Physicians' Academy for Cardiovascular Education

Effects of novel BET-inhibitor on the HDL lipidome and glucose metabolism

Siebel AL et al., J. metabol. 2016

Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial

Siebel AL, Trinh SK, Formosa MF, et al.
J. metabol. 2016;65:904-914


RVX-208 is a bromodomain and extra terminal domain (BET) protein inhibitor [1-3]. Studies in monkeys and a phase I clinical trial have shown elevation of ApoA-I and HDL-c elevation upon treatment [1,4]. ApoA-I is a major protein of HDL. HDL can directly modulate the glucose metabolism through multiple mechanisms [5-7]. In clinical setting, elevation of HDL reduces blood glucose in individuals with T2DM [5,7]. Recent data show that HDL particle number, composition and function are more related to CVD outcome than conventional HDL-c content[8-10]. In this light, ApoA-I inhibitors like RVX-208 are of particular interest, as they alter the HDL particle number, the lipid composition and function of existing particles [9,11].
The objectives of current study were to determine the RVX-208 effects on the HDL lipidome and postprandial glucose metabolism in individuals with prediabetes following glucose intake. Individuals followed a randomised, double-blinded RVX-208/placebo cross over design for 4 weeks, separated by a wash-out period of 21-35 days.

Main results


This is the first study that shows that an oral BET inhibitor may modulate the glucose metabolism. RVX-208 treatment resulted in reduced appearance of oral glucose in the circulation, as well as reduced endogenous glucose production and consequent glucose disposal. This resulted in a glucose delay after glucose challenge, but also a sustained peak in plasma glucose levels. RVX-208 affected HDL lipid composition and HDL particle size distribution, thereby modifying HDL lipid classes towards a healthy lipid profile and promoting a shift from small to medium-sized particles.    


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