CETP inhibition to reduce cardiovascular risk: where are we now?
- Professor Philip Barter receives the Anitschkow Award
- New data from ILLUMINATE suggests potential role for HDL in glucose homeostasis
- 79th EAS Congress, Gothenburg, Sweden, Sunday 26th June
Professor Philip Barter, Director of The Heart Research Institute in Sydney, Australia was the recipient of this year’s prestigious Anitschkow Award. Professor Barter has been a world leader of research investigating the metabolism and function of plasma lipoproteins, specifically high density lipoprotein (HDL). In the Anitschkow Lecture Professor Barter gave an eloquent overview of the current status of cholesteryl ester transfer protein (CETP) inhibition as a strategy for reducing cardiovascular risk, placing available evidence into perspective. ‘We will soon have answers that will help to resolve the current state of confusion about CETP inhibition.’
Professor Barter also reported new findings from ILLUMINATE, shortly to be reported in Circulation. Post hoc subgroup analysis of more than 6,000 patients with type 2 diabetes showed that those treated with atorvastatin alone had progressive increases in blood glucose and HbA1c, whereas treatment with the combination of torcetrapib plus atorvastatin abolished these adverse effects. Additionally, torcetrapib was associated with improvement in insulin resistance, whereas insulin resistance worsened in patients treated with atorvastatin alone. However, after adjustment for HDL the effects of torcetrapib were not significant. These data may imply a potential role for HDL in glucose homeostasis.
The epidemiological data are beyond dispute that HDL cholesterol is inversely related to cardiovascular risk. Experimental studies have shown that HDL have atheroprotective activities including a key role in cellular cholesterol efflux, anti-inflammatory action, a role in enhancement of progenitor-mediated endothelial repair, as well as stimulation of pancreatic beta cell insulin synthesis and secretion. In the TNT trial, patients with low LDL cholesterol levels and HDL cholesterol levels <40 mg/dL had a 40-60% increase in risk of major cardiovascular events,1 implying that strategies to reduce the risk of cardiovascular disease should include both lowering of LDL cholesterol and concomitantly raising HDL cholesterol.
The emphasis of recent research by Professor Barter and his group has been on novel therapeutic approaches to raising HDL cholesterol, specifically inhibition of CETP. Although the mechanism is still not completely understood, CETP does appear to play a key role in lipid transport, by promoting the transfer of cholesteryl esters from anti-atherogenic HDL to proatherogenic apolipoprotein B (apoB)–containing lipoproteins. Previous evidence has suggested that this may involve an equilibration process of cholesteryl ester among other lipoproteins. When CETP is inhibited, levels of HDL and apo A-I increase, LDL and apoB levels decrease and the cholesterol content of VLDL also decreases.
Evidence in rabbits provided the first insights into the possibilities of CETP inhibition. Rabbits have a high level of CETP activity and are highly susceptible to atherosclerosis; inhibition of CETP decreases atherosclerosis. Genetic evidence is inconsistent, although a recent meta-analysis of 46 studies of genetic polymorphisms of CETP showed that those polymorphisms that are associated with lower CETP mass or activity had higher HDL cholesterol levels and lower coronary risk.2 On balance, the totality of evidence in humans is consistent with that observed in rabbits.
These findings provided the rationale for wider investigation of the therapeutic potential of these agents. However, the first in class, torcetrapib, resulted in significant excess mortality (by 60%) and excess major cardiovascular events (by 25%) in the ILLUMINATE trial prompting the closure of the trial and the drug.3 This was despite raising HDL cholesterol by 70% and lowering of LDL cholesterol by 25%, on top of statin therapy. Prof. Barter said that the notion that CETP inhibition results in the production of dysfunctional HDL is not supported by evidence; indeed, findings from experimental studies have shown the reverse, with improvement in the ability of HDL to promote cholesteryl ester efflux, in association with enhanced HDL particle functionality.
The alternative hypothesis that torcetrapib had adverse effects unrelated to CETP inhibition is supported by evidence of off-target effects on blood pressure, electrolytes and aldosterone levels in clinical and experimental trials.4-7
The question remained: were these effects specific to torcetrapib or a class effect of these agents? However, mid-term data from studies with two other investigational drugs, dalcetrapib and anacetrapib show that these agents do not share the off-target effects of torcetrapib.8,9 Clearly data from long-term outcomes studies are needed to finally answer the question whether CETP inhibition has a role in prevention of cardiovascular disease. Two are ongoing – data from dal-OUTCOMES will be the first to provide insight to resolve this ongoing controversy.
Professor Barter said: ‘There is a compelling case for further testing of this hypothesis, provided that the CETP inhibitor selected for study does not have off-target adverse effects. The evidence from mid-term studies with dalcetrapib and anacetrapib suggests that these agents do not share the off-target effects of torcetrapib.’
‘Trials give clues – they do not provide mechanisms. If the results of the ongoing outcomes trials with dalcetrapib and anacetrapib are positive, all we can conclude is that CETP inhibition is a beneficial strategy for reducing cardiovascular risk; it will not provide conclusive evidence of the HDL hypothesis.’
dal-OUTCOMES is expected to report in either late 2012, early 2013.
References
1. Barter PJ, Caulfield M, Eriksson M et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22.
2. Thompson A, Di Angelantonio E, Sarwar N et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA 2008;299:2777-88.
3. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-12.
4. Nissen SE, Tardif JC, Nicholls SJ, et al; ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304-16.
5. Kastelein JJ, van Leuven SI, Burgess L, et al; RADIANCE 1 Investigators. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007;356:1620-30.
6. Bots ML, Visseren FL, Evans GW, et al; RADIANCE 2 Investigators. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 2007;370:153-60.
7. Forrest MJ, Bloomfield D, Briscoe RJ, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008;154:1465-73.
8. Stein EA, Roth EM, Rhyne JM, et al. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J 2010;31:480-8.
9. Cannon CP, Shah S, Dansky HM, et al; the DEFINE Investigators. Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease. N Engl J Med. 2010.