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Reviving Interest in Lipid Targets Beyond LDL-C: Promising Expansion of Targetable Factors

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 - 33rd Annual Congress of the European Society of Cardiology

Paris, France / August 27-31, 2011

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

Considerable excitement was generated here at the ESC by the potential of new therapies to complete the revolution in cardiovascular (CV) risk reduction initiated with LDL-C control. While the large mortality reductions achieved in a series of historic trials with statins redefined CV risk management, pathogenic levels of other lipid proteins, particularly HDL-C and triglycerides (TG) and less frequently measured factors, such as lipoprotein phospholipase A2 (Lp-PLA2) have prognostic importance and appear to drive events.

While it is not clear whether all factors are modifiable, there is a consensus that targets other than LDL-C must be addressed in order to achieve further risk reductions. These next steps in risk reduction now appear to be emerging. “The LDL-C story has been very compelling, but we have taken this about as far as it can go,” reported Prof. Philippe Gabriel Steg, Director, Coronary Care Unit, Hôpital Bichat-Claude Bernard, Paris, France. Noting that the creation of atherosclerotic plaques is a dynamic process that involves a variety of interdependent factors, he suggested that efforts to build on the success of statins would depend on a profound blockade of a broad array of factors that contribute to atherogenesis.

Of several initiatives to target lipid proteins other than LDL-C, the most advanced appear to be those with novel agents targeting HDL-C and Lp-PLA2, which is an inflammatory enzyme in atherosclerotic plaques associated with increased risk of thrombotic events. Currently, the only therapies that provide substantial increases in HDL-C are niacin and fibrates, but there are no level 1 data to confirm that either reduces CV events. Therapies that target Lp-PLA2 remain experimental, but new data presented at the ESC intensified interest in both low HDL-C and elevated Lp-PLA2 in the context of major trials with clinical end points.

Focus on Raising HDL-C

Renewed interest in HDL-C was generated by the multinational phase IIb dal-VESSEL trial that evaluated the cholesteryl ester transfer protein (CETP) modulator dalcetrapib for safety. This new-generation CETP modulator is being brought forward because it has not demonstrated the off-target effects, such as hypertension and endothelial dysfunction, which derailed the first-generation agent torcetrapib. The double-blind trial was the final step in proving safety prior to a phase III event-based trial designed to generate regulatory approval.

In dal-VESSEL, 476 patients with coronary heart disease (CHD) or a CHD-risk equivalent and HDL-C <1.3 mmol/L were randomized to dalcetrapib 600 mg or placebo and followed for 36 weeks. The primary end points were flow- mediated dilation (FMD) as measured in the brachial artery at 12 weeks and ambulatory blood pressure monitoring (ABPM) at 4 weeks. Secondary end points included both measures at 36 weeks, changes in lipids and overall safety.

As anticipated by earlier studies, the CETP modulator had no effect on ABPM and did not adversely affect FMD. It did, however, increase HDL-C by 27% (P<0.001) by week 4 and by 31% (P<0.001) by 36 weeks. Of particular significance in regard to potential clinical benefit, most of the increase in HDL-C was represented by an increase in apolipoprotein A-1, which is believed critical to promoting efflux of cholesterol from cells and is associated with anti-inflammatory effects.

“This trial was designed to evaluate safety and the results indicate that this is a different agent than torcetrapib. These data justify an end point trial, and this is exciting,” Dr. Thomas F. Lüscher, University of Zurich, Switzerland, told delegates. He suggested that the results restore promise for HDL-C as a target.

Invited by the ESC to provide perspective on these results of dal-VESSEL, Prof. Keith A.A. Fox, Royal Infirmary, Edinburgh, UK, agreed. He cited a study on the CETP inhibitor anacetrapib, which was also free of the off-target effects thought to counter the potential benefits of HDL-C increases with torcetrapib. Prof. Fox agreed that there is renewed interest in HDL-C as a pharmacologic target. Due to the overwhelming correlation between elevated HDL-C levels and protection from events, developments in this area are of major potential importance to the next stage of risk reduction.

Measuring Plaque Burden

The positive results of dal-VESSEL were reinforced by another phase IIb trial called dal-PLAQUE. This was a multicentre imaging study conducted in 130 patients randomized to dalcetrapib 600 mg or placebo. Co-primary end points were magnetic resonance imaging indices of plaque burden after 24 months and F18-fluorodeoxyglucose positron emission/computed tomography assessment of arterial inflammation after 6 months. As in dal-VESSEL, HDL-C was increased by 31%. There was no evidence of a pro-inflammatory effect, while the CETP modulator was associated with significant protection against increased plaque burden.

Encouraged by results of both of these studies, an ongoing event-driven trial, called dal-OUTCOMES, recently completed randomization of more than 15,000 acute coronary syndromes (ACS) patients and is expected to provide results in 2013.

Potential in Targeting Lp-PLA<sub>2</sub>

Similar promise is being generated by efforts to specifically target Lp-PLA<sub>2</sub>. A study to improve estimates of the impact of a change in Lp-PLA<sub>2</sub> levels on the risk of CV events in patients with CHD was conducted in conjunction with and in anticipation of pending results from an event trial with darapladib, which specifically targets this enzyme. Statistical modelling to estimate the additional CHD risk attributable to Lp-PLA<sub>2</sub> was conducted by taking baseline data from the STABILITY (Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial and applying it against the 4-year risk of the composite CHD end point of myocardial infarction (MI), coronary insufficiency, angina pectoris and coronary death as assessed with the Framingham risk score (FRS). When divided by quartiles, each increase in Lp-PLA<sub>2</sub> level above the first added a 10% to 15% increase in risk, reclassifying relative risk scores as determined by FRS in 36% of the patients, and providing a magnitude of added risk information that the authors claimed is equivalent to the HDL-C:total cholesterol ratio.

“While these data demonstrate that Lp-PLA<sub>2</sub> is a sensitive predictor of secondary risk, the STABILITY trial will allow us to determine whether this is a modifiable risk factor,” explained Prof. Lars Wallentin, Department of Cardiology, Uppsala Clinical Research Center, Sweden. Again, like HDL-C, the evidence that Lp-PLA<sub>2</sub> is a sensitive marker of risk now has to be confirmed with a study showing that acting on this marker reduces events and is safe.

Addressing Residual Risk After Statin Therapy

Treating residual risk after maximal control of LDL-C is likely to be relevant to all or most individuals with a history of CV disease, but is expected to be particularly relevant to individuals with metabolic syndrome or diabetes mellitus. In these individuals, characteristic dyslipidemias include low HDL-C and elevated TG so that residual risk after statin therapy is believed to be relatively large. In a study presented here at the ESC, investigators from Sweden even suggested that there might be an interaction between low HDL-C and elevated insulin resistance.

“When we defined high risk as HDL-C <1.03 mmol/L in men or <1.3 mmol/L in women, and a HOMA2-IR >1.5, the hazard ratio for CVD events after adjusting for classical CV risk factors was 2.57 (95% CI, 1.57-4.21) compared with low-risk HDL-C-HOMA,” reported Dr. Axel C. Carlsson, Karolinska Institute, Stockholm, Sweden. While he suggested that measuring both HDL-C and insulin resistance might be useful for more accurately evaluating CV risk in patients with metabolic syndrome or diabetes, Dr. Carlsson also indicated that it underscores a risk profile independent of LDL-C in these individuals.

Clinical trials with statins over more than 15 years stimulated much of the research that has helped define the pathophysiology of both atherosclerotic plaque growth and the plaque ruptures which define thrombotic events. Within this research, it is clear that elevated LDL-C is not alone in precipitating plaque growth and a pro-inflammatory state.

Summary

The evidence that control of factors other than LDL-C is important to CV risk reduction is strong enough that many guidelines already advocate strategies that will modify other targets, especially low HDL-C. However, these recommendations have been made in the absence of level 1 evidence of a significant reduction of hard end points, such as CV events or mortality. The promise of benefit from treating non-LDL-C risk markers will be tested in several planned or ongoing multinational trials. If the potential is realized, it will produce a major evolution in CV risk management, particularly in individuals whose dyslipidemias include abnormalities other than elevated LDL-C.

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