June 4, 2012 (Milan, Italy) — After a series of negative trial results, the concept of raising high-density lipoprotein (HDL) as a therapeutic approach to reducing cardiovascular risk looks to be in a sorry state. But lipid experts at the recent European Atherosclerosis Society (EAS) 2012 Congress were adamant that the HDL hypothesis was not yet dead and that it is imperative that research in this direction continue.

At a session on the subject, Dr Alan Tall (Columbia University, New York) summarized the situation: "The HDL hypothesis is certainly under attack. And there have been a lot of setbacks. But we mustn't throw the baby out with the bathwater. I think we need a new, modified HDL hypothesis."

Dr Philip Barter (Heart Research Institute, Sydney, Australia), who is one of the leading HDL researchers worldwide, is fervent in the belief that HDL-based therapeutics will still be successful. "I am not convinced that the recent negative reports disprove the HDL hypothesis," he told heartwire . "My basic message is don't give up yet. There is just too much we don't know."

Dr Philip Barter

And EAS president Dr John Chapman (Hôpital de la Pitié-Salpêtrière, Paris, France) had a similar opinion. "There is no question that it's too soon to give up on HDL," he told heartwire . "There is no doubt that low HDL increases the risk of cardiovascular disease by about 40%. The worldwide epidemiological data on this are vast. It explodes the risk, but we just don't understand why."

The next frontier or not?

Dr John Chapman

After the great success of lowering low-density lipoprotein (LDL), the idea of raising the "good" HDL cholesterol was seen as the natural next step in the battle against heart disease. Driven by epidemiological studies and discovery of the apolipoprotein (apo) A1 Milano variant of the HDL complex--which was found to be associated with a low risk of cardiovascular disease and regression of atherosclerosis in intravascular ultrasound [IVUS] studies, gaining it the label of "liquid Drano for the coronary arteries"--raising HDL became the next holy grail. The approach was described as the "next frontier" and "second magic bullet."

But things have not gone quite as planned. While the negative results of the first major trial of an HDL-raising drug, torcetrapib, were attributed to its off-target side effect of raising blood pressure, there have been three more recently reported trials, all of which cast doubt on the strategy of raising HDL. These were the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study with niacin, dal-OUTCOMES with dalcetrapib (Roche), and a genetic study published a couple of weeks ago in the Lancet, which showed that individuals with gene variants that increase HDL levels did not have a reduced risk of heart disease [1]. This resulted in a front-page story in the New York Times casting doubt over the whole HDL hypothesis [2].

I think we all got a little too optimistic that any increase in HDL will be good.

Tall commented: "The New York Times article suggested that we have been pulling the wool over the eyes of the public about HDL. It made me feel a bit defensive, but there is some truth to it. Although AIM-HIGH and dal-OUTCOMES were both underpowered, if you put it all together with the recent genetic study, it isn't looking good. We are at a watershed. I think we all got a little too optimistic that any increase in HDL will be good. It does now appear that it is not as simple as just raising HDL per se. But perhaps we need to focus on which type of HDL we are raising."

Tall emphasized to heartwire that there is still reason for hope. "There is strong evidence from epidemiological studies, and we have shown efficacy of HDL in promoting cholesterol efflux from macrophages. There are a whole battery of studies in both animals and humans on this. Synthetic HDL particles have been shown to be good at sucking cholesterol out of the artery. But that is very different from a small increase in circulating HDL. We want to make sure that the HDL formed is empty and so has the capacity to take up cholesterol. The large trials of HDL-raising therapies so far may have just raised already overladen HDL. That is one possibility."

He suggested that a modified HDL hypothesis could be that HDL function, such as macrophage cholesterol efflux, may relate to coronary heart disease more than simply HDL levels. "So there is still hope for the field."

Barter: Interpretation of genetic study "flawed"

Barter offered the theory that studies conducted so far were not an adequate test of the HDL hypothesis. Addressing the genetic study recently published in the Lancet, Barter said its interpretation had been seriously flawed.

"One gene that is associated with an increase in HDL and a reduction in [cholesteryl ester-transfer protein] CETP--a variant of a CETP gene--was shown to be associated with a significant reduction in cardiovascular disease, but because this gene is also associated with a reduction in LDL, the benefit couldn't be attributed to HDL," he told heartwire . "But this is the third study to show that a gene variant of CETP is associated with a reduction in cardiovascular risk. The conclusion is that, when you have a reduction in CETP activity with higher HDL and lower LDL levels, there is less cardiovascular disease."

He noted that the HDL increase associated with most of the genes evaluated in the Lancet study was small, apart from the endothelial lipase gene, which showed a large increase in HDL, but this did not reduce coronary heart disease. 'All that means is that the HDL that is increased with that gene variant doesn't have enhanced function or has reduced function.'

"We need to know how genetics affect HDL function, but this is much more difficult to measure. HDL is very complicated; it is no good just measuring the amount of something that is there. We need to know what it is doing."

The many functions of HDL

Barter explained that HDL has many functions: in addition to removing cholesterol from macrophages, it also inhibits LDL oxidation, promotes endothelial repair, and has antidiabetic, anti-inflammatory, and antithrombotic properties. "We don't know which of these properties are clinically important. We don't know which function to measure.

"To measure all these things in one sample might cost $1000. It is infeasible to do that in a large-scale study. We need a lot more basic research into HDL, we need to find out whether all its functions correlate with each other, and we need to look at which functions of HDL are compromised in diabetic and obese patients."

He also pointed out that HDL is very heterogeneous. "There are many different subpopulations, and we don't know which subpopulations are the most functional. And for a treatment that increases HDL, we have to analyze which subpopulations and which functions of HDL it is increasing."

Barter suggested that different functions of HDL may be more important at different times. "While the story started with cholesterol efflux--and this is one highly likely protective mechanism--it is almost certainly not the only one. The anti-inflammatory or antithrombotic properties may be more important after an event."

He also noted that the biggest predictor of HDL concentration is environmental factors--obesity, insulin resistance, diabetes--which will not have been accounted for in genetic studies. "The actual HDL concentration is influenced enormously by lifestyle factors. You can't control for this in a gene-association study."

Barter also questioned whether low levels of HDL signify a real increased risk of heart disease or whether they are just a marker of something else that is protective. "In epidemiology, the level of HDL is predictive of risk. So in this regard, the level of HDL does appear to correlate with protective functions. But does that mean this relationship is causal? If other factors are adjusted for, the relationship is still there. This still doesn't make it causal--it may reflect something else we don't know about."

Barter thinks that's unlikely to be the case. HDL, he notes, has many actions that should be protective; in animal studies, for example, raising HDL reduces atherosclerosis. "Maybe humans are unique, but I think it is inconceivable that HDL it is not protective in humans--but this has not been proven yet."

More large outcome trials under way

After the torcetrapib failure, many have been of the opinion that CETP inhibitors are making dysfunctional HDL. But Barter argues that this is not established. He says the off-target toxicity of torcetrapib is a "highly plausible explanation" for its lack of benefit. "And in dal-OUTCOMES, HDL was increased by 30%, but there was no effect on LDL, and it may be that we need both an increase in HDL and a reduction in LDL to show benefit. This is consistent with the genetics."

He says there are two main conclusions that can be reached from all the HDL controversy in the past few weeks: one, that the HDL hypothesis has not yet been tested properly, so it must not yet be buried; and two, the CETP hypothesis should not be abandoned until a much more potent inhibitor has been tested.

In fact, a more potent CETP inhibitor is indeed now being tested in the Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial with anacetrapib (Merck), which increases HDL by up to 140% and reduces LDL by 35% to 45%. Another CETP inhibitor, evacetrapib (Lilly), which has a similar profile, is about to start a large-scale trial. "If these trials do not show benefit, then I think we can say CETP inhibition is not the way to go, but it is too premature to reach this conclusion now," Barter commented.

Another large trial should settle the debate over niacin. The Heart Protection Study--Treatment of HDL to Reduce the Incidence of Vascular Events (HPS THRIVE) trial in 25 000 patients (the results of which are expected early next year) should answer the questions that AIM-HIGH didn't. But none of these trials will prove the HDL hypothesis, as all the agents have other actions in addition to raising HDL.

Other approaches

In another talk at the EAS meeting, Dr Kausik Ray (St George's, University of London, UK) outlined some of the many new approaches to boosting HDL in development. These include:

  • Infusing artificial and recombinant formulations of apoA1 (which forms HDL in the body); several products are in phase 2 trials in acute settings.

  • Delipidation of HDL, which involves taking a large quantity of blood, removing the cholesterol from the HDL, and then reinfusing the blood.

  • RVX-208: A drug that increases the endogenous production of apoA1, which is now being tested in IVUS studies in humans.

  • Agents that increase ABCA1, the protein that mediates the transport of cholesterol out of the cell so that it can be cleared from the body.

Ray said that these therapies would give a better insight into the HDL hypothesis. New basic research suggests that it is the small HDL particles (prebeta HDL) that need to be increased, but CETP inhibitors lead to a rise in large-particle HDL, which is not as effective in promoting reverse cholesterol transport, he explained.

Because the apoA1 products in development appear to raise small HDL particles, Ray said he thought that these were a more hopeful approach.

It's not what you do, it's the way that you do it.

"If ongoing trials with the apoA1 products in the acute coronary syndrome setting are positive, this will undoubtedly result in a paradigm shift," he commented. "But until we get a positive outcome from a trial with an HDL-based strategy, we haven't got a handle on how to go forward. If we get a positive trial, we would then need to work out what proportion of benefit was related to the HDL level and/or function."

But Ray was also adamant that HDL's day is not yet over. "We now know that HDL is a lot more complex than we initially thought, but it is still irrefutable that low HDL is a marker of risk."

Chapman concluded: "We need to neutralize the risk associated with low HDL, but we still don't have enough biological knowledge on how to do this. I believe it's a case of 'it's not what you do, it's the way that you do it.' We've just got to work out what the best way is."

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