The Effectiveness of Antidiabetic Drugs in Treating Dementia: A Peek into Pharmacological and Pharmacokinetic Properties

Abstract

Dementia dramatically affects the activities of daily living and quality of life; thus, many therapeutic approaches for overcoming dementia have been developed. However, an effective treatment regimen is yet to be developed. As diabetes is a well-known risk factor for dementia, drug repositioning and repurposing of antidiabetic drugs are expected to be effective dementia treatments. Several observational studies have been useful for understanding the effectiveness of antidiabetic drugs in treating dementia, but it is difficult to conclusively analyze the association between antidiabetic drug treatment and the risk of developing dementia after correcting for potential confounding factors. Mechanism-based approaches may provide a better understanding of the effectiveness of antidiabetic drugs for treating dementia. Since the peripheral circulation and the central nerve system are separated by the blood–brain barrier, it is important to understand the regulation of the central glucose metabolism. In this review, we discuss the pharmacological and pharmacokinetic properties of antidiabetic drugs in relation to treating dementia.

Thiazolidinedione use is associated with reduced risk of dementia in patients with type 2 diabetes mellitus: A retrospective cohort study

“…A large number of preclinical studies in vivo and in vitro have demonstrated the potential protective effects of TZDs on dementia. TZDs can penetrate the blood–brain barrier, especially pioglitazone 8 . They can activate PPAR‐γ, which are expressed in various regions of the brain, regulating a range of activities that positively influence the pathology of Alzheimer's disease, including reducing insulin resistance, inhibiting inflammation, improving mitochondrial function, and reducing tau and amyloid pathology 9,30,31 .…”

“…A recent large‐scale cohort study conducted in Korea found that in T2DM patients receiving metformin‐based dual oral therapy, use of metformin + TZDs and sulfonylureas + TZDs could significantly reduce the risk of all‐cause dementia by 20% and 4% respectively compared with use of metformin + sulfonylureas 33 . Variation in the magnitude of HRs could be due to different comparators, as some evidence indicated that metformin and sulfonylurea might also have effects on dementia risk 8,34 . Lu et al applied a matching strategy to investigate the use of antidiabetic drugs and dementia risk in the Chinese population living in Taiwan 31 .…”

“…AGIs were chosen as the comparator because TZDs and AGIs are two classes of second‐line oral glucose lowering agents commonly used at the same stage of T2DM in China 23 . AGIs (mainly acarbose) are poorly absorbed after oral administration 8 . They work mainly in the small intestine to delay carbohydrate absorption by competitively inhibiting enzymes that convert complex nonabsorbable carbohydrates into simple absorbable carbohydrates 24 .…”

“…They work mainly in the small intestine to delay carbohydrate absorption by competitively inhibiting enzymes that convert complex nonabsorbable carbohydrates into simple absorbable carbohydrates 24 . Therefore, AGIs do not exert pharmacological effects in the body and cannot cross the blood–brain barrier to reach the brain 8 . New use of TZDs or AGIs was defined as the first prescription of a drug from either class, with no fill of TZDs and AGIs in a baseline washout period of 6 months.…”

“…Growing evidence from epidemiological and preclinical studies has suggested that T2DM and dementia share many similar pathological mechanisms, 5 among which insulin resistance and resulting hyperinsulinemia are two main characteristics of T2DM, contributing to a higher risk of dementia in elderly people 5 . In view of their common pathogenesis, and given the lack of effective treatment for dementia, repositioning and repurposing antidiabetic drugs for preventing or treating dementia have attracted accumulating attention in recent years 6–8 …”