title: Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Twenty unmedicated males with prediabetes received 100mg b.i.d. RVX-208 and placebo for 29-33days 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 4weeks 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 30min 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.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Siebel
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Si Khiang
authors.initials: SK
authors.lastname: Trinh
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Melissa F
authors.initials: MF
authors.lastname: Formosa
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Piyushkumar A
authors.initials: PA
authors.lastname: Mundra
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Alaina K
authors.initials: AK
authors.lastname: Natoli
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Medini
authors.initials: M
authors.lastname: Reddy-Luthmoodoo
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Huynh
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Anmar A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Carey
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Gerrit
authors.initials: G
authors.lastname: van Hall
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dalla-Man
authors.affiliation: LabCorp, Raleigh, USA.
authors.forename: Jim D
authors.initials: JD
authors.lastname: Otvos
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.affiliation: ResVerlogix Corp., San Francisco, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
authors.affiliation: ResVerlogix Corp., San Francisco, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Gordon
authors.affiliation: ResVerlogix Corp., San Francisco, USA.
authors.forename: Norman C W
authors.initials: NC
authors.lastname: Wong
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Sviridov
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Barter
authors.affiliation: Heart Centre, The Alfred Hospital, Melbourne, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Duffy
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Electronic address: bronwyn.kingwell@bakeridi.edu.au.
authors.forename: Bronwyn A
authors.initials: BA
authors.lastname: Kingwell
mesh_terms: D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D050260:Carbohydrate Metabolism / Q000187:drug effects* / Q000502:physiology; D008076:Cholesterol, HDL / Q000097:blood*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D011236:Prediabetic State / Q000097:blood / Q000188:drug therapy*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D052999:Quinazolinones
chemical_list: D016632:Apolipoprotein A-I; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D011799:Quinazolines; D052999:Quinazolinones; C000628794:apabetalone
keywords: Clinical trial; Glucose metabolism; High-density lipoprotein; Prediabetes; Type 2 diabetes