Fight Aging!

If you are familiar with research into those parts of lipid metabolism presently considered relevant to the development of atherosclerosis, near entirely focused on the mechanisms by which cholesterol is transported around the body in the bloodstream, then you will know that the CETP protein is considered a target for therapies. This is due to (a) its role in transferring cholesterol between transport particles such as high density lipoprotein (HDL) and low-density lipoprotein (LDL), and (b) suggestive data for gene variants to affect risk of cardiovascular disease.

LDL particles carry cholesterol outwards from the liver into the arteries where atherosclerotic plaques form. HDL particles carry cholesterol back to the liver from the rest of the body. Present therapies aimed at reducing the amount of LDL-cholesterol, such as statins and PCSK9 inhibitors, have their origins in the discovery of human mutants with lower LDL-cholesterol and lower lifetime cardiovascular risk. In practice, the resulting drugs produce only modest benefits, failing to reverse atherosclerosis even when greatly reducing LDL-cholesterol, and only reducing risk of heart attack and stroke by at most 20%, if we are being generous in our interpretation of the data. Similarly, attempts to enhance HDL transport to drain cholesterol from arteries have met with failure.

Today's open access paper is an interesting look at one slice of all of this biochemistry, focused on CETP and whether or not it is a target worth pursuing. The development of many ways to achieve small gains derived from evidence for influence of one gene or another on cholesterol transport has perhaps made some people a little hesitant to jump on yet another similar gene and similar attempt. Yet one can line up a bunch of evidence to suggest that targeting CETP will achieve some benefits, not just for cardiovascular disease, and funding has been found for clinical trials of CETP-targeted therapies.

Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity

Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that is a member of the lipid transfer protein family. It facilitates the bidirectional exchange of cholesteryl esters and triglycerides among lipoprotein particles leading to a net mass transfer of cholesteryl esters from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particles. In addition, triglycerides are transferred in the opposite direction from LDL and VLDL to HDL.

Interest in CETP inhibition as a therapeutic target began with the discovery in observational studies that some CETP gene polymorphisms were associated with reduced coronary heart disease (CHD) incidence and CHD mortality, although these results have not been entirely consistent. However, taking all evidence into consideration, observational studies, Mendelian randomization (MR) analyses, and randomized clinical trials of pharmaceutical agents indicate that CETP inhibition confers cardiovascular benefit and reduces risk of atherosclerotic cardiovascular disease (ASCVD). Additionally, emerging evidence suggests that CETP inhibition may promote longevity, presumably by lowering the risk of several conditions associated with aging such as new-onset type 2 diabetes mellitus (T2D), dementia, chronic kidney disease (CKD), and age-related macular degeneration (AMD), as well as promoting survival in septicemia. Some of these effects are likely mediated through improved functionality of the HDL particle, including its role on cholesterol efflux and antioxidative, anti-inflammatory, and antimicrobial activities.

At present, there is robust clinical evidence to support the benefits of reducing CETP activity for ASCVD risk reduction, and plausibility exists for the promotion of longevity by reducing risks of several other conditions. An ongoing large clinical trial program of the latest potent CETP inhibitor, obicetrapib, is expected to provide further insight into CETP inhibition as a therapeutic target for these various conditions.