Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial

Diabetes Obes Metab. 2014 Apr;16(4):334-43. doi: 10.1111/dom.12221. Epub 2013 Oct 31.


Aim: Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight or obese men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.

Methods: Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 h after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.

Results: Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at the end of treatment. With AZD7687 doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.

Conclusions: Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

Keywords: diacylglycerol o-acyltransferase; diarrhoea; gastrointestinal hormones; lipid metabolism; triglycerides.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / adverse effects
  • Acetates / therapeutic use*
  • Adult
  • Anti-Obesity Agents / adverse effects
  • Anti-Obesity Agents / therapeutic use*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
  • Diacylglycerol O-Acyltransferase / drug effects
  • Diarrhea / chemically induced*
  • Dose-Response Relationship, Drug
  • Gastric Emptying / drug effects
  • Glucagon-Like Peptide 1 / drug effects
  • Humans
  • Intestinal Absorption / drug effects
  • Male
  • Middle Aged
  • Obesity / drug therapy*
  • Peptide YY / drug effects
  • Pyrazines / adverse effects
  • Pyrazines / therapeutic use*
  • Treatment Outcome
  • Weight Loss / drug effects


  • Acetates
  • Anti-Obesity Agents
  • Pyrazines
  • Peptide YY
  • AZD7687
  • Glucagon-Like Peptide 1
  • DGAT1 protein, human
  • Diacylglycerol O-Acyltransferase