HDL Mimetics Infusion and Regression of Atherosclerosis: Is It Still Considered a Valid Therapeutic Option?

Abstract

Purpose of ReviewThis review aims to summarize and discuss the recent findings in the field of using HDL mimetics for the treatment of patients with coronary artery disease.Recent FindingsFollowing the largely disappointing results with the cholesteryl ester transfer protein inhibitors, focus moved to HDL functionality rather than absolute HDL cholesterol values. A number of HDL/apoA-I mimicking molecules were developed, aiming to enhance reverse cholesterol transport that has been associated with an atheroprotective effect. Three HDL mimetics have made the step from bench-testing to clinical trials in humans and are discussed here: apoA-I Milano, CSL-112, and CER-001. Unfortunately, with the exception of CSL-112 where the results of the clinical trial are not yet known, none of the agents was able to demonstrate a clinical benefit.SummaryHDL mimetics have failed to date to prove a beneficial effect in clinical practice. Reverse cholesterol transport remains a challenging therapeutic pathway to be explored.

What is new in lipid‐lowering therapies in diabetes?

“…Preliminary studies showed CER‐100 can rapidly mobilise large amounts of cholesterol into the HDL fraction. However, once again larger safety and efficacy trials did not observe any differences in atheroma regression in the CER‐100 group …”

“…This has led to a shift in focus towards the functional properties of HDL (particularly its role in reverse cholesterol transport) rather than raising HDL levels. There are three main steps to reverse cholesterol transport: (i) cholesterol efflux, where HDL/apolipoprotein A‐1 (apoA‐1) remove excess cholesterol from cells; (ii) lipoprotein remodelling, where HDL undergoes structural modifications; and (iii) hepatic lipid intake, where HDL releases cholesterol to the liver for final excretion . Several HDL mimetics have been tested in humans.…”

“…Recombinant apoA‐I Milano is based on a naturally occurring mutation where carriers are characterised by exceptionally low prevalence of CVD due to increased induction of reverse cholesterol transport. Unfortunately, a recent RCT involving 122 post‐ACS patients failed to demonstrate incremental regression of coronary atherosclerosis …”

“…CSL‐112 is a reconstituted HDL particle consisting of native apoA‐I and phospholipids. It appears to be safe after two phase I trials and was associated with a dose‐dependent increase in apoA‐I levels post infusion and also significantly enhanced and increased cholesterol efflux . A large phase III study is currently underway with the aim to determine the potential benefit of CSL‐112 in reducing CV events.…”

“…There are three main steps to reverse cholesterol transport: (i) cholesterol efflux, where HDL/apolipoprotein A-1 (apoA-1) remove excess cholesterol from cells; (ii) lipoprotein remodelling, where HDL undergoes structural modifications; and (iii) hepatic lipid intake, where HDL releases cholesterol to the liver for final excretion. 34 Several HDL mimetics have been tested in humans. Recombinant apoA-I Milano is based on a naturally occurring mutation where carriers are characterised by exceptionally low prevalence of CVD due to increased induction of reverse cholesterol transport.…”