Dementia risk heightened after stopping metformin treatment

Metformin treatment discontinuation has been found to lead to increased incidence of dementia among older adults, and this association cannot be explained by changes in glucose control or insulin use.

In a large study, early metformin terminators had a 21-percent greater risk of dementia compared with routine users (hazard ratio, 1.21, 95 percent confidence interval [CI], 1.12–1.30). [JAMA Netw Open  2023;6:e2339723]

Mediation analysis showed that the acceleration of dementia diagnosis that can be explained by changes in HbA1c levels or insulin use was small, ranging from 0 years (95 percent CI, −0.02 to 0.02 years) for the change in insulin use at 5 years post-termination to 0.07 years (95 percent CI, 0.02–0.13 years) for the change in HbA1c levels at 1 year post-termination.

The findings, according to the investigators, are consistent with evidence from other observational studies showing an association between metformin use and lower dementia incidence. [J Alzheimers Dis 2018;65:1225-1236; J Gerontol A Biol Sci Med Sci 2014;69:1299-1305]

Gastrointestinal adverse events

Individuals with type 2 diabetes are already at increased risk of dementia. In turn, metformin treatment not only reduces the incidence of diabetes complications and diabetes-related and all-cause mortality but also the risk of dementia by improving glucose control or by mechanisms unrelated to diabetes, such as activation of adenosine monophosphate–activated protein kinase (which can imitate starvation) or by inhibition of aromatase (which may be linked to lower blood pressure). [Ann Intern Med 2014;160:517-525; J Diabetes Investig 2013;4:640-650; Lancet 1998;352:854-865; Hypertension 2016;68:446-454]

Among metformin users, however, gastrointestinal adverse effects are one of the culprits for medication cessation. These events have been associated with poor medication adherence, leading to some users switching to other glucose-lowering agents. [Diabetes Care 2012;35:731-737; J Res Pharm Pract 2017;6:73-76; Patient Prefer Adherence 2019;13:1433-1441; BMJ Open 2018;8:e021505]

For people with kidney disfunction, metformin may also be discontinued due to it being associated with increased mortality. Current guidelines recommend stopping metformin when the estimated glomerular filtration rate (eGFR) drops below 30 or 45 mL/min/1.73 m² of height, depending on benefits and risks of continued use. [Patient Prefer Adherence 2019;13:1433-1441; Lancet Diabetes Endocrinol 2015;3:605-614; JAMA 2014;312:2668-2675; J Pharm Technol 2018;34:28-36]

The present study may have potential implications for diabetes treatment in late life, according to the investigators.

“For individuals with diabetes at particularly high risk of dementia, such as carriers of APOE ε4 or individuals with a family history of dementia, it may be particularly beneficial to find ways to manage or mitigate gastrointestinal adverse effects (eg, switching to slower-release formulations of metformin or taking the medication with food in the evening) instead of replacing metformin with other agents given that participants in this study remained on antidiabetes drugs after early termination with metformin,” they pointed out.

Next steps

The study included a large cohort of metformin users without a history of kidney disease at metformin initiation: 12,220 were early metformin terminators (mean age at index prescription 59.4 years, 46.2 percent women, 62.7 percent White) and 29,126 were routine users (mean age at index prescription 61.1 years, 46.6 percent women, 62.8 percent White).

“Formally evaluating the heterogeneity of the metformin estimate across known risk factors for dementia is an important extension of our work. Given considerable interest in drug repurposing for dementia, further confirmatory work would be required to extrapolate to prediabetic or nondiabetic populations,” the investigators said.