk of cardiovascular disease should include both lowering the level of LDL-C and raising that of HDL-C

5 One strategy is to inhibit the cholesteryl ester transfer protein (CETP)

6 What does CETP do?

7 Reverse cholesterol transport Liver CE SR-B1 SR-B1 FC Bile HDL CE LCAT FC Extrahepatic Tissues (including the artery wall Free Cholesterol

8 Plasma from humans and rabbits (but not that of rodents or most other species) contains a factor (CETP) that transfers cholesteryl esters from HDL to other lipoproteins Barter et al: Biochim Biophys Acta. 1978;531:233

9 Role of CETP in reverse cholesterol transport Liver LDL-R CE SR-B1 CE FC SR-B1 CETP VLDL/LDL Bile HDL CE LCAT FC Extrahepatic Tissues (including the artery wall Free Cholesterol

10 Mechanism of action of CETP HDL CETP CETP VLDL CE CE CE CE CETP CE CETP CE CE LDL Barter et al; Biochem J. 1982; 208:1-7

11 Effect of CETP inhibition on plasma cholesterol transport CE Liver SR-B1 LDL-R CE FC SR-B1 CETP VLDL/LDL Bile HDL CE LCAT FC Extrahepatic Tissues (including the artery wall Free Cholesterol

12 Effect of CETP inhibition on lipoprotein Levels HDL-C and apoa-i levels increased LDL-C and apob levels decreased Cholesterol content of VLDL decreased

13 What do we know about the relationship between CETP and atherosclerosis?

14 CETP IN ANIMAL STUDIES (Rodents) Rodents naturally deficient in CETP Rodents naturally resistant to development of atherosclerosis Expression of CETP in transgenic mice and rats increases atherosclerosis in most (but not all) models

15 CETP IN ANIMAL STUDIES (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

16 Meta-analysis of CETP Genotypes and CHD in Humans 46 studies had data on 27,196 coronary cases and 55,338 controls. Those polymorphisms that were associated with lower CETP mass and lower CETP activity had higher HDL-C and a significantly reduced coronary risk. Thompson et al JAMA2008;299:

17 But Inhibiting CETP with torcetrapib in humans did not reduce atherosclerosis in three imaging trials and caused harm in a large-scale end-point trial (ILLUMINATE)

Lipids (mg/dl) ILLUMINATE: On Trial Lipid Levels By Study Month Torcetrapib/ Atorvastatin Group (Post Run-In) 140 127 120 100 80 79.7 115 112 112 112 77.5 80.9 82.

18 Lipids (mg/dl) ILLUMINATE: On Trial Lipid Levels By Study Month Torcetrapib/ Atorvastatin Group (Post Run-In) TG -9% (-27,+13)* HDL-C +72.1% (34.7) LDL-C -24.9% (28.5) 20 0 Baseline Study Month Barter et al, NEJM 2007;357:

Event Free (%) ILLUMINATE: Primary Endpoint: Time to First MCVE*: Kaplan-Meier Plot 100 98 96 94 92 90 Hazard Ratio 1.25 P=0.

19 Event Free (%) ILLUMINATE: Primary Endpoint: Time to First MCVE*: Kaplan-Meier Plot Hazard Ratio 1.25 P=0.001 Atorvastatin (A) events = 373 Torcetrapib/Atorvastatin (T/A) events = Days from Randomization *Major cardiovascular event: CHD death, non-fatal MI, stroke or hospitalization for unstable angina Barter et al, NEJM 2007;357:

Event Free (%) ILLUMINATE: Secondary Endpoint Time to Death: Kaplan-Meier Plot 100 99 98 97 96 95 Atorvastatin deaths = 59

20 Event Free (%) ILLUMINATE: Secondary Endpoint Time to Death: Kaplan-Meier Plot Atorvastatin deaths = 59 Torcetrapib/Atorvastatin deaths = 93 Hazard Ratio 1.58 P= Days from Randomization Barter et al, NEJM 2007;357:

21 What was the reason for the adverse outcome with torcetrapib in the ILLUMINATE trial? Possible explanations Inhibiting CETP is pro-atherogenic Inhibiting CETP generates dysfunctional HDL Torcetrapib had an adverse off-target pharmacology unrelated to CETP

22 What was the reason for the adverse outcome with torcetrapib in the ILLUMINATE trial? Possible explanations Inhibiting CETP is pro-atherogenic Inhibiting CETP generates dysfunctional HDL Torcetrapib had an adverse off-target pharmacology unrelated to CETP

23 CETP deficiency and cholesterol efflux HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoe- and ABCG1-dependent pathway Matsuura et al. J Clin Invest 2006;116: Inhibition of CETP by torcetrapib causes a modest increase in the ability of HDL to promote net cholesterol efflux at the 60 mg dose, and a more dramatic increase at the 120 mg dose in association with enhanced particle functionality Yvan-Charvet et al. ATVB 2007;27:1132.

24 CETP deficiency and cholesterol efflux HDLs isolated from patients treated with anacetrapib have either an enhanced ability to promote the efflux of cholesterol from macrophages. Furthermore, the enhanced particle functionality in anacetrapib-treated patients was greater at higher HDL concentrations Yvan-Charvet L et al ATVB 2010;30:

25 CHD Death or Non-Fatal MI (Hazard Ratio) Post-hoc Exploratory Analyses in the Torcetrapib/Atorvastatin Group Hazard ratios for CHD Death or Non-Fatal MI by quintile of on-trial HDL-C (referent group is HDL-C < 60 mg/dl stratum) * 0.57 * 0.43 * *P< < >93 Quintiles of HDL-C (mg/dl) at Month 3 Cox proportional hazard model adjusted for age, gender and baseline HDL-C. Barter, Am J Cardiol. 2009;104(10 Suppl):10E

26 Atheroma Regression at Highest HDL-C Levels with Torcetrapib in the ILLUSTRATE trial LS Mean Change Percent Atheroma Volume P=0.004 for trend Q1 (<56) Q2 (56-69) Q3 ( ) Q4 (>86) Quartiles of Achieved HDL Cholesterol (mg/dl) Nicholls et al. Circulation 2008

27 What was the reason for the adverse outcome with torcetrapib in the ILLUMINATE trial? Possible explanations Inhibiting CETP is pro-atherogenic Inhibiting CETP generates dysfunctional HDL Torcetrapib had an adverse off-target pharmacology unrelated to CETP

28 Off-target pharmacological effects of torcetrapib unrelated to CETP inhibition In patients receiving torcetrapib in the ILLUMINATE Trial there was a significant: Increase in blood pressure Decrease in serum potassium Increase in serum bicarbonate Increase in serum sodium Increase in serum aldosterone The adverse outcome in the ILLUMINATE trial may thus have been the consequence of an off-target pharmacology of torcetrapib unrelated to CETP inhibition. Barter et al, NEJM 2007;357:

29 Off-target pharmacological effects of torcetrapib unrelated to CETP inhibition Torcetrapib increases blood pressure in rats, a species that does not have CETP. Analogues of torcetrapib that do not inhibit CETP raise blood pressure to an extent similar to that observed with torcetrapib Other CETP inhibitors such as dalcetrapib and anacetrapib do not raise blood pressure Forrest et al. Br J Pharmacol. 2008;154: ). Hu et al. Endocrinology 2009;150:

30 Off-target pharmacological effects of torcetrapib unrelated to CETP inhibition Torcetrapib induces synthesis and secretion of both aldosterone and cortisol from human adrenal cells in tissue culture. Other CETP inhibitors such as dalcetrapib and anacetrapib do not have these off-target effects Forrest et al. Br J Pharmacol. 2008;154: ). Hu et al. Endocrinology 2009;150: Capponi et al. Circulation 2008;118:S:452.

31 However, there was one unexpected piece of good news from the ILLUMINATE trial

32 Effects on diabetic control in ILLUMINATE There were 6101 patients with type 2 diabetes in the ILLUMINATE trial Treatment with torcetrapib resulted in a highly significant improvement in diabetic control Barter et al. Circulation 2011; 124:555

33 So, what is the future of CETP inhibition as an anti-atherogenic strategy in humans? Given: (i) The evidence in rabbits that inhibiting CETP protects and (ii) That off-target adverse effects of torcetrapib (unrelated to CETP inhibition) may have been responsible for the adverse outcome in the ILLUMINATE trial There is a compelling case for further testing the hypothesis that inhibiting CETP will be anti-atherogenic in humans so long as the hypothesis is tested with inhibitors that do not share the off-target pharmacology of torcetrapib

34 Dalcetrapib

35 dal-outcomes Trial 15,600 patients 4-12 weeks after an index ACS event Statin therapy to optimal LDL-C level Dalcetrapib 600 mg Placebo 2.5-year follow-up Primary End Point CHD death, non-fatal MI, atherothrombotic stroke, unstable angina requiring hospitalization or resuscitated cardiac arrest Schwartz et al. Am Heart J. 2009;158:

36 Anacetrapib

37 DEFINE trial Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib 1620 patients with CHD or CHD risk equivalents Statin therapy to achieve LDL-C <100 mg/dl Anacetrapib 100 mg Placebo 76 week follow-up Primary End Point Lipid efficacy and the safety Cannon et al. NEJM. 2010; 363:

38 LDL-C (mg/dl) (SE) HDL-C (mg/dl) (SE) DEFINE trial 100 LDL-C 120 HDL-C (p<0.001) (p<0.001) Anacetrapib Placebo 20 Anacetrapib Placebo 0 Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 0 Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 Anacetrapib n = Placebo n = Study Week Anacetrapib n = Placebo n = Study Week Cannon et al. NEJM. 2010; 363:

39 DEFINE trial Anacetrapib had no effect on levels of BP, electrolytes or aldosterone Primary Bayesian Analysis: The event distribution in DEFINE indicates a 94% predictive probability of dismissing a torcetrapib type increase in CV Events Cannon et al. NEJM. 2010; 363:

40 ILLUMINATE Trial 2007 (torcetrapib) DEFINE Trial 2010 (anacetrapib) ILLUMINATE Trial (2007) N=15,067 - Torcetrapib CVD/MI/S/UA Revascularization CVD/MI/S/UA/Rev Barter et al, NEJM 2007;357: Cannon et al. NEJM. 2010; 363: DEFINE trial (2010) N = 1,623 - Anacetrapib CVD/MI/S/UA Revascularization D/MI/S/UA/Rev CETP-I Better CETP-I worse

30,000 patients with occlusive arterial disease in North America, Europe and Asia Background LDL-lowering with atorvastatin Randomized to anacetrapib

41 30,000 patients with occlusive arterial disease in North America, Europe and Asia Background LDL-lowering with atorvastatin Randomized to anacetrapib 100 mg vs. placebo Scheduled follow-up: 4 years Primary outcome: Coronary death, myocardial infarction or coronary revascularization

Cholesteryl ester transfer protein inhibitors - what have we learnt? Philip Barter The Heart Research Institute Sydney, Australia

Cholesteryl ester transfer protein inhibitors - what have we learnt? Philip Barter The Heart Research Institute Sydney, Australia Philip Barter Disclosures Received honorariums for lectures, consultancies