Metformin and the risk of dementia based on an analysis of 396,332 participants

Abstract

Background: AMPK has attracted widespread interest as a potential therapeutic target for age-related diseases, given its key role in controlling energy homeostasis. Metformin (Met) has historically been used to treat Type 2 diabetes and has been shown to counteract age-related diseases. However, studies regarding the relationship between Met and a variety of age-related classifications of cognitive decline have reported mixed findings. Objective: To assess the potential effect of Met on the onset of dementia and discuss the possible biological mechanisms involved. Methods: This study was registered in the PROSPERO database (CRD420201251468). PubMed, Embase, and Cochrane Library were searched from inception to 25 May 2021, for population-based cohort studies. Effect estimates with 95% confidence intervals (CIs) were pooled using the random-effects model. Meta-regression and subgroup analyses were performed to explore sources of heterogeneity and the stability of the results. Results: Fourteen population-based cohort studies (17 individual comparisons) involving 396,332 participants were identified. Meta-analysis showed that Met exposure was significantly associated with reduced risk of all subtypes of dementias [relative risk (RR) = 0.79, 95% CI = 0.68–0.91; p < 0.001]. Conversely, no significant reduction in risk was observed for those who received Met monotherapy at the onset of vascular dementia (VD), Parkinson’s disease (PD), and Alzheimer’s disease (AD). The effect was more prominent in patients who had long-term Met exposure (⩾4 years) (RR = 0.38, 95% CI = 0.32–0.46; p < 0.001), while no such significant effect was found with short-term Met exposure (1–2 years) (RR = 1.20, 95% CI = 0.87–1.66; p < 0.001). Moreover, no association was observed for Met exposure in participants of European descent (RR = 1.01, 95% CI = 0.66–1.54; p = 0.003) compared with those from other countries. Conclusion: Based on the evidence from population-based cohort studies, our findings suggest that the AMPK activator, Met, is a potential geroprotective agent for dementias, particularly among long-term Met users. Due to the significant heterogeneity among the included studies, we should interpret the results with caution.

Heterogeneous treatment effects of metformin on risk of dementia in patients with type 2 diabetes: A longitudinal observational study

“…Our findings were in line with previous studies indicating that metformin conferred a protective effect against dementia in people with T2D. 13,14,16,17,39 For instance, one national cohort study involving 210,237 showed that new users of metformin had a reduced risk of dementia compared to non-users, with an adjusted hazard ratio (HR) of 0.88 (95% CI, 0.84 −0.92). 16 Another retrospective cohort study involving 28,640 older veterans with T2D showed that metformin initiators had a lower risk of dementia than new users of sulfonylureas over an average follow-up of 5 years (HR, 0.89; 95% CI, 0.79 −0.99).…”

“…Our findings were in line with previous studies indicating that metformin conferred a protective effect against dementia in people with T2D 13,14,16,17,39 . For instance, one national cohort study involving 210,237 showed that new users of metformin had a reduced risk of dementia compared to non‐users, with an adjusted hazard ratio (HR) of 0.88 (95% CI, 0.84 −0.92) 16 .…”

“…[13][14][15] While some studies found a lower risk of dementia associated with metformin, 13,14,16 not all studies supported this finding. 15 A recent meta-analysis of 14 population-based cohort studies showed that metformin was significantly associated with a reduced risk of all-cause dementia, but with statistically significant heterogeneity between studies (P < 0.001), 17 indicating that certain individuals or subgroups may experience varying treatment effects from metformin. Although some studies have conducted subgroup analyses, such conventional "one-variable-at-a-time" subgroup analysis is susceptible to erroneous inferences and has limited ability to address intricate interactions among multiple patient characteristics that are believed to influence a patient's response to the treatment.…”

Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta‐analysis

“…5‐6). Of the 100 included reviews, 32 related diabetes to cognitive function in mixed diabetic populations, 2,6,8,26–54 seven examined the effect of type 1 diabetes, 3,55–60 19 focused on type 2 diabetes, 5,7,61–77 14 observed brain structure in diabetes, 1,4,78–89 two examined genetic and other biomarkers of dementia 90,91 and 26 focused on cognitive effects of antidiabetic treatment 14,15,20–22,92–112 . Of the 27 studies included in the meta‐analyses, 15 related metformin use to risk of dementia, 113–127 10 were used in the thiazolidinedione meta‐analysis, 113,122–130 four for pioglitazone, 126,129–131 seven for DPP‐4is, 123,125–127,132–134 five for α‐glucosidase inhibitors, 123,126,127,129,135 two for meglitinides, 126,129 seven for insulin, 122,123,125,127,129,136,137 11 for sulphonylureas,…”

Bioequivalence and Safety Assessment of 2 Formulations of Low‐Dose Metformin Hydrochloride under Fasting Conditions in Healthy Chinese Participants: A Randomized Phase 1 Clinical Trial

“…1,2 The incidence and prevalence of type 2 diabetes mellitus are high, particularly in developing countries such as China, 3 therefore the development of generic metformin hydrochloride (MH) tablets is urgently needed to fill the market gap created by the high demand for original metformin sustained-release tablets for patients with type 2 diabetes. 4,5 Recently, a growing number of studies have suggested benefits of the off-label use of metformin in different conditions, 6 such as the promotion of successful pregnancy in patients with polycystic ovarian syndrome with infertility due to anovulation, 7 weight loss, [8][9][10] cardiovascular protection, 11,12 breast and colorectal cancer, 13,14 glioblastoma, 15,16 amelioration of inflammation, 17,18 as a potential geroprotective agent for dementia, 19,20 and stimulation of hair growth. 21,22 These additional benefits of the off-label use of metformin exacerbate the mismatch between the supply and demand for the original drug.…”