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

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

Background

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

• Lipidomic analysis of the HDL fraction after RVX-208:
  Significant increase in 10 of the 24 lipid classes after correction for multiple testing.
• Lipoprotein particles after RVX-208:
  11% increase in medium-sized HDL particles (p=0.01), 10% decrease in small-sized HDL particles (p=0.04), 40% decrease in total IDL particles (p=0.02). No effect on total HDL particle concentration, HDL particle size, LDL or VLDL/chylomicron particle concentration, total TG concentration.
• Plasma glucose, insulin, C-peptide, incretin concentration after RVX-208:
  No fasting or postprandial glucose and insulin differences between treatments. In response to glucose load, plasma glucose and insulin concentration peaked at a similar concentration between treatments, but were 30 min delayed (p=0.003) with a prolonged sustained glucose elevation. Insulin:glucose ratio was lower (p=0.021). No overall treatment effect on c-peptide concentration although c-peptide concentration was higher later in time course. No effect on incretin concentration.
• Glucose kinetics after RVX-208:
  Total glucose appearance and disappearance were lower (p=0.016). Endogenous glucose production was marginally suppressed (p=0.014) and ingested glucose appearance was reduced and delayed (p=0.003).
• Safety:
  All measures remained within normal clinical ranges but serum creatinine was 5% increased (p=0.006), estimated glomerular filtration rate reduced (p=0.051), circulating chloride reduced (p=0.04), RBC count was 2% lower (p=0.05).
  

Conclusion

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.    

References

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