Abstract and Introduction
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.
Introduction
Dementia, a syndrome characterized by a decline of cognition function, has become a major health burden worldwide.[1] It reportedly affected 57.4 million people globally in 2019, and is projected to affect 152.8 million people in 2050 as a result of aging and population growth.[2] In the United States (US), 15% of adults above 68 years have been diagnosed with dementia.[3] The most prevalent type of dementia is Alzheimer's disease (AD), which accounts for 60%–70% of all dementia cases,[4] followed by vascular dementia (VD) (15%–20%).[5]
A growing number of mechanistic and epidemiological studies have shown that diabetes is an independent risk factor for cognitive decline and the development of dementia (7). Type 2 diabetes (T2D) is an age-related disease characterized by insulin resistance and pancreatic β-cell dysfunction that led to abnormally high levels of blood glucose.[6] Its pathophysiological mechanisms are similar to several of those of dementia, such as oxidative stress, inflammation, vascular disease, and insulin resistance.[7] It is well known that individuals with T2D are at high risk of cerebrovascular disease, a key cause of cognitive impairment and dementia.[8] In addition, insulin resistance in individuals with T2D promotes the accumulation of β-amyloid (Aβ) and aberrant tau phosphorylation, which are the central pathophysiological process of AD.[9]
Glucose-lowering drugs (GLDs) are a cornerstone for controlling diabetes and ameliorating end-organ damage.[10] Preclinical studies have suggested that newer GLDs, including dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors, may also help prevent or delay the onset of dementia through multiple mechanisms, such as decreasing insulin resistance and oxidative stress, and attenuating amyloid deposition and tau phosphorylation.[11–15] However, evidence from population studies in humans on whether newer GLDs could protect against the risk of dementia remains unknown.[16–24] In addition, it remains unclear whether the effects of newer GLDs on cognitive function vary across different types of dementia.
Currently, there are no randomized controlled trials (RCTs) published to evaluate the effects of newer GLDs on risk of dementia and there is limited literature on post hoc analysis.[24] We performed a meta-analysis of 21 cardiovascular and renal outcome trials showing that newer GLDs might have a benefit on VD but not all-cause dementia.[25] However, this study was subjected to several limitations (e.g., dementia not being the pre-specified outcome and relatively short follow-ups in these trials).[25] The data from observational studies with a longer duration follow-up would provide more information regarding the association between newer GLDs and risk of dementia. Two meta-analyses have been conducted to evaluate the association between GLDs and dementia risk.[26,27] However, the association between newer GLDs and risk dementia remains inconclusive because few studies assessing such association were included in both meta-analyses.[26,27] Since then, several observational studies have been published.[20–24] Therefore, we conducted this systematic review and meta-analysis of observational studies to address the following questions: (1) What is the association between different classes of newer GLDs and risk of dementia? (2) Does the association vary with different types of dementia (e.g., AD and VD)? and (3) What are the methodological challenges and limitations in recent studies on this subject?
J Am Geriatr Soc. 2023;71(7):2096-2106. © 2023 Blackwell Publishing
