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. Duffy & 2 others Peter J. Meikle, Bronwyn A. Kingwell

Research output: Contribution to journalArticleResearchpeer-review

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, Andrew L. ; Trinh, Si Khiang ; Formosa, Melissa F ; Mundra, Piyushkumar A ; Natoli, Alaina K ; Reddy-Luthmoodoo, Medini ; Huynh, Kevin ; Khan, Anmar A. ; Carey, Andrew L. ; van Hall, Gerrit ; Cobelli, Claudio ; Dalla-Man, Chiara ; Otvos, Jim D. ; Rye, Kerry-Anne ; Johansson, Jan Erik ; Gordon, Allan ; Wong, Norman C.W. ; Sviridov, Dmitri ; Barter, Philip J ; Duffy, Stephen J. ; Meikle, Peter J. ; Kingwell, Bronwyn A. / Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes : A randomized controlled trial. In: Metabolism. 2016 ; Vol. 65, No. 6. pp. 904-914.
@article{5c167c4c01e0458fa8a8df6d978f7ad1,
title = "Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial",
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.",
keywords = "Clinical trial, Glucose metabolism, High-density lipoprotein, Prediabetes, Type 2 diabetes",
author = "Siebel, {Andrew L.} and Trinh, {Si Khiang} and Formosa, {Melissa F} and Mundra, {Piyushkumar A} and Natoli, {Alaina K} and Medini Reddy-Luthmoodoo and Kevin Huynh and Khan, {Anmar A.} and Carey, {Andrew L.} and {van Hall}, Gerrit and Claudio Cobelli and Chiara Dalla-Man and Otvos, {Jim D.} and Kerry-Anne Rye and Johansson, {Jan Erik} and Allan Gordon and Wong, {Norman C.W.} and Dmitri Sviridov and Barter, {Philip J} and Duffy, {Stephen J.} and Meikle, {Peter J.} and Kingwell, {Bronwyn A.}",
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Siebel, AL, Trinh, SK, Formosa, MF, Mundra, PA, Natoli, AK, Reddy-Luthmoodoo, M, Huynh, K, Khan, AA, Carey, AL, van Hall, G, Cobelli, C, Dalla-Man, C, Otvos, JD, Rye, K-A, Johansson, JE, Gordon, A, Wong, NCW, Sviridov, D, Barter, PJ, Duffy, SJ, Meikle, PJ & Kingwell, BA 2016, 'Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial' Metabolism, vol. 65, no. 6, pp. 904-914. https://doi.org/10.1016/j.metabol.2016.03.002

Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes : A randomized controlled trial. / Siebel, Andrew L.; Trinh, Si Khiang; Formosa, Melissa F; Mundra, Piyushkumar A; Natoli, Alaina K; Reddy-Luthmoodoo, Medini; Huynh, Kevin; Khan, Anmar A.; Carey, Andrew L.; van Hall, Gerrit; Cobelli, Claudio; Dalla-Man, Chiara; Otvos, Jim D.; Rye, Kerry-Anne; Johansson, Jan Erik; Gordon, Allan; Wong, Norman C.W.; Sviridov, Dmitri; Barter, Philip J; Duffy, Stephen J.; Meikle, Peter J.; Kingwell, Bronwyn A.

In: Metabolism, Vol. 65, No. 6, 01.06.2016, p. 904-914.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes

T2 - A randomized controlled trial

AU - Siebel, Andrew L.

AU - Trinh, Si Khiang

AU - Formosa, Melissa F

AU - Mundra, Piyushkumar A

AU - Natoli, Alaina K

AU - Reddy-Luthmoodoo, Medini

AU - Huynh, Kevin

AU - Khan, Anmar A.

AU - Carey, Andrew L.

AU - van Hall, Gerrit

AU - Cobelli, Claudio

AU - Dalla-Man, Chiara

AU - Otvos, Jim D.

AU - Rye, Kerry-Anne

AU - Johansson, Jan Erik

AU - Gordon, Allan

AU - Wong, Norman C.W.

AU - Sviridov, Dmitri

AU - Barter, Philip J

AU - Duffy, Stephen J.

AU - Meikle, Peter J.

AU - Kingwell, Bronwyn A.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

KW - Clinical trial

KW - Glucose metabolism

KW - High-density lipoprotein

KW - Prediabetes

KW - Type 2 diabetes

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U2 - 10.1016/j.metabol.2016.03.002

DO - 10.1016/j.metabol.2016.03.002

M3 - Article

VL - 65

SP - 904

EP - 914

JO - Metabolism

JF - Metabolism

SN - 0026-0495

IS - 6

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