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

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

Literature - Siebel AL et al., J. metabol. 2016


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

1. Bailey D, Jahagirdar R, Gordon A, Hafiane A, Campbell S, Chatur S, et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol 2010;55:2580–9.
2. McLure KG, Gesner EM, Tsujikawa L, Kharenko OA, Attwell S, Campeau E, et al. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS One 2013;8:e83190.
3. Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc Natl Acad Sci U S A 2013;110:19754–9.
4. Nicholls SJ, Gordon A, Johansson J, Wolski K, Ballantyne CM, Kastelein JJ, et al. Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial. J Am Coll Cardiol 2011;57:1111–9.
5. Drew BG, Duffy SJ, Formosa MF, Natoli AK, Henstridge DC, Penfold SA, et al. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus. Circulation 2009;119:2103–11.
6. Drew BG, Rye KA, Duffy SJ, Barter P, Kingwell BA. The emerging role of HDL in glucose metabolism. Nat Rev Endocrinol 2012;8:237–45.
7. Barter PJ, Rye KA, Tardif JC, Waters DD, Boekholdt SM, Breazna A, et al. Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE) trial. Circulation 2011;124:555–62.
8. Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 2014;371:2383–93.
9. Kingwell BA, Chapman MJ, Kontush A, Miller NE. HDL targeted therapies: progress, failures and future. Nat Rev Drug Discov 2014;13:445–64.
10. Camont L, Lhomme M, Rached F, Le Goff W, Negre-Salvayre A, Salvayre R, et al. Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities. Arterioscler Thromb Vasc Biol 2013;33:2715–23.
11. Kingwell BA, Chapman MJ. Future of high-density lipoprotein infusion therapies: potential for clinical management of vascular disease. Circulation 2013;128:1112–21.

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