AimsTreatment with liraglutide 3.0 mg has been associated with gallbladder‐related adverse events. To conduct a single‐centre, double‐blind, 12‐week trial comparing the effect of 0.6 mg liraglutide and steady‐state liraglutide 3.0 mg with placebo on gallbladder emptying in adults with body mass index (BMI) ≥27 kg/m2 and without diabetes.MethodsParticipants were randomized 1:1 to once‐daily subcutaneous liraglutide (n = 26) or placebo (n = 26), starting at 0.6 mg with 0.6‐mg weekly increments to 3.0 mg, with nutritional and physical activity counselling. A 600‐kcal (23.7 g fat) liquid meal test was performed at baseline, after the first dose and after 12 weeks. The primary endpoint was the 12‐week maximum postprandial gallbladder ejection fraction (GBEFmax), measured over 240 minutes after starting the meal.ResultsBaseline characteristics were similar between groups (mean ± SD overall age 47.6 ± 10.0 years, BMI 32.6 ±3.4 kg/m2, 50% women). Mean 12‐week GBEFmax (treatment difference −3.7%, 95% confidence interval [CI] −13.1, 5.7) and area under the GBEF curve in the first 60 minutes (−390% × min, 95% CI −919, 140) did not differ for liraglutide 3.0 mg (n = 23) vs placebo (n = 24). The median (range) time to GBEFmax was 151 (11‐240) minutes with liraglutide 3.0 mg and 77 (22‐212) minutes with placebo. Similar findings were noted after the first 0.6‐mg liraglutide dose. Gastrointestinal disorders, notably nausea and constipation, were the most frequently reported adverse events.ConclusionsTreatment with liraglutide did not affect the GBEFmax but appeared to prolong the time to GBEFmax.

Fatty acid amide hydrolase (FAAH) degrades 2 major classes of bioactive fatty acid amides, the N-acylethanolamines (NAEs) and N-acyl taurines (NATs), in central and peripheral tissues. A functional polymorphism in the human FAAH gene is linked to obesity and mice lacking FAAH show altered metabolic states, but whether these phenotypes are caused by elevations in NAEs or NATs is unknown. To overcome the problem of concurrent elevation of NAEs and NATs caused by genetic or pharmacological disruption of FAAH in vivo, we developed an engineered mouse model harboring a single-amino acid substitution in FAAH (S268D) that selectively disrupts NAT, but not NAE, hydrolytic activity. The FAAH-S268D mice accordingly show substantial elevations in NATs without alterations in NAE content, a unique metabolic profile that correlates with heightened insulin sensitivity and GLP-1 secretion. We also show that N-oleoyl taurine (C18:1 NAT), the most abundant NAT in human plasma, decreases food intake, improves glucose tolerance, and stimulates GPR119-dependent GLP-1 and glucagon secretion in mice. Together, these data suggest that NATs act as a class of lipid messengers that improve postprandial glucose regulation and may have potential as investigational metabolites to modify metabolic disease.

GLP-2 receptor activation in rodents acutely increases the volume of the gallbladder, which might explain the risk of gallbladder diseases associated with GLP-2RA treatment observed in humans. GLP-1RA-induced prolongation of human gallbladder refilling may explain the gallbladder events observed in GLP-1RA clinical trials.