Beyond Glycated Hemoglobin (HbA1c): A Systematic Review of Metabolic Interventions, Insulin Resistance, and Cognitive Function Across the Obesity-to-Diabetes Continuum

Abstract

Insulin resistance may contribute to cognitive vulnerability before persistent hyperglycemia becomes apparent; however, its clinical relevance as a predictor of cognitive change or therapeutic target remains uncertain. This systematic review with narrative synthesis evaluated the effects of metabolically targeted interventions on insulin resistance and cognitive function in middle-aged and older adults across the obesity-to-type 2 diabetes continuum. MEDLINE via PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for studies published from January 1, 2021, to December 31, 2025. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Eligible designs included randomized controlled trials, prospective randomized parallel-group studies, and longitudinal analyses nested within randomized trials that reported metabolic outcomes alongside cognitive or neuroimaging outcomes. Of the 552 records identified, five studies met the eligibility criteria, comprising four intervention studies and one longitudinal analysis nested within a randomized trial. The interventions comprised lifestyle modification, combined physical and cognitive exercise, dapagliflozin, nutritional supplementation, and moxibustion, with follow-up periods ranging from 12 weeks to two years. Three intervention studies reported concurrent improvements in insulin resistance and cognitive outcomes, whereas one found no significant improvement in insulin resistance and limited neuropsychological benefit. In the single included longitudinal analysis, oral glucose tolerance test (OGTT)-derived measures and the triglyceride-glucose (TyG) index showed more consistent associations with less favorable cognitive or neuroimaging changes than glycated hemoglobin (HbA1c), which demonstrated mixed associations. Three intervention studies raised some concerns regarding risk of bias, one was judged to be at high risk, and the prognostic analysis was assessed as having moderate risk. Overall, measures of insulin resistance may provide information complementary to HbA1c and may have potential as early risk or treatment-response markers for cognitive health. Nevertheless, the small and heterogeneous evidence base, relatively short follow-up periods, and absence of formal mediation analyses preclude causal conclusions. Larger, longer-term, and methodologically rigorous trials are needed to determine whether improving insulin sensitivity can meaningfully alter cognitive trajectories.