A Randomized, Placebo-Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High-Density Lipoprotein Cholesterol in Subjects With Dyslipidemia

Clin Pharmacol Drug Dev. 2019 Oct;8(7):871-883. doi: 10.1002/cpdd.704. Epub 2019 Jul 3.


GPR109A (HM74A), a G-protein-coupled receptor, is hypothesized to mediate lipid and lipoprotein changes and dermal flushing associated with niacin administration. GSK256073 (8-chloro-3-pentyl-1H-purine-2,6[3H,7H]-dione) is a selective GPR109A agonist shown to suppress fatty acid levels and produce mild flushing in short-term clinical studies. This study evaluated the effects of GSK256073 on lipids in subjects with low high-density lipoprotein cholesterol (HDLc). Subjects (n = 80) were randomized (1:1:1:1) to receive GSK256073 5, 50, or 150 mg/day or matching placebo for 8 weeks. The primary end point was determining the GSK256073 exposure-response relationship for change from baseline in HDLc. No significant exposure response was observed between GSK256073 and HDLc levels. GSK256073 did not significantly alter HDLc levels versus placebo, but rather revealed a trend at the 150-mg dose for a nonsignificant decrease in HDLc (-6.31%; P = .12) and an increase in triglycerides (median, 24.4%; 95% confidence interval, 7.3%-41.6%). Flushing was reported in 21%, 25%, and 60% of subjects (5, 50, and 150 mg, respectively) versus 24% for placebo. Results indicated that selective activation of the GPR109A receptor with GSK256073 did not produce niacin-like lipid effects. These findings add to the increasing evidence that niacin-mediated lipoprotein changes occur predominantly via GPR109A-independent pathways.

Keywords: GPR109A; HDLc; HM74A; lipids; niacin.

Publication types

  • Adaptive Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cholesterol, HDL / analysis*
  • Drug Administration Routes
  • Dyslipidemias / drug therapy*
  • Dyslipidemias / metabolism
  • Female
  • Flushing / chemically induced*
  • Humans
  • Male
  • Middle Aged
  • Niacin / adverse effects
  • Receptors, G-Protein-Coupled / agonists
  • Treatment Outcome
  • Xanthines / administration & dosage*
  • Xanthines / adverse effects
  • Xanthines / pharmacology


  • 8-chloro-3-pentyl-1H-purine-2,6(3H,7H)-dione
  • Cholesterol, HDL
  • HCAR2 protein, human
  • Receptors, G-Protein-Coupled
  • Xanthines
  • Niacin