Metformin: Sex/Gender Differences in Its Uses and Effects—Narrative Review

Ilias, Ιoannis; Rizzo, Manfredi; Zabulienė, Lina

doi:10.3390/medicina58030430

Cited by 20 publications

(14 citation statements)

References 151 publications

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“…It is also prescribed for children aged at least 10 years. The pharmacokinetics of metformin have been reported to be similar in women and men, considering the weight differences between the sexes [ 76 ].…”

Section: Resultsmentioning

confidence: 99%

View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences

Froldi

2024

Pharmaceuticals

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Metformin is a synthetic biguanide used as an antidiabetic drug in type 2 diabetes mellitus, achieved by studying the bioactive metabolites of Galega officinalis L. It is also used off-label for various other diseases, such as subclinical diabetes, obesity, polycystic ovary syndrome, etc. In addition, metformin is proposed as an add-on therapy for several conditions, including autoimmune diseases, neurodegenerative diseases, and cancer. Although metformin has been used for many decades, it is still the subject of many pharmacodynamic and pharmacokinetic studies in light of its extensive use. Metformin acts at the mitochondrial level by inhibiting the respiratory chain, thus increasing the AMP/ATP ratio and, subsequently, activating the AMP-activated protein kinase. However, several other mechanisms have been proposed, including binding to presenilin enhancer 2, increasing GLP1 release, and modification of microRNA expression. Regarding its pharmacokinetics, after oral administration, metformin is absorbed, distributed, and eliminated, mainly through the renal route, using transporters for cationic solutes, since it exists as an ionic molecule at physiological pH. In this review, particular consideration has been paid to literature data from the last 10 years, deepening the study of clinical trials inherent to new uses of metformin, the differences in effectiveness and safety observed between the sexes, and the unwanted side effects. For this last objective, metformin safety was also evaluated using both VigiBase and EudraVigilance, respectively, the WHO and European databases of the reported adverse drug reactions, to assess the extent of metformin side effects in real-life use.

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Section: Resultsmentioning

confidence: 99%

View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences

Froldi

2024

Pharmaceuticals

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“…Because even mild thyroid dysfunction affects lipid and glucose metabolism, 39 a significant proportion of undiagnosed patients with hypothyroidism may receive statin and/or metformin therapy. Compared with women, men are treated with metformin and statins more often and in higher doses 40,41 . However, extrapolation of the data obtained is possible only to this population, relatively often receiving metformin plus a statin, and cannot be extended to patients with more common variants of hypothyroidism, which is undoubtedly a limitation of our study.…”

Section: Discussionmentioning

confidence: 97%

“…Compared with women, men are treated with metformin and statins more often and in higher doses. 40,41 However, extrapolation of the data obtained is possible only to this population, relatively often receiving metformin plus a statin, and cannot be extended to patients with more common variants of hypothyroidism, which is undoubtedly a limitation of our study. In the study by Palui et al, 42 the rate of normalization of thyrotropin levels in response to metformin treatment was higher in patients with negative thyroid antibodies than in subjects with autoimmune thyroiditis.…”

Section: Discussionmentioning

confidence: 97%

Rosuvastatin potentiates the thyrotropin‐lowering effect of metformin in men with non‐autoimmune subclinical hypothyroidism and prediabetes

Krysiak

Kowalcze

2022

Clinical Pharmacy Therapeu

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What is known and objective: Metformin treatment decreases thyrotropin levels in individuals with hypothyroidism and this effect seems to be mediated by the 5 0adenosine monophosphate-activated protein kinase pathway in the pituitary. The activity of this pathway is also stimulated by statins. The current study was aimed at investigating whether the impact of metformin on hypothalamic-pituitary-thyroid axis activity is affected by statin use. Methods:The study included three matched groups of men with non-autoimmune hypothyroidism and prediabetes: patients treated for at least 6 months with highintensity rosuvastatin therapy (20-40 mg daily) [groups A (n = 24) and C (n = 19)] and men not receiving statin therapy [group B (n = 24)]. Over the entire study period (6 months), groups A and B received metformin (2.55-3 g daily). Moreover, groups A and C continued rosuvastatin therapy. The lipid profile, glucose homeostasis markers, and plasma concentrations of thyrotropin, total and free thyroid hormones, prolactin, FSH, LH, ACTH and insulin-like growth factor-1 were determined at baseline and 6 months later.

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“…Overall, there is a known paucity of clinical trial data regarding the study of disease and effects of medications on women (28). Further work is required to understand sex differences in the metabolism and effects of metformin in animal models and humans (29).…”

Section: Discussionmentioning

confidence: 99%

Metformin Protects Against Noise-Induced Hearing Loss in Male Mice

Kennedy,

Shuster,

Amanipour

et al. 2023

Otol Neurotol

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Hypothesis Metformin treatment will protect mice from noise-induced hearing loss (NIHL). Background We recently identified metformin as the top-ranking, Food and Drug Administration–approved drug to counter inner ear molecular changes induced by permanent threshold shift–inducing noise. This study is designed to functionally test metformin as a potential otoprotective drug against NIHL. Methods Male and female B6CBAF1/J mice were obtained at 7 to 8 weeks of age. A cohort of the females underwent ovariectomy to simulate menopause and eliminate the effect of ovarian-derived estrogens. At 10 weeks of age, mice underwent a permanent threshold shift–inducing noise exposure (102.5 or 105 dB SPL, 8–16 kHz, 2 h). Auditory brainstem response (ABR) thresholds were obtained at baseline, 24 h after noise exposure, and 1 week after noise exposure. Mice were administered metformin (200 mg/kg/d) or a saline control in their drinking water after the baseline ABR and for the remainder of the study. After the 1-week ABR, mice were euthanized and cochlear tissue was analyzed. Results Metformin treatment reduced the 1-week ABR threshold shift at 16 kHz (p < 0.01; d = 1.20) and 24 kHz (p < 0.01; d = 1.15) as well as outer hair cell loss in the 32–45.5 kHz range (p < 0.0001; d = 2.37) in male mice. In contrast, metformin treatment did not prevent hearing loss or outer hair cell loss in the intact or ovariectomized female mice. Conclusions Metformin exhibits sex-dependent efficacy as a therapeutic for NIHL. These data compel continued investigation into metformin's protective effects and demonstrate the importance of evaluating the therapeutic efficacy of drugs in subjects of both sexes.

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Metformin: Sex/Gender Differences in Its Uses and Effects—Narrative Review

Cited by 20 publications

References 151 publications

View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences

View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences

Rosuvastatin potentiates the thyrotropin‐lowering effect of metformin in men with non‐autoimmune subclinical hypothyroidism and prediabetes

Metformin Protects Against Noise-Induced Hearing Loss in Male Mice

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