Synthetic HDL: Plaquebuster? Or Just Bust?

Synthetic HDL

HDL Apo A protein. Laguna Design/Getty images

As everyone knows, HDL cholesterol is “good cholesterol,” because elevated HDL levels have been correlated with a reduced risk of coronary artery disease. HDL scours excess cholesterol from the tissues and returns it to the liver for processing. Accordingly, researchers have spent many years trying to develop treatments that will increase HDL levels, and thus boost the process of removing “bad” cholesterol.

These efforts have been largely disappointing.

One path of research that once seemed the most promising is in the area of HDL mimetics - a synthetic form of HDL that “mimics” the effect of ApoA, the HDL lipoprotein.

What Are HDL Mimetics?

Like all lipoproteins, HDL particles consist of lipids (in this case, cholesterol), and special proteins that transport the lipid through the bloodstream. The proteins that make up HDL lipoproteins are a family of proteins called ApoA. ApoA is the “active ingredient” of the HDL particle. It is the ApoA that gathers up excess cholesterol from arterial walls and carries it away. So the HDL cholesterol we measure with blood tests is cholesterol that has been removed from tissue, and is on its way back to the liver for processing.

It makes sense, then, that if we can increase the amount of ApoA proteins in our bloodstream we can increase the cholesterol removal process, and presumably, reduce the risk of developing atherosclerosis.

HDL mimetics are drugs that mimic, as closely as possible, the ApoA proteins. They are in effect synthetic HDL particles. Several are in development, but the research and development process has been slow and halting.

Experience with HDL Mimetics

The first clinical experience with an HDL mimetic was reported in 2003.

An HDL mimetic called ApoA-1 Milano, administered as five weekly intravenous injections, resulted in significant shrinkage of plaques in a handful of men with coronary artery disease. (The amount of shrinkage was actually quite tiny, but it was shrinkage, and it was statistically significant.)

ApoA-1 Milano was discovered by studying 40 people from a small town in Italy who were known to live remarkably long and healthy lives, despite having markedly reduced HDL levels. Investigators discovered that these people had a “mutant” form of HDL (the ApoA-1 Milano) that was not detected by routine blood testing, but that proved to be very effective in preventing cardiovascular disease. Researchers were able to synthesize the DNA mutation that produced this new HDL, and subsequently added this new DNA to a strain of laboratory bacteria, –thus creating a “factory” for the production of the ApoA-1 Milano.

This study raised tremendous excitement among cardiologists and, thanks to news reports, among the general public.

But in the intervening years we have heard next to nothing about ApoA-1 Milano.

There has been quite a bit of activity in the background, however. The rights to ApoA-1 Milano have changed hands several times, and several drug companies are known to be working on HDL mimetics. But by now it seems quite clear that the process of developing these drugs is, to say the least, difficult and expensive.

Further, in 2014 a second HDL mimetic (CER-001, from Cerenis Therapeutics) was tested in a clinical trial called CHI-SQUARED, and failed to demonstrate a benefit in reducing plaque volumes.

Where Do HDL Mimetics Stand Now?

Enthusiasm has greatly dimmed since 2003. These drugs have proven to be very difficult to develop and manufacture, and based on the results of CHI-SQUARED they are not destined to be universally effective. While we cannot know for sure, it looks like the big drug companies have backed away from them. They are being developed by smaller companies with limited resources.

In addition, researchers’ general enthusiasm for raising HDL levels as a means of preventing heart disease has dropped significantly in recent years, with the spectacular failure of CETP inhibitors like torcetrapib, and more recently, niacin. Drug companies have spent billions trying to find drugs that both increase HDL levels and reduce heart disease, to no effect. Skeptics are even beginning to question the entire “HDL hypothesis,” i.e., that high HDL levels are always good.

So synthetic HDL is still under development and may yet turn out to be a great boon to medicine. But there’s a lot more work that needs to be done. And even if this effort pans out, this type of drug needs to be administered (at yet-to-be determined doses and intervals) intravenously; and given the years of endeavor and the money that has been spent, we can expect these drugs to be prohibitively expensive. So we should not hold our breaths.

Bottom Line

The best way to increase our HDL levels is by adopting a healthy lifestyle. This method has the benefit of reducing our risk irrespective of our actual HDL levels.


Tardif J-C, Ballantyne CM, Barter P, et al. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. European Heart Journal. 29 April 2014 DOI:

Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003; 290:2292.

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