AHA 2012: Dal-OUTCOMES: More questions than answers?

Final results from the dal-OUTCOMES trial with the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib were presented at the American Heart Association Scientific Sessions 2012 Late-breaking Clinical Trials Session and simultaneously published on-line.

Schwartz GC, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. New Engl J Med 2012; Published online November 5, 2012.

HDL Forum previously reported on the termination of dalcetrapib following the second pre-specified interim analysis of the dal-OUTCOMES trial.1 At this analysis, which included 1,135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination on the basis of futility. The Hazard ratio for the primary outcome, a composite of death from coronary heart disease, nonfatal myocardial infarction, ischaemic stroke, unstable angina, or cardiac arrest with resuscitation, was 1.04, 95% CI 0.93-1.16, p=0.52. Similarly, there was a neutral effect for dalcetrapib on the individual components of the primary outcome. It is important to emphasise that dalcetrapib was not terminated for safety reasons.

So what further insights do we have about dalcetrapib and CETP inhibition in general?

Dr Gregory Schwartz, University of Colorado School of Medicine, Denver, USA and lead author of the paper highlighted two new findings.

First, there was no association between baseline HDL cholesterol levels and the risk of the primary outcome. Second, treatment with dalcetrapib increased mean systolic blood pressure (by 0.6 mmHg, p<0.001) and median high-sensitivity C-reactive protein (CRP, by 0.2 mg/L) compared with placebo (p<0.001). Professor Alan Tall, Columbia University, New York, discussant for the trial placed these findings in perspective.

  • Why was there a lack of association between baseline HDL cholesterol levels and risk for the primary outcome in dal-OUTCOMES?

This finding contrasts with observational data and previous post hoc analyses, such as those from the Treating to New Targets Trial (TNT) in high-risk patients with stable CHD.2 This might suggest that in this population, optimally managed with statins, dual antiplatelet therapy, beta-blockers, agents acting on the renin-angiotensin system and coronary revascularization, plasma levels of HDL cholesterol may be less relevant in determining cardiovascular risk. However, experimental studies showing that infusion of reconstituted lipid-poor HDL in ACS patients led to regression of atheroma counter this argument.

A second factor to be considered is whether the level of HDL cholesterol raising is relevant. In dal OUTCOMES and other phase II trials, dalcetrapib was shown to consistently raise plasma levels of HDL cholesterol by about 30%, with negligible effect on apolipoprotein B-containing lipoproteins.3.4 Therefore it might be that a more dramatic effect on HDL cholesterol is needed.

The profile of lipoprotein changes might also be relevant. Both anacetrapib and evacetrapib, two CETP inhibitors in phase III trials, have been shown to both substantially raise HDL cholesterol (by ~140% with anacetrapib and 80-85% with evacetrapib) AND lower plasma levels of apoB-containing lipoporoteins.5,6 Indeed, a recent analysis investigating common genetic variation at the CETP gene suggested that both effects were implicated as determinants of coronary risk.7 However, so far there is no evidence to enable us to tease out which is more relevant to the potential benefits of CETP inhibition in vivo.

Finally, HDL cholesterol might be a poor surrogate for cardiovascular outcomes. This proposal has growing support. HDL particles have a wide range of biological activities, including cellular cholesterol efflux activity, and anti-inflammatory and anti-oxidative actions, which are potentially vasculoprotective. Consequently, improving HDL functionality, rather than plasma levels of HDL cholesterol, might be more relevant to atheroprotection.

  • Was the potential benefit of dalcetrapib on HDL outweighed by effects on blood pressure or CRP?

It is important to emphasise that dalcetrapib was not terminated for safety reasons; there was no adverse signal associated with these small changes in blood pressure and CRP. Studies with the CETP inhibitors in development, anacetrapib or evacetrapib, have not shown any underlying adverse effect on blood pressure in phase II trials, implying that these findings observed with dalcetrapib are not consistent with a class effect for the CETP inhibitors. The effect of dalcetrapib on CRP does merit further study to determine whether this may be explained by vascular or metabolic effects.

  • Finally, what does the termination of dalcetrapib mean for the therapeutic potential of CETP inhibition?

This remains an open question in the absence of hard outcomes data from trials with the other two CETP inhibitors in advanced development, REVEAL (anacetrapib) and ACCELERATE (evacetrapib). However, we will have to wait some time; data from REVEAL are not expected until 2017.

HDL Forum comment: Professor Kausik K. Ray, Professor of Cardiovascular Disease Prevention, St George’s University of London, UK

The key take home message from dal-OUTCOMES is that modest CETP inhibition and raising of HDL cholesterol (by 30%) does not reduce cardiovascular outcomes in ACS patients. The trial does not suggest that agents which are more potent inhibitors of CETP, such as anacetrapib or evacetrapib, will not be effective as treatments. Furthermore, there is no evidence to suggest that other compounds, such as RVX 208, de-lipidated HDL or apo A1 mimetics, will not alter HDL function via a different pathway and so reduce cardiovascular outcomes.

References

1. CETP inhibition after dalcetrapib? A perspective from the HDL Forum Editors. http://www.hdlforum.org/latest-news/344-cetp-inhibition-after-dalcetrapib-a-perspective-from-the-hdl-forum-editors.

2. Barter P, Gotto AM, LaRosa JC et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-10.

3. Lüscher TF, Taddei S, Kaski JC et al. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. Eur Heart J 2012;33:857-65.

4. Fayad ZA, Mani V, Woodward M et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 2011;378:1547-59.

5. 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;363:2406-15

6. Nicholls SJ, Brewer B, Kastelein JJP et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol. JAMA 2011;306:2099-109.

7. Voight BF, Peloso GM, Orho-Melander M et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. The Lancet 2012;380:572-80.

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