AHA – Dalcetrapib failure a long way from settling HDL controversy

The only conclusion that can be drawn about the dal-Outcomes study, other than that Roche’s dalcetrapib does not prevent cardiovascular events, is that it could take some time before the controversy over the benefits of raising high-density lipoprotein is settled.

The two other drugs in the cholesteryl ester transfer protein (CETP) class still in pivotal trials – Eli Lilly’s evacetrapib and Merck & Co’s anacetrapib – are recognised as more potent, and a blockbuster could yet emerge from this class (Roche’s dalcetrapib failure not end of the road for CETP, May 8, 2012). However, one of those trials has only just begun to recruit patients and it must be frustrating for big pharma to know that it might be years before the hundreds of millions of dollars thrown at this class are paid back, if indeed they ever are.

Lack of class effect

There is no doubt that dal-Outcomes confirmed that dalcetrapib was effective in raising high-density lipoprotein (HDL) – the “good” cholesterol – in patients with acute coronary syndrome, and had this been a primary endpoint of the trial it might be judged as a success. However, as a drug designed to prevent heart attacks, strokes and other cardiovascular events, it was a failure.

A possible culprit was a mild increase in systolic blood pressure and c-reactive proteins that could have offset any benefit of raising HDL, study investigator Dr Gregory Schwartz of the University of Colorado said in presenting the findings at the American Heart Association scientific sessions.

Torcetrapib also showed a rise in systolic blood pressure in its pivotal trial, which ended early because of an excess of deaths in the intervention arm. This is an ominous sign for evacetrapib and anacetrapib, the two remaining compounds in the class, although neither has so far been shown to increase blood pressure.

“Together this information suggests a slight increase in blood pressure does not represent a class effect, but this cannot be ruled out,” said Alan Tall, a Columbia University professor of medicine and AHA’s designated commentator on dal-Outcomes.

Revealing how little is known about the benefits of raising HDL, dal-Outcomes found that patients in the placebo arm with high HDL at baseline were not less likely to have cardiovascular complications than those with lower HDL. In essence, this is a sign that lowering HDL might have little effect in preventing these complications. One hypothesis emerging from dalcetrapib’s failure is that greater increases in HDL are necessary for any benefit to be seen.

Still, analysts have assigned numbers to the two remaining CETP inhibitors, with consensus forecasts putting anacetrapib sales at $368m in 2018 and evacetrapib at $68m, according to EvaluatePharma.

Bad HDL?

Another explanation was offered by Dr Tall. He suggested that dalcetrapib stimulated production of a “dysfunctional” variety of HDL that does not help transport low-density lipoproteins (LDL) – the “bad” cholesterol – from partially blocked blood vessels.

“The big question is: Does raising HDL through CETP inhibition produce HDL that is atherogenic? That we absolutely do not know,” Gregg Fonarow, a cardiology of professor at the University of California-Los Angeles, told EP Vantage. “Dal-Outcomes shows us that HDL went up 30%. If the epidemiology is true, there would have been a 60-90% reduction in events. Yet it didn’t occur.”

Greater hopes have been placed on the last two CETP inhibitors standing, not just because of their lack of effect on blood pressure, but also because they have so far shown a greater effect on HDL and a benefit in lowering LDL.

Dr Fonarow notes that, because of the LDL-lowering effect, anacetrapib and evacetrapib have a greater potential to prevent cardiovascular complications. However, it might not be possible to confirm that raising HDL is a benefit.

“If you lower LDL further, on top of a statin, by 40% we’re going to expect about a 40% relative reduction in risk,” he said. “Here was our closest test of pure HDL raising, and yet a reduction in events was not seen.”

With the Aim-High study assessing Abbott Laboratories’ extended-release niacin Niaspan on top of LDL-lowering therapy having shown no clinical benefit, there is much left to be proved (Aim-High adds fuel to the HDL debate, May 27, 2011). “This study together with Aim-High greatly challenges this HDL hypothesis,” Dr Fonarow said.

To contact the writer of this story email Jonathan Gardner in Los Angeles at [email protected]