Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Canadian Cardiovascular Congress

Vancouver, British Columbia / October 22-26, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The evidence that HDL-C is one of the most powerful predictors of cardiovascular (CV) events is overwhelming. The relationship works in both directions, so that depressed levels correlate with increased risk and elevated levels correlate with protection. The statins provided the opportunity to prove the hypothesis that LDL-C was a treatable risk factor, but proof of the HDL-C hypothesis has awaited a safe and effective agent. New compounds that have recently entered phase III studies have that potential, but benefit will likely depend on stimulating the protective mechanisms of HDL-C rather than raising HDL-C alone.

Specific Characteristics of HDL-C

“HDL-C is protective for reasons not captured by just measuring HDL-C cholesterol levels,” stated Dr. Gordon Francis, Director, Healthy Heart Program and Professor of Medicine, Division of Endocrinology and Metabolism, University of British Columbia, Vancouver. He provided part of the explanation for the setbacks in proving the HDL-C hypothesis in previous clinical trials. He also noted that HDL-C has at least 37 different species and is composed of approximately 100 different proteins. In fact, proteins represent more of its composition than cholesterol.

Recognizing this complexity now appears to be critical, because HDL-C has many functions, and these are highly dependent on the specific characteristics of HDL-C species. While the primary function attributed to HDL-C is efflux of cholesterol from cells, it is also associated with antioxidant, antithrombotic and anti-inflammatory properties; favourable effects on endothelial function and repair; and improved glucose metabolism. The ability of HDL-C to transport cholesterol back to the liver for excretion may be important, particularly its role in removing cholesterol from macrophages recruited to atherosclerotic plaques, but other functions are likely relevant for modifying CV risk.

An opportunity to test these hypotheses has been provided by a new generation of cholesteryl ester transfer protein (CETP) modulators/inhibitors that have already reached phase III studies. The failure of the CETP inhibitor torcetrapib proved a major challenge to the HDL-C hypothesis when it increased all-cause mortality despite a 72% increase in HDL-C. Yet subsequent studies have indicated that its off-target effects, such as blood pressure (BP) elevations and hyperaldosteronism, complicated the opportunity for clinical benefits. The newer CETP modulators/inhibitors dalcetrapib and anacetrapib have now entered phase III studies after phase II trial findings indicated that they are free of these or other off-target effects.

Awaiting Phase III Evidence

The phase III trial with dalcetrapib, now fully recruited, is called dal-OUTCOMES and is expected to generate results some time in 2013, according to Dr. Jean-Claude Tardif, Director of Research, Montréal Heart Institute, Quebec. According to Dr. Tardif, who is among the senior investigators directing the trial, dal-OUTCOMES has randomized 15,872 patients between 4 and 12 weeks after an acute coronary syndrome to dalcetrapib 600 mg or placebo. The primary efficacy measure is time to first occurrence of coronary heart disease death, non-fatal acute myocardial infarction (MI), hospitalization for biomarker negative acute coronary syndrome (with ECG abnormalities), resuscitated cardiac arrest or non-fatal/fatal stroke of atherothrombotic origin.

Reassurance regarding the safety profile of dalcetrapib has been shown by 2 completed multicentre phase II trials, dal-VESSEL and dal-PLAQUE.

In dal-VESSEL, 476 patients were randomized to dalcetrapib 600 mg or placebo and evaluated for changes in BP and flow-mediated dilation (FMD). There was no change in BP. As a marker of endothelial function, FMD was neither improved nor adversely affected. Although not an outcomes trial, the lead investigator Dr. Thomas F. Lüscher, University of Zurich, Switzerland, noted that there was a lower number of adjudicated CV events in the active treatment arm (2 vs. 5) over a study lasting only 36 weeks. “Dalcetrapib reduced CETP activity, increased Apo A1 and elevated HDL-C levels by 31% without affecting LDL-C or Apo B 100 levels,” he reported.

In dal-PLAQUE, 130 patients were randomized with the goal of demonstrating a difference in plaque burden using imaging studies. According to Dr. Zahi A. Fayad, Director, Cardiovascular Imaging Research, Mount Sinai School of Medicine, New York City, this study linked dalcetrapib HDL-C elevations with reductions in vascular inflammation and vascular changes. “On MRI, there was evidence of less progression of plaque burden as measured by total vessel area after 24 months on dalcetrapib compared with placebo,” Dr. Fayad reported.

The phase III study with anacetrapib is called REVEAL. It is expected to generate results several years from now. Also encouraged by phase II data, this trial is randomizing approximately 30,000 patients with a previous MI, cerebrovascular disease, peripheral arterial disease (PAD) or diabetes to anacetrapib 100 mg or placebo. The primary end point is MI or coronary revascularization procedure. Both dal-OUTCOMES and REVEAL are deliberately designed to test these agents in patient populations at high risk of events in order to demonstrate CV protection over a relatively short period of time.

A New Outlook on HDL-C Raising: Quality vs. Quantity

While both of these newer CETP modulators/inhibitors have the potential to prove the HDL-C hypothesis, their differences may provide valuable insight into the mechanisms of CV protection if one proves more effective than the other. Anacetrapib has been associated with a greater increase in plasma levels of HDL-C than dalcetrapib in the clinical trials conducted so far; however, dalcetrapib allows regeneration of pre-ß HDL-C, which is the major substrate for ABCA-1-dependent cholesterol efflux. According to Dr. Francis, anacetrapib, like torcetrapib, inhibits pre-ß HDL-C regeneration and alpha-1 HDL-C particle formation, both of which are implicated in promoting the cholesterol efflux capability of HDL-C.

This same point was made by Dr. Jay Heinecke, Professor of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle. He cited a recently published study that found that levels of HDL-C, although correlated with cholesterol efflux from macrophages, only accounted for about 40% of the variability (Khera et al. N Engl J Med 2011;364:127-35). His own work in defining dysfunctional HDL-C has also led to studies of protein composition that predict different effects from different HDL-C- raising agents, depending on how they influence protein composition. He provided a variety of experimental data suggesting that the quality of the HDL-C is more important than the quantity. “We need new metrics when evaluating HDL-C. We now have considerable evidence that HDL-C levels alone do not necessarily predict HDL-C function in regard to anticipated effects in modifying CV risk,” Dr. Heinecke told delegates.

Support for Further Clinical Data

Dr. Jacques Genest, Director, Centre for Innovative Medicine, Research Institute of the McGill University Health Centre, Montréal, Quebec, also indicated that the future of HDL-C as a target of therapy depends on efforts to improve the quality rather than the quantity of HDL-C. “HDL-C shows great promise, but we need biomarkers of function, not measures of HDL-C mass, to understand its role,” Dr. Genest confirmed. He stated that he is a “strong believer that we have to go forward” with dal-OUTCOMES and REVEAL.

As the HDL-C hypothesis is retested, it will be pursued with evolving criteria. While raising HDL-C may be important, it is possible that different CV risk reductions are mediated by different functions, depending on how a given HDL-C- raising agent affects the different HDL-C subtypes. Although the story is more complex than previously understood, the potential for benefit from emerging agents is even greater as the specific molecular mechanisms of HDL-C function are better understood and more specifically targeted.

Summary

Large phase III outcome trials are now underway with new-generation HDL-C-raising agents. Both of the agents now being tested are of the same drug class as torcetrapib, which previously failed to show benefit, but neither appears to share the off-target effects that seem to have defeated this agent. However, the 2 newer agents are also different from each other in regard to relative effects on the functions of HDL-C. These differences may provide critical insight into how this risk factor can be repositioned from a marker of events into a targetable mediator of events. ?

Note : At the time of printing, CETP modulators/inhibitors are not licensed in Canada.