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Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial
Author(s) -
Denison H.,
Nilsson C.,
Löfgren L.,
Himmelmann A.,
Mårtensson G.,
Knutsson M.,
ALShurbaji A.,
Tornqvist H.,
Eriksson J. W.
Publication year - 2014
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12221
Subject(s) - postprandial , medicine , gastric emptying , peptide yy , endocrinology , tolerability , placebo , weight loss , glucagon like peptide 1 , hormone , pharmacology , diabetes mellitus , insulin , type 2 diabetes , obesity , adverse effect , neuropeptide , stomach , neuropeptide y receptor , receptor , alternative medicine , pathology
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.