O106 Maximising the benefits of bariatric surgery through targeting ghrelin: a randomised, double-blind, placebo-controlled crossover study in people with suboptimal weight loss after bariatric surgery

Abstract

Abstract Introduction One in 5 people have a suboptimal weight-loss (WL) response to bariatric surgery. The causes are unclear, but patients report resumed hunger and increased food intake, eating behaviours driven by the orexigenic hormone, ghrelin. This proof-of-concept study aimed to evaluate the impact of reducing circulating acyl-ghrelin, the biologically active isoform, on appetite and energy intake in people with suboptimal WL and aberrant ghrelin profile after bariatric surgery. Methods Thirty-five patients with <20%WL from 12 months after Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) and aberrant circulating ghrelin profile underwent 10 days of treatment with a novel, highly-selective ghrelin o-acyltransferase inhibitor, GLWL-01, and placebo. The primary endpoint was within-person change in ad libitum energy intake during a test meal on day 10. Secondary endpoints assessed subjective appetite, food cravings, macronutrient intake, gut hormones, cardiometabolic profile and body composition. Ethical approval was obtained. Results Thirty-one participants (26 RYGB, 9 SG) completed both cycles. GLWL-01 produced a 58.9±27.2% decrease in fasting plasma acyl-ghrelin and 29.3±27.1% increase in desacyl-ghrelin after 10 days. Marked reduction in subjective hunger, food cravings and hedonic influence on appetite was observed with GLWL-01, however objective appetite measures – ad libitum and free-living energy intake – did not change. Circulating levels of cardiovascular risk-conferring lipoproteins significantly improved and no adverse impact on glycaemic control was observed. Conclusion Pharmacological modulation of the ghrelin system may be used as part of a personalised therapeutic approach to optimise clinical outcomes in patients with suboptimal WL after bariatric surgery. Take-home message This first-in-human mechanistic study shows that pharmacological modulation of the ghrelin system is a promising therapeutic strategy for maximising weight loss response to bariatric surgery.