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

Abstract

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.