Metformin use in prediabetes: A review of evidence and a focus on metabolic features among peri‐menopausal women

Abstract The prevalence of prediabetes has more than doubled over the past two decades. Although hormones associated with the menstrual cycle may offer some protection against diabetes by enhancing insulin sensitivity and suppressing gluconeogenesis, the prevalence of diabetes among women remains high at 10.5%. Notably, among the perimenopausal population, the prevalence catches up to—and even surpasses—that of men starting from the 70–74 age group, according to the 2021 International Diabetes Federation (IDF) report. This narrative review examines the benefits and potential risks of metformin across diverse populations, with a particular emphasis on women in the perimenopausal phase. Metformin's interaction with hormonal regulation significantly influences both its therapeutic efficacy and long‐term side effect profile, contributing to sex‐specific differences in treatment response. Consequently, its effectiveness varies among women at different stages of menopause, potentially due to differential impacts on inflammatory markers and modulation of the hypothalamic–pituitary‐ovarian (HPO) and hypothalamic–pituitary‐thyroid (HPT) axes. Emerging evidence also highlights metformin's potential in managing conditions such as polycystic ovary syndrome (PCOS), breast tissue inflammation and endometrial disorders within this demographic. Given these potential and multifaceted benefits, this review highlights the need for further randomized controlled trials (RCTs) to investigate metformin's role among perimenopausal and menopausal women and to better understand how menopausal status may influence its efficacy. Plain language summary The number of people with prediabetes has more than doubled in the last 20 years. By 2021, about 720 million people worldwide were living with this condition, and that number is expected to reach 1 billion by 2045. While hormones that fluctuate with the menstrual cycle might help protect against diabetes, the overall rate of diabetes among women is still concerning, at 10.5%. For women going through menopause, the situation is even more serious. From the age of 70 to 74, the rates of diabetes in women surpass those in men. This may be because menopause reduces levels of protective hormones like estrogen and progesterone, which help guard against type 2 diabetes (T2D). Despite this growing issue, there hasn't been much research focused on prediabetes in women going through menopause and how the changes in hormones might affect treatment guidelines. To address this lack of information, our review focused on the use of metformin for women in the perimenopausal stage with prediabetes, aiming to help prevent them from developing T2D in the future. We gathered insights from recent clinical trials to summarize the benefits and risks of metformin for various groups, particularly perimenopausal women. Our findings indicate that metformin can be effective for managing prediabetes, although opinions vary. It's currently the only diabetes medication recommended for prediabetes by the American Diabetes Association (ADA), supported by significant studies like the Diabetes Prevention Program (DPP) and the Coronary Endothelial Dysfunction Multicentre Prospective Study (CODYCE study). Metformin's effectiveness seems to increase when combined with lifestyle changes, such as diet and exercise. Some challenges exist, though, like concerns that it might only work for those at a high risk of developing T2D, potential side effects, and the availability of other options, such as lifestyle adjustments or a new medication called tirzepatide. Still, many experts argue that metformin remains valuable because it allows for early intervention, particularly when lifestyle changes alone may not be enough. We also found that metformin might work differently for men and women due to variations in hormone interactions, differing gut bacteria, and weight‐related factors that can influence its effectiveness. Interestingly, metformin seems to work better for women who have not yet gone through menopause. This might be because it helps with weight loss and reduces inflammation, which are important for postmenopausal health. Moreover, metformin has shown promise in addressing other health issues that postmenopausal women may face, such as inflammation in breast tissue, certain types of cancer, endometrial problems (as an alternative to hormone therapy), and polycystic ovarian syndrome (PCOS). In conclusion, our review stresses the importance of creating specific guidelines for managing prediabetes (e.g., metformin therapy) in the perimenopausal population. Understanding how sex hormones interact with blood sugar control is crucial for developing effective treatments tailored to women at different stages of menopause.