Sex Differences in Response to Treatment with Glucagon-like Peptide 1 Receptor Agonists: Opportunities for a Tailored Approach to Diabetes and Obesity Care

Abstract

The available data suggest differences in the course of type 2 diabetes mellitus (T2DM) between men and women, influenced by the distinguishing features of the sex. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a relatively new class of antidiabetic drugs that act by mimicking the function of endogenous glucagon-like peptide 1. They constitute valuable agents for the management of T2DM as, in addition to exerting a strong hypoglycemic action, they present cardiorenal protective properties, promote weight loss, and have a good safety profile, particularly with respect to the risk of hypoglycemia. Due to the precedent of studies having identified sexual dimorphic elements regarding the action of other antidiabetic agents, ongoing research has attempted to examine whether this is also the case for GLP-1 RAs. Until now, sex differences have been observed in the impact of GLP1-RAs on glycemic control, weight reduction, and frequency of adverse events. On the contrary, the question of whether these drugs differentially affect the two sexes with respect to cardiovascular risk and incidence of major adverse cardiovascular events remains under investigation. Knowledge of the potential sex-specific effects of these medications is extremely useful for the implementation of individualized therapeutic plans in the treatment of T2DM. This narrative review aims to present the available data regarding the sex-specific action of GLP-1 RAs as well as to discuss the potential pathophysiologic mechanisms explaining these dissimilarities.

The Potential of Semaglutide Once-Weekly in Patients Without Type 2 Diabetes with Weight Regain or Insufficient Weight Loss After Bariatric Surgery—a Retrospective Analysis

“…There is evidence that central GLP-1 effects could be modulated by sex steroids; e.g., female rats are more sensitive than males to the anorexigenic effect of a centrally administered GLP-1 receptor agonist. The anorexigenic effect of estrogen and modulation of GLP-1 activity could involve the ventral tegmental area (VTA) and the nucleus accumbens (NAc) [26,27]. Further studies are urgently needed to identify gender-related differences in efficacy and toxicity of GLP-1 RA in the pre-and post-bariatric population for a tailored approach to obesity management.…”

Factors associated with gastrointestinal side effects after liraglutide treatment for type 2 diabetes

“…Through mediation analysis, TSH had no mediating effect on sex and GISE, and possibly small sample size caused that. Some studies showed the apparent sex-specific differences in the frequency of GSEA partially attributed to higher exposures to liraglutide in females, possibly due to their lower average body weight ( 31 ) and the greater prevalence of functional GID among females ( 32 ). Therefore, it is necessary to take measures to prevent GSEA in women with type 2 diabetes treated with liraglutide.…”

Impact of Sex and Gender on Clinical Management of Patients with Advanced Chronic Liver Disease and Type 2 Diabetes

“…Conflicting data on gender differences in incretin-treated patients emerged from a study that considered data from two Korean national databases, where females were about twice as likely as males to report adverse events related to the use of GLP-1 RA, with a reporting ratio M/F of 2.34. Adverse events were predominantly gastrointestinal upset and headache (the latter with a hazard ratio of 7.97), and no significant difference was found between the two sexes in episodes of nocturnal hypoglycaemia [ 170 , 171 ]. Regarding the effects on HbA1c, gender did not prove to be a predictor of a more or less significant reduction, unlike what emerged in several previous studies.…”