Gender differences in the response to GLP-1 RA therapies

Elisabetta Brun, Chiara Giuliani, Anna Bogazzi, Maria Rosaria Cristofaro, Annalisa Giancaterini, Annalisa Giandalia, Riccardo Candido, Graziano Di Cianni, Salvatore De Cosmo, Patrizia Ruggeri, Angela Napoli, ‘Gender Medicine’ Strategic Group of the Italian AMD

Abstract. Introduction. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) have become firmly established in the treatment of obesity and type 2 diabetes. However, the potential applications of GLP-1 RAs extend across the entire spectrum of endocrinology and metabolism. Despite the growing focus on gender medicine, there is limited evidence regarding differences in the response to GLP-1 RA therapies between females and males. Objective and rationale. The purpose of this review is to provide a comprehensive overview of the role of GLP-1 RAs in both sexes and to address a therapeutic perspective supported by findings in the literature. Research methods. We conducted a systematic search of online databases (PubMed, Cochrane, Embase, Scopus, Google), updated until December 2024. The search incorporated terms such as glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor, GLP-1 receptor agonist (GLP-1 RA), and incretins, along with terms related to the male and female sexes. We identified 138 potential references. After screening were selected as relevant to the present topic: 3 meta-analyses, 20 narrative and systematic reviews, 22 observational studies and 15 case reports (included due of scarcity of data), all published in international journals. Results. Although evidence is limited, the effectiveness of GLP-1 RAs in obesity and diabetes appears to be greater in females than in males, partly due to greater bioavailability and potentially greater side effects. Additionally, better therapeutic adherence to GLP-1 RAs is observed in females, in contrast to what is reported for other drugs, such as statins and antihypertensives. Among the pleiotropic effects of GLP-1 RAs, the following appear particularly important: 1. reducing dementia, especially in females (evidence Ia); 2. reducing hepatosteatosis (evidence Ia); 3. improving fertility in both females and males (evidence IIb); 4. reducing osteoporosis (evidence IIb); 5. strengthening the immune system in both sexes (evidence IIb).