Sex Differences in Adverse Drug Reactions of Metformin: A Longitudinal Survey Study

Abstract

Introduction In general, women more often experience metformin-associated adverse drug reactions (ADRs) than men. Objectives We aimed to assess whether sex differences in reported ADRs for metformin are observed at different times after initiation, and to explore their concurrence with sex differences in the dose of metformin over time. This may guide future studies in assessing the involved mechanisms of sex differences in metformin-associated ADRs and may guide sex-specific management of ADRs in clinical practice. Methods This study has a longitudinal design using data about patients initiating metformin collected by the Dutch National Pharmacovigilance Center Lareb through their Intensive Monitoring program. Patients were asked to complete a web-based questionnaire six times after initiation (i.e., at 2 weeks, 6 weeks and at 3, 6, 9, and 12 months). The outcome variables were the proportion of patients reporting any ADR (primary) and the dose of metformin (secondary). Sex differences in the proportions of ADRs and in the dose were tested at each assessment using Pearson Chi-Squared tests and Wilcoxon rank-sum tests, respectively. Using Bonferroni adjustment for multiple testing, a p value < 0.01 was considered statistically significant. Results The number of included patients was 1712 (40.9% women). Women reported an ADR more often than men, which was statistically significant at the assessment at 2 weeks (34% vs 25%, p < 0.001), and 6 weeks (37% vs 28%, p = 0.001) after initiation. In general, women were reported to be prescribed a lower dose than men, which became statistically significant at the 9-month assessment (p < 0.01). Conclusions Sex differences in reported ADRs were seen in the first weeks after metformin initiation, whereas statistically significant differences in self-reported prescribed dosing were observed after several months. Patients, in particular women, might benefit from being prescribed lower metformin doses at treatment initiation.

Sex-Specific Association of Endogenous PCSK9 With Memory Function in Elderly Subjects at High Cardiovascular Risk

“…Endogenous PCSK9 levels ( p = 0.005), total cholesterol ( p < 0.001), HDL ( p = 0.001), and LDL ( p = 0.001), circulating leptin ( p = 0.038) were higher in female ( Table 1 ). Women were less treated with metformin ( p = 0.044), in line with the literature reporting a higher risk of adverse drug reactions, and possible drug discontinuation, with metformin in women (de Vries et al, 2020 ) and were more frequently treated with β-blockers ( p = 0.028), consistently with a recent cohort study (Walli-Attaei et al, 2020 ). Male had higher executive function, short-term memory, and praxic and mental representation skills, as reflected by TMT-A z-score ( p = 0.047), FDS z-score ( p = 0.005), and CDT z-score (0.016) ( Table 1 ).…”

Gender differences in adverse event reports associated with antidiabetic drugs

“…Gastrointestinal complaints such as diarrhea, nausea, and abdominal discomfort symptoms were common in metformin which is the first choice for diabetes with the highest volume of prescriptions. In a recent study using Dutch Pharmacovigilance data, female metformin users reported more common gastrointestinal side effects than men, with the greatest difference in nausea reporting rates (8.1% vs. 23.5%) 14 . GLP1-RA is another class strongly associated with the risk of gastrointestinal events, but whether it is gender-dependent is unknown 19 .…”

“…Regarding antidiabetic drugs, studies on the gender difference in AEs are rare, and even in clinical trials, the impact of gender was not usually assessed. Meanwhile, unfavorable results for women such as a more adverse cardiovascular disease risk profile, a higher likelihood of failing treatment goals, and more reported AEs after metformin treatment, than men, were occasionally demonstrated 11 – 14 . While two studies encompass the entire range of drugs to assess gender differences in AE reporting, they were not focused on antidiabetic class 7 , 8 .…”

A Systematic Review of Antiaging Effects of 23 Traditional Chinese Medicines

“…Aspirin and metformin are commonly used synthetic antiaging drugs [ 13 , 14 ], but these drugs also have significant side effects. Aspirin causes antiplatelet aggregation, and long-term use can easily cause bleeding, and patients taking metformin will have diarrhea, nausea, abdominal discomfort, and other adverse reactions [ 15 , 16 ]. The discovery and development of antiaging drugs is difficult, and the progress is slow.…”