Treatment of hypothalamic obesity with GLP-1 analogs

Introduction

Congenital and acquired damage to hypothalamic nuclei or neuronal circuits controlling satiety and energy expenditure results in hypothalamic obesity (HO). To date, successful weight loss and satiety has only been achieved in a limited number of affected patients across multiple drug trials. Glucagon-like peptide-1 (GLP-1) acts via central pathways that are independent from the hypothalamus to induce satiety. GLP-1 receptor agonists (GLP-1RAs) may provide an alternative approach to treating HO.

Methods

We performed a comprehensive search in Medline, Google Scholar, and clinical trials registries (ClinicalTrials.gov; clinicaltrialsregister.eur). This nonsystematic literature review was conducted to identify scientific papers published from January 2005 to February 2024 using the Pubmed and Embase databases. Key words used were GLP-1, GLP-1RA, hypothalamic obesity, suprasellar tumor, and craniopharyngioma.

Results

Our search identified 7 case studies, 5 case series, and 2 published clinical trials relating to the use of GLP-1RAs in HO. All case studies demonstrated weight loss and improved metabolic function. In contrast, results from case series were variable, with some showing no weight loss and others demonstrating moderate to significant weight loss and improved metabolic parameters. In the ECHO clinical trial, nearly half the subjects randomized to weekly exenatide showed reduced body mass index (BMI). Paradoxically, BMI reduction was greater in patients with more extensive hypothalamic injuries.

Conclusion

GLP-1RAs potentially offer a new approach to treating HO. There is a need to stratify patients who are more likely to respond. Further randomized controlled trials are required to determine their efficacy either in isolation or combined with other therapies.