GLP-1 and Its Analogs: Does Sex Matter?

Abstract

While obesity and diabetes are prevalent in both men and women, some aspects of these diseases differ by sex. A new blockbuster class of therapeutics, glucagon-like peptide 1 (GLP-1) analogs (eg, semaglutide), shows promise at curbing both diseases. This review addresses the topic of sex differences in the endogenous and therapeutic actions of GLP-1 and its analogs. Work on sex differences in human studies and animal research is reviewed. Preclinical data on the mechanisms of potential sex differences in the endogenous GLP-1 system as well as the therapeutic effect of GLP-1 analogs, focusing on the effects of the drugs on the brain and behavior relating to appetite and metabolism, are highlighted. Moreover, recent clinical evidence of sex differences in the therapeutic effects of GLP-1 analogs in obesity, diabetes, and cardiovascular disease are discussed. Lastly, we review evidence for the role of GLP-1 analogs in mood and reproductive function, with particular attention to sex differences. Overall, while we did not find evidence for many qualitative sex differences in the therapeutic effect of clinically approved GLP-1 analogs, a growing body of literature highlights quantitative sex differences in the response to GLP-1 and its analogs as well as an interaction of these therapeutics with estrogens. What also clearly emerges is the paucity of data in female animal models or women in very basic aspects of the science of GLP-1-gaps that should be urgently mended, given the growing popularity of these medications, especially in women.

Keywords: GLP-1; estrogens; exendin-4; obesity; semaglutide; sex differences.

Figure 1.

Overview of preclinical evidence for sex-specific effects of GLP-1 and GLP-1R activation and their interaction with estrogens. Created with biorender.com. Abbreviations: ARC, arcuate nucleus; DMH, dorsomedial hypothalamus; DRN, dorsal raphe nucleus; GLP-1, glucagon-like peptide 1; GLP-1R, glucagon-like peptide 1 receptor; Hipp, hippocampus; LC, locus coeruleus; LH, lateral hypothalamus; LS, lateral septum; NAc, nucleus accumbens; NTS, nucleus of the solitary tract; PBN, parabrachial nucleus; PPG, preproglucagon; PVN, paraventricular nucleus; PVT, paraventricular thalamus; SuM, supramammillary nucleus; VTA, ventral tegmental area.

Figure 2.

Overview of clinical evidence for sex-specific effects of glucagon-like peptide 1 analogs and their potential interaction with estrogens. Created with biorender.com.

Figure 3.

The expression of Gcg, the glucagon-like peptide 1 precursor gene, is similar in adult male and female rats in the brain's nucleus of the solitary tract as well as throughout the gastrointestinal tract. Tissue was obtained from adult male (n = 3-14) and female (n = 3-9) Sprague–Dawley rats. Gene expression was determined by RT-PCR, as described previously (33). Unpublished observations.