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

Andrew L. Siebel, Si Khiang Trinh, Melissa F Formosa, Piyushkumar A Mundra, Alaina K Natoli, Medini Reddy-Luthmoodoo, Kevin Huynh, Anmar A. Khan, Andrew L. Carey, Gerrit van Hall, Claudio Cobelli, Chiara Dalla-Man, Jim D. Otvos, Kerry-Anne Rye, Jan Erik Johansson, Allan Gordon, Norman C.W. Wong, Dmitri Sviridov, Philip J Barter, Stephen J. DuffyPeter J. Meikle, Bronwyn A. Kingwell

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23 Citations (Scopus)

Abstract

Aims High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) can modulate glucose metabolism through multiple mechanisms. This study determined the effects of a novel bromodomain and extra-terminal (BET) inhibitor (RVX-208) and putative apoA-I inducer on lipid species contained within HDL (HDL lipidome) and glucose metabolism. Materials and methods Twenty unmedicated males with prediabetes received 100 mg b.i.d. RVX-208 and placebo for 29-33 days separated by a wash-out period in a randomized, cross-over design trial. Plasma HDL-cholesterol and apoA-I were assessed as well as lipoprotein particle size and distribution using NMR spectroscopy. An oral glucose tolerance test (OGTT) protocol with oral and infused stable isotope tracers was employed to assess postprandial plasma glucose, indices of insulin secretion and insulin sensitivity, glucose kinetics and lipolysis. Whole plasma and HDL lipid profiles were measured using mass spectrometry. Results RVX-208 treatment for 4 weeks increased 6 sphingolipid and 4 phospholipid classes in the HDL lipidome (p ≤ 0.05 versus placebo), but did not change conventional clinical lipid measures. The concentration of medium-sized HDL particles increased by 11% (P = 0.01) and small-sized HDL particles decreased by 10% (P = 0.04) after RVX-208 treatment. In response to a glucose load, after RVX-208 treatment, plasma glucose peaked at a similar level to placebo, but 30 min later with a more sustained elevation (treatment effect, P = 0.003). There was a reduction and delay in total (P = 0.001) and oral (P = 0.003) glucose rates of appearance in plasma and suppression of endogenous glucose production (P = 0.014) after RVX-208 treatment. The rate of glucose disappearance was also lower following RVX-208 (P = 0.016), with no effect on glucose oxidation or total glucose disposal. Conclusions RVX-208 increased 10 lipid classes in the plasma HDL fraction, without altering the concentrations of either apoA-I or HDL-cholesterol (HDL-C). RVX-208 delayed and reduced oral glucose absorption and endogenous glucose production, with plasma glucose maintained via reduced peripheral glucose disposal. If sustained, these effects may protect against the development of type 2 diabetes.

Original languageEnglish
Pages (from-to)904-914
Number of pages11
JournalMetabolism
Volume65
Issue number6
DOIs
Publication statusPublished - 1 Jun 2016
Externally publishedYes

Keywords

  • Clinical trial
  • Glucose metabolism
  • High-density lipoprotein
  • Prediabetes
  • Type 2 diabetes

Cite this

Siebel, A. L., Trinh, S. K., Formosa, M. F., Mundra, P. A., Natoli, A. K., Reddy-Luthmoodoo, M., Huynh, K., Khan, A. A., Carey, A. L., van Hall, G., Cobelli, C., Dalla-Man, C., Otvos, J. D., Rye, K-A., Johansson, J. E., Gordon, A., Wong, N. C. W., Sviridov, D., Barter, P. J., ... Kingwell, B. A. (2016). Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial. Metabolism, 65(6), 904-914. https://doi.org/10.1016/j.metabol.2016.03.002