Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study

Abstract

Type 2 diabetes (diabetes) is characterized by accelerated cognitive decline and higher dementia risk. Controversy exists regarding the impact of metformin, which is associated with both increased and decreased dementia rates. The objective of this study was to determine the association of metformin use with incident dementia and cognitive decline over 6 years in participants with diabetes compared with those not receiving metformin and those without diabetes. RESEARCH DESIGN AND METHODSA prospective observational study was conducted of N 5 1,037 community-dwelling older participants without dementia aged 70-90 years at baseline (the Sydney Memory and Ageing Study). Exclusion criteria were dementia, major neurological or psychiatric disease, or progressive malignancy. Neuropsychological testing measured cognitive function every 2 years; a battery of tests measured executive function, memory, attention/speed, language, and visuospatial function individually. These were used to determine the measure of global cognition. Incident dementia was ascertained by a multidisciplinary panel. Total brain, hippocampal, and parahippocampal volumes were measured by MRI at baseline and 2 years (n 5 526). Data were analyzed by linear mixed modeling, including the covariates of age, sex, education, BMI, heart disease, hypertension, stroke, smoking, and apolipoprotein E«4 carriage. RESULTSOf n 5 1,037, 123 had diabetes; 67 received metformin (DM1MF) and were demographically similar to those who did not (DM-noMF) and participants without diabetes (no-DM). DM1MF had significantly slower global cognition and executive function decline compared with DM-noMF. Incident dementia was significantly higher in DM-noMF compared with DM1MF (odds ratio 5.29 [95% CI 1.17-23.88]; P 5 0.05). CONCLUSIONSOlder people with diabetes receiving metformin have slower cognitive decline and lower dementia risk. Large randomized studies in people with and without diabetes will determine whether these associations can be attributed to metformin.

Sex differences in risk factors for cognitive decline and dementia, including death as a competing risk, in individuals with diabetes: Results from the ADVANCE trial

“…Increased HbA1c has been linked to diabetes-associated cognitive decrements, CD and dementia 6,12,33,34 ; However, when treatments for improving glycaemic control were considered in observational studies, there was an indication that some glucoselowering agents, such as metformin, 35 were associated with a lower risk of cognitive impairment and dementia. [35][36][37][38] Intervention studies, on the other hand, including our own results from the ADVANCE trial, 25 did not yield evidence for intensive glycaemic control ameliorating the risk of CD/dementia. 1,33,39 While the causative pathway between diabetes and dementia needs to be further determined, 40 a multifactorial pathogenesis has been suggested for CD and dementia in diabetes, involving abnormal insulin signalling, cerebrovascular injury and accelerated neurodegeneration, among many other putative biological mechanisms.…”

“…Increased HbA1c has been linked to diabetes‐associated cognitive decrements, CD and dementia 6,12,33,34 ; However, when treatments for improving glycaemic control were considered in observational studies, there was an indication that some glucose‐lowering agents, such as metformin, 35 were associated with a lower risk of cognitive impairment and dementia 35–38 . Intervention studies, on the other hand, including our own results from the ADVANCE trial, 25 did not yield evidence for intensive glycaemic control ameliorating the risk of CD/dementia 1,33,39 .…”

Metformin, Macrophage Dysfunction and Atherosclerosis

“…Metformin, as an oral biguanide hypoglycemic drug, is mainly used in the clinical therapy of T2DM and it has efficacy and safety as mono- and combination therapy with other anti-hyperglycemic medications ( 186 , 187 ). In addition to its protective role in diabetes-associated CVD and potentially CVD occurring in patients without diabetes, multiple other therapeutic effects of metformin have been recognized, including reducing the risk of dementia (improving cognitive impairment) ( 188 ), weight loss ( 189 ), anti-aging ( 190 , 191 ), suppressing air pollution damage (inhibiting inflammation and thrombosis) ( 107 ), improving PCOS ( 192 , 193 ), and reversing lung fibers ( 194 ), inhibiting hair loss ( 195 ), reducing the risk of death from kidney failure and kidney disease ( 196 , 197 ), and preventing and treating some cancers ( 198 – 201 ). Macrophages are distributed in the circulation and tissues and aggregate under a variety of pathological conditions and play an important role in many pathological processes by regulating inflammation, such as cardiovascular disease ( 202 ), obesity ( 203 ), T2DM ( 203 ), T2DM ( 203 ), cancer ( 204 ), aging ( 205 ) and dementia ( 206 ).…”

Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

“…Metformin is the first-line therapy for diabetes mellitus. In diabetic patients, metformin demonstrated a neuroprotective effect and reduced the risk of developing dementia [ 226 , 227 ]. One study of metformin involved non-diabetic, overweight (BMI over 25) populations with MCI.…”