Raising high-density lipoprotein cholesterol – what does 2008 offer?

HDL Forum spoke to Professor Philip Barter, Director of the Heart Research Institute, and Professor Kerry-Anne Rye, Head of the Lipid Research Group, Heart Research Institute, Sydney, Australia about new therapeutic developments for raising high-density lipoprotein (HDL) cholesterol, ‘good’ cholesterol, in 2008.

Q: Which therapeutic developments for raising HDL cholesterol will be the focus of 2008?

Professor Barter: For 2008, I feel that the focus will predominantly be on niacin, specifically on combination products with niacin. Niacin has been available for clinical use for over 50 years, more recently as an extended-release formulation. While niacin is certainly effective in raising HDL cholesterol levels, flushing, the main side effect of therapy, can be problematic clinically.

Combining niacin with an agent (laropiprant) that blocks prostaglandin D2 receptors, which account for most of the flushing response, is a logical approach to counter this problem. Clinical data presented in 2007 have shown that the combination of niacin and laropiprant is effective in raising HDL cholesterol levels with reduced flushing. This combination will extend the use of niacin to people who previously could not tolerate this drug.

Q: Do we have any outcomes trials evaluating this combination?

Professor Barter: The ongoing HPS2-THRIVE trial is currently investigating the efficacy and tolerability of this combination in about 20,000 patients, testing whether adding this formulation to simvastatin provides additional benefit compared with simvastatin monotherapy. An important aspect of this trial is the planned inclusion of about 7,000 patients with diabetes in the study population, aimed at evaluating tolerability in this group. While the data will not be available in 2008, the trial will certainly provide important information on the clinical use of this niacin combination.

Q: Are there other niacin products that will be of interest?

Professor Barter: The other niacin product that will be a focus of 2008 is the combination of niacin and simvastatin, which has very recently received marketing approval in the USA. Previous angiographic trials provide the rationale for this development. The HDL Atherosclerosis Treatment Study (HATS) showed regression of atherosclerosis, together with significant reduction in cardiovascular events, with the combination of niacin plus simvastatin. Additionally, in ARBITER-2, the benefit of this combination on atherosclerosis progression was over and above that observed with statin alone.

Q: While niacin has proven HDL-raising efficacy, does it impact on HDL function?

Professor Rye: Investigating the effect of niacin on HDL function is very much something that is under investigation. For example, our Lipid Research Group will be looking to see whether niacin inhibits inflammation using experimental animal models. Additionally, we will be characterising the changes in HDL when people take niacin.

Professor Barter: Even though niacin is an old drug, we still do not know how it raises HDL nor how it protects against vascular disease. It is only now that some of this basic research is being done. I anticipate a lot of new information about how niacin works in the coming 1-2 years.

Q: Treating atherogenic dyslipidaemia associated with metabolic syndrome or type 2 diabetes is a clinical priority – what therapeutic products targeted to these groups will make news in 2008?

Professor Barter: The evidence suggests that there is a real role for the fibrates - PPARα (peroxisome proliferator activated receptor α) agonists – in patients with metabolic syndrome. In these patients, fibrate therapy has led to disproportionately large reductions in cardiovascular events which cannot be explained solely by changes in lipids. Whether this is also attributable to an effect on visceral fat warrants further investigation.

The efficacy and tolerability of the combination of fenofibrate plus simvastatin vs. simvastatin alone in patients with type 2 diabetes is under investigation in the ongoing ACCORD study. While this is a complex trial, recent termination of the intensive glycaemic treatment arm due to adverse effects may help to simplify the trial and re-focus on the lipid arm.

Novel selective PPARα agonists undergoing development are of particular interest in people with metabolic syndrome.

Despite current concerns about central nervous system side effects, I would anticipate that there will also be a lot of new data on rimonabant, particularly as its effects on raising HDL cholesterol appear to be explained by more than the weight reducing effect. If we consider that the biggest reason for having low HDL cholesterol in 2008 is abdominal obesity, as in the metabolic syndrome, then any agent that helps to combat this is likely to be of benefit in the clinical setting. Provided that rimonabant is not advocated solely for cosmetic use, it will have a future.

Q: Does CETP inhibition still have a potential role? And if so, when would we anticipate data becoming available?

Professor Barter: The CETP (cholesteryl ester transfer protein) inhibitors are still very much a possibility for therapeutic development. In animal studies, CETP inhibition has been universally successful. In humans, the only outcome study to date has been with a flawed drug. The hypothesis is still alive, and waiting to be disproved.

Roche has very recently announced that it will be proceeding with Phase III development with its drug (R1658). As well, there are several other CETP inhibitors in early development. One of these compounds, anacetrapib, was shown to be very effective in raising HDL cholesterol, if not more so than torcetrapib, and devoid of any effects on blood pressure, in data published in the Lancet December 2007. However, we will not see any outcomes data with another CETP inhibitor until 2011 at the earliest.

Q: Further down the line, what agents are likely to merit interest as potential HDL cholesterol raising agents?

Professor Rye: The ApoA-I (apolipoprotein A-I) mimetics are being actively investigated by a number of different companies. Briefly, these agents are very short peptides that mimic key functions of HDL, specifically their ability to bind lipid and remove cholesterol from cells. The most widely known mimetic, D4F has been shown to be effective in reducing atherosclerotic lesions in animal studies and has been reported to have anti-inflammatory properties, although this was not confirmed in other studies. However, there are issues with this mimetic, in terms of bioavailability as it is not metabolised. The isomeric form L4F is a possible alternative being investigated.

Professor Barter: As a group the ApoA-I mimetics are interesting and offer practical advantages over reconstituted ApoA-I or HDL.

As a final note, there is real interest in RVX-208, a novel orally administered small molecule that acts at a very early stage to increase synthesis of apoA-I in the liver, thereby raising HDL levels and improving cholesterol efflux. Studies investigating effects on atherosclerosis in experimental animal models are planned and a decision will be made later this year whether this product will proceed to clinical development. Provided no major adverse effects are identified, this drug is likely to have huge potential.

In the meantime, I believe that niacin will continue to remain at the forefront of therapeutic agents for raising HDL cholesterol for the next 5 years. The combination with laropiprant is likely to prove particularly worthwhile from the viewpoint of the practising clinician.