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

Huilin Tang; Hui Shao; C Elizabeth Shaaban; Keming Yang; Joshua Brown; Stephen Anton; Yonghui Wu; Adam Bress; William T Donahoo; Steven T DeKosky; Jiang Bian; Jingchuan Guo

doi:10.1111/jgs.18306

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

J Am Geriatr Soc. 2023 Jul;71(7):2096-2106. doi: 10.1111/jgs.18306. Epub 2023 Feb 23.

Authors

Huilin Tang¹, Hui Shao^{1

2}, C Elizabeth Shaaban³, Keming Yang⁴, Joshua Brown^{1

2}, Stephen Anton^{5

6}, Yonghui Wu⁷, Adam Bress⁸, William T Donahoo⁹, Steven T DeKosky^{10

11}, Jiang Bian⁷, Jingchuan Guo^{1

2}

Affiliations

¹ Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA.
² Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA.
³ Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁴ Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵ Department of Aging and Geriatric Research, College of Medicine, University of Florida, Gainesville, Florida, USA.
⁶ Department of Clinical and Health Psychology, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA.
⁷ Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA.
⁸ Division of Health System Innovation and Research, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.
⁹ Division of Endocrinology, Diabetes and Metabolism, College of Medicine, University of Florida, Gainesville, Florida, USA.
¹⁰ Department of Neurology and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA.
¹¹ 1Florida Alzheimer's Disease Research Center (ADRC), University of Florida, Gainesville, Florida, USA.

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.

Keywords: DPP-4 inhibitors; GLP-1RAs; SGLT2 inhibitors; dementia; type 2 diabetes.

Publication types

Meta-Analysis
Systematic Review
Research Support, N.I.H., Extramural

MeSH terms

Dementia* / complications
Dementia* / prevention & control
Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / drug therapy
Diabetes Mellitus, Type 2* / epidemiology
Dipeptidyl-Peptidase IV Inhibitors* / adverse effects
Glucose
Humans
Hypoglycemic Agents / adverse effects
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use

Substances

Hypoglycemic Agents
Dipeptidyl-Peptidase IV Inhibitors
Glucose
Sodium-Glucose Transporter 2 Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding