title: Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial.
abstract: OBJECTIVE
  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.
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Denison
authors.forename: C
authors.initials: C
authors.lastname: Nilsson
authors.forename: L
authors.initials: L
authors.lastname: Löfgren
authors.forename: A
authors.initials: A
authors.lastname: Himmelmann
authors.forename: G
authors.initials: G
authors.lastname: Mårtensson
authors.forename: M
authors.initials: M
authors.lastname: Knutsson
authors.forename: A
authors.initials: A
authors.lastname: Al-Shurbaji
authors.forename: H
authors.initials: H
authors.lastname: Tornqvist
authors.forename: J W
authors.initials: JW
authors.lastname: Eriksson
mesh_terms: D000085:Acetates / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D005746:Gastric Emptying / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000187:drug effects; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy*; D019894:Peptide YY / Q000187:drug effects; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000085:Acetates; D019440:Anti-Obesity Agents; D011719:Pyrazines; D019894:Peptide YY; C578442:AZD7687; D052216:Glucagon-Like Peptide 1; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase
keywords: diacylglycerol o-acyltransferase; diarrhoea; gastrointestinal hormones; lipid metabolism; triglycerides