Newer glucose‐lowering drugs and risk of dementia: A systematic review and meta‐analysis of observational studies

Abstract

Background Preclinical studies have suggested potential beneficial effects of newer glucose‐lowering drugs (GLDs) including dipeptidyl peptidase (DPP)‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), and sodium glucose co‐transporter‐2 (SGLT2) inhibitors, in protecting humans against cognitive decline and dementia. However, population studies aiming to demonstrate such cognitive benefits from newer GLDs have produced mixed findings. This meta‐analysis aimed to evaluate the association between newer GLDs and risk of dementia in adults with type 2 diabetes (T2D). Methods Electronic databases were searched up to March 11, 2022 to include observational studies that examined the association between DPP‐4 inhibitors, GLP‐1RAs, and SGLT2 inhibitors and risk of dementia (including all‐cause dementia, Alzheimer's disease [AD], and vascular dementia [VD]) in people with T2D. We conducted a random‐effects meta‐analysis to calculate the relative risk (RR) with 95% confidence interval (CI) for each class of newer GLD. Results Ten studies (from nine articles) involving 819,511 individuals with T2D were included. Three studies found that SGLT2 inhibitor users had a lower risk of all‐cause dementia than non‐SGLT2 inhibitor users (RR, 0.62; 95% CI, 0.39–0.97). Five studies found that users versus nonusers of GLP‐1RAs were associated with a significant reduction in the risk of all‐cause dementia (RR, 0.72; 95% CI, 0.54–0.97). However, a meta‐analysis for AD and VD was unavailable for SGLT2 inhibitors and GLP‐1RAs because only one study was included for each drug. In seven studies, users vs. nonusers of DPP‐4 inhibitors were significantly associated with a decreased risk of all‐cause dementia (RR, 0.84; 95% CI, 0.74–0.94) and VD (RR, 0.59; 95% CI, 0.47–0.75) but not AD (RR, 0.82; 95% CI, 0.63–1.08). Conclusion Newer GLDs were associated with a decreased risk of all‐cause dementia in people with T2D. Because of the observational nature and significant heterogeneity between studies, the results should be interpreted with caution. Further research is warranted to confirm our findings.

Is it time to repurpose geroprotective diabetes medications for prevention of dementia?

“…22 Despite the observed connections between diabetes and dementia, none of the available diabetes medications have been repurposed to prevent or treat cognitive decline in dementia. Should findings by Tang et al 8 prompt the change in clinical practice toward tailoring individualized diabetes pharmacotherapy to reduce risk for dementia? Should we consider repurposing diabetes medications to prevent dementia even in people without diabetes?…”

“…Should we consider repurposing diabetes medications to prevent dementia even in people without diabetes? In the absence of RCTs adequately powered to assess cognitive outcomes, rigorously conducted observational studies and meta-analyses of observational data, such as the one by Tang et al, 8 remain a valuable hypothesis-generating resource. Reassuringly, these findings suggest that patients with diabetes are not harmed by newer glucose lowering drugs, and may in fact benefit F I G U R E 1 Postulated mechanisms by which newer diabetes medications with geroprotective properties may reduce incidence of dementia.…”

“…Given the strong epidemiologic and pathophysiologic connections between diabetes and dementia, it is not surprising that glucose‐lowering drugs have been of interest for the prevention of dementia. In the current issue of the Journal of the American Geriatrics Society, Tang and co‐authors 8 aimed to resolve inconsistencies in the existing observational data by performing a systematic review and a meta‐analysis to examine the associations between the use of dipeptidyl peptidase‐4 (DPP‐4) inhibitors, glucagon‐like peptide 1 receptor agonists (GLP‐1RAs) and sodium‐glucose co‐transporter 2 (SGLT2) inhibitors in people with T2D and the risk for incident all‐cause dementia, Alzheimer's disease and vascular dementia. Ten observational prospective studies that met the inclusion criteria for meta‐analysis encompassed more than 800,000 people with T2D (44% men), with a mean baseline age of 68 years and a median duration of follow‐up of 4.5 years.…”

“…Therefore, it is not surprising that GLP-1RAs were associated with a greater risk reduction for all-cause dementia than DPP-4 inhibitors. 8 GLP-1RAs and SGLT2 inhibitors, originally developed to lower blood glucose, have been found to exhibit powerful pleiotropic effects which can roughly be grouped into three inter-related categories (Figure 1): peripheral (metabolic), central (neuroprotective), and fundamental (geroprotective). First, GLP-1RAs and SGLT2 inhibitors, beyond glucose lowering, ameliorate peripheral diabetes-related metabolic risk factors implicated in the pathogenesis of dementia, including obesity, hypertension, endothelial dysfunction, inflammation, and peripheral insulin resistance.…”

“…It should be noted that the beneficial effects of DPP4‐inhibitors are attributed to an increase in endogenous GLP‐1 availability; GLP‐1RAs are more effective at the activation of GLP‐1 receptors than the endogenous GLP‐1. Therefore, it is not surprising that GLP‐1RAs were associated with a greater risk reduction for all‐cause dementia than DPP‐4 inhibitors 8 . GLP‐1RAs and SGLT2 inhibitors, originally developed to lower blood glucose, have been found to exhibit powerful pleiotropic effects which can roughly be grouped into three inter‐related categories (Figure 1): peripheral (metabolic), central (neuroprotective), and fundamental (geroprotective).…”