Safety and tolerability of liraglutide 3.0 mg in overweight and obese adults: the SCALE obesity and prediabetes randomised trial

Background and aims: The primary objective of this trial was to investigate the efficacy of the GLP‐1 receptor agonist (RA) liraglutide 3.0 mg, as adjunct to diet and exercise, for weight management. Key safety and tolerability data are presented. Materials and methods: Individuals (BMI >27 kg/m2 with >1 comorbidity or >30 kg/m2) were advised on a 500 kcal/day deficit diet and exercise programme and randomised 2:1 to once daily sc liraglutide 3.0 mg (n=2487) or placebo (n=1244). Certain event types (deaths, select CV disorders, pancreatitis, neoplasms, thyroid disorders requiring thyroidectomy) underwent blind independent assessment. Results: Baseline characteristics: age 45.1 years, 78.5% female, body weight 106.2 kg, BMI 38.3 kg/m2. Liraglutide 3.0 mg induced greater weight loss (primary endpoint; 8.0%) vs placebo (2.6%) after 56 weeks (estimated treatment difference [ETD] ‐5.4%; p1% of individuals. 3 deaths occurred: liraglutide 3.0 mg (n=1) vs placebo (n=2) (1 CV‐related death in each group). Liraglutide treatment was not associated with increased risk of depression or suicidality. Gallbladder‐related AEs were more common with liraglutide 3.0 mg vs placebo (2.5% vs 1.0%), due to more events of 'cholelithiasis' and 'cholecystitis'. The frequency of pancreatitis was higher with liraglutide (0.3%) vs placebo (0.1%). 1 individual per group co‐reported gallbladder‐related AEs and pancreatitis. An increase in mean serum lipase activity was seen with liraglutide, but few individuals (2.5% vs 1.1% with placebo) had levels >3 times the UNR. Most elevations were transient and not predictive of pancreatitis. Liraglutide reduced mean SBP and DBP vs placebo at week 56 (ETD ‐2.8 and ‐0.9 mmHg, p2 consecutive visits occurred in 5.1% vs 1.4% of individuals, respectively. CV events were similar with liraglutide (8.7%) vs placebo (9.9%). There were no cases of medullary thyroid carcinoma or C‐cell hyperplasia and liraglutide did not increase calcitonin. Injection site reaction rates were 22.4 and 14.9 events/100 patient years of exposure (PYE) with liraglutide and placebo, respectively, with similar allergic reaction rates between treatments (2.6 and 3.2 events/100 PYE). Conclusion: The safety profile of liraglutide 3.0 mg was consistent overall with the known effects of a GLP‐1RA. The clinical significance of the imbalance in gallbladder and pancreatitis events is currently unknown.