The second of a Series of papers presented at the Annual Meeting of The European Association for the Study of Diabetes (EASD) in Milan, Italy (Sept 28 – Oct 2) and published in The Lancet Obstetrics, Gynaecology & Women's Health discusses the wide-ranging issues relating to use of GLP-1 RA drug use in women. The authors, that include Professor Paul Franks, Lund University, Helsingborg Hospital, Helsingborg, Sweden and Professor Claire Meek, Leicester Diabetes Research Centre and Leicester NIHR Biomedical Research Centre, Leicester, UK and colleagues, issue a call to action to improve the evidence based across the board for GLP-1 RA use in women worldwide.
The prevalence of obesity is estimated to be slightly higher in women than in men, and this difference varies according to socioeconomic status. A recent analysis by the Global Burden of Disease group estimated the global prevalence of overweight or obesity in 2021 to be 46·7% in females and 43·4% in males, with projections for 2050 reaching 60·3% and 57·4%, respectively. This gender gap is more pronounced in low- and middle-income countries (LMICs) (with the bigger gap in sub-Saharan Africa and south Asia), whereas men in high-income countries can have higher prevalence rates. This trend is likely to continue in the coming decades and relates to socioeconomic inequalities, highlighting how broader social barriers disproportionately affect women in many regions of the world.
Weight loss with GLP-1 RAs is greater in women than in men, yet improvements in blood sugar control are comparable. The increased weight-loss efficacy observed in women could be attributable to several mechanisms. Higher systemic drug exposure has been observed in women, even after adjustment for body mass. Women treated with GLP-1 RAs can also experience enhanced suppression of food-motivated behaviours and increased inhibition of palatable food intake. Pre-clinical have highlighted possible interactions between GLP-1 signalling and oestrogen.
Real-world studies comparing adverse event rates between women and men treated with these medications have shown a higher overall frequency of reported side-effects in women, including increased rates of headache, vomiting, and dizziness, even though placebo-controlled trials suggest similar rates in both sexes. Thus more studies are needed to quantify the side-effect profiles in women and develop mitigation strategies. And it is well established that weight gain can be rapid after stopping GLP-1 RA medications. Gaining fat without gaining extra muscle raises concerns for longer-term health and physical function in women, and needs more research to ensure these powerful medications support good wellbeing for women long-term.
Trial data to date support the overall psychiatric safety profile of GLP-1 receptor agonists while reinforcing the importance of individualised risk assessment. Careful and routine screening for depression, anxiety, and eating disorders before treatment initiation and during follow-up is recommended (in both sexes).
Despite independent manufacturing estimates estimating that, for example, semaglutide could be manufactured for below $1 per month supply (oral) and $5 per month (injections), recent analyses across 99 countries indicate that nearly 80% of adults who meet clinical eligibility criteria for GLP-1 receptor agonists live in LMICs, where access remains minimal. In many of these settings, retail prices exceed $90 per month, placing treatment beyond the reach of women who rely on publicly funded care or out-of-pocket payments.
The paper covers multiple areas where GLP-1 RAs impact women's health and the need for more research in all of them. One example is many women with type 2 diabetes from LMICs are lean, and the BMI threshold at which type 2 diabetes starts to develop is often lower than for those of European ancestry – thus the effects of significant weight loss could have a more pronounced impact in these women. Polyendocrine metabolic ovarian syndrome (PMOS; formerly polycystic ovary syndrome) affects around 12% of women worldwide, with rates highest in the eastern Mediterranean region and south-east Asia. Despite weight loss leading to various improvements in health status in women with PMOS, GLP-1 RAs are not generally available or centrally funded for use in PMOS in most health-care systems.
The authors conclude extensive research on GLP-1 RA use in women is needed across various domains: mental health and eating disorders; contraception, fertility, and polyendocrine metabolic ovarian syndrome; optimising pre-pregnancy health; preventing complications; safety during pregnancy and breastfeeding; optimising health and body composition during menopause; optimising cardiovascular health and preventing multimorbidity; and frailty and healthy ageing.
In their call to action, the authors say:
• Women face the highest burden of obesity and its related complications, and should have access to high-quality, equitable, multidisciplinary obesity care worldwide
• Sex-stratified and ethnicity-stratified reporting of clinical trials related to GLP-1 receptor agonist use should be mandatory to facilitate future meta-analyses
• As the main users of GLP-1 receptor agonists and incretin-based therapies, women's care should be guided by high-quality studies assessing their treatment's efficacy and safety, specifically in conditions affecting women (eg, before, during, and after pregnancy)
• Existing access pathways to GLP-1 receptor agonists disadvantage women—to maximise the treatment's benefits, companies, health-care funders, research funders, insurers, and policy makers should promote equitable access to high-quality, genuine GLP-1 RAs for women worldwide
The authors conclude: "Tackling the global challenges in access to GLP-1 receptor agonists provides substantial opportunities to improve women's health internationally. However, achieving equitable access will require coordinated action to strengthen supply chains, enhance regulatory vigilance against falsified and compounded products, and embrace innovative therapies – such as oral agents – that are stable, scalable, and potentially more affordable…Advancing women-centred obesity care demands targeted research, including trials inclusive of diverse ethnic groups, women of reproductive age, and LMIC populations, alongside women-focused cost-effectiveness and implementation studies."
