Metformin may mitigate perils of dementia in older T2D patients

In the vulnerable old individuals with type 2 diabetes (T2D), metformin is neuroprotective, with a recent study reporting that the drug reduces the speed of cognitive decline and staves off the risk of developing dementia.

The decline in cognition and incident dementia rates was similar to that observed among individuals without diabetes, despite the higher burden of cardiovascular and dementia risk factors in those with diabetes, according to investigators from the University of New South Wales Sydney in Australia.

The analysis included 1,037 community-dwelling older participants aged 70–90 years from the Sydney Memory and Ageing Study. A total of 123 participants had T2D (12 percent), of which 67 had been receiving metformin either as a single medication or in combination with other drugs.

Metformin duration was >5 years in the majority, >10 years in one-quarter (24 percent), and <12 months in five participants. Those who did not receive the drug were treated by diet alone. Other glucose-lowering medications used were sulfonylureas, insulin, glitazones, and acarbose.

Over a follow-up of 6 years, the rate of decline in global cognition in the metformin group did not differ relative to the nondiabetic control group but was slower relative to the T2D group treated with other medications (p=0.032). The same was true for the rate of decline in executive function. [Diabetes Care 2020;doi:10.2337/dc20-0892]

Ninety-one participants developed dementia: 73 in the no-T2D group, eight in the no-metformin T2D group, and four in the metformin group. Multivariable Cox regression analysis revealed that the glucose-lowering drug conferred an 81-percent reduction in the risk of incident dementia (hazard ratio [HR], 0.19, 95 percent confidence interval, 0.04–0.85; p=0.030).

“The current study adds to the existing literature supporting that metformin may have neuroprotective effects,” with most epidemiological studies of patients with diabetes showing that the use of the drug was associated with lower dementia risk and better cognitive function, the investigators noted. [J Alzheimers Dis 2011;24:485-493; BioMed Res Int 2016;2016:7208429]

Indeed, in a cohort of older people (aged >65 years) with newly diagnosed diabetes, incident dementia rates at 5 years were lower by 35 percent among those prescribed metformin vs sulfonylureas. [Neurology 2017;89:1877-1885]

An AMPK activator that suppresses hepatic glucose production, increases insulin-mediated glucose uptake, and decreases fatty acid oxidation, metformin is used globally in the first-line treatment of T2D. The drug has been shown to advanced glycation end products, which facilitate tissue degeneration and contribute to the microvascular complications of hyperglycaemia in neural, renal, and vascular tissues. [N Engl J Med 2014;371:1547-1548; Horm Metab Res 2012;44:891-895]

How the glucose-lowering drug may protect against cognitive decline and subsequent dementia may involve its effect on neuronal survival via activation of the mammalian target of rapamycin pathway in the brain, namely suppressed tau phosphorylation and cerebral inflammation, the investigators explained. [Proc Natl Acad Sci 2010;107:2183021835]

“Randomized controlled studies are required to determine whether metformin may have a protective effect against dementia or cognitive decline, both in people with diabetes and, given [the drug’s] long safety record, older people without diabetes,” they added.