THE ROLE OF HYPOGLYCEMIC AGENTS IN AMELIORATING COGNITIVE FUNCTIONS AND PSYCHIATRIC SYMPTOMS: FROM THE PSYCHIATRIC PATIENT TO EVIDENCE-BASED AND PHARMACOEPIDEMIOLOGIC APPROACHES FOR SUPPORTING THE CLINICAL PRACTICE
Background: Research highlights a complex link between diabetes-related factors such as insulin resistance, hyperglycemia, and chronic inflammation, all contributing to cognitive decline. Schizophrenia and depression, which often co-occur with type 2 diabetes mellitus, show a bidirectional relationship with diabetes, involving both brain and systemic responses. Antidiabetic drugs such as metformin and drug targeting Glucagon-Like Peptide-1 (GLP-1) are being proposed for psychiatric and cognitive treatments, although their use for non-diabetic purposes remains debated. Methods: The role of antidiabetic drugs in ameliorating psychiatric and cognitive functions was explored across various real-world settings where these drugs are already used for glycemic control. A meta-analysis and meta-regression were conducted to study metformin in schizophrenic patients. Innovative approaches regarding disproportionality analysis of concomitant therapies in pharmacovigilance databases were used to explore all antidiabetic drugs (ATC code: A10) in combination with antidepressants. Survival analysis was performed using Danish healthcare registers to evaluate the potential benefits of GLP-1 analogues (GLP-1a) in older patients. Results: Metformin showed a positive trend without reaching strong statistical significance in ameliorating psychiatric symptoms in a meta-analysis of randomized controlled trials involving schizophrenic patients [SMD (95%CI) = -0.40 (-0.82;0.01), OR (95%CI) = 0.5 (-2.4;3.4)] and reducing the reporting risk of therapy failure in depressive patients [ROR95=1.14, PPR(p)= 1.07 (0.00), EBGM95=0.96 ERAM95=0.89 in FAERS and ROR95=1.48 PPR(p)= 1.34 (0.00) EBGM95=1.22 and ERAM95=0.86 in VigiBase]. GLP-1a and DPP-4 inhibitors (DPP-4i) resulted in better outcomes with a preference for GLP-1a for reducing the risk of major cognitive impairment (dementia) in old diabetic patients [aHR (95% CI) = 1.5 (1.16-2.04), p = 0.003 for DPP-4i compared to GLP1-a (reference group)]. GLP-1a resulted also in a lower reporting rate of therapy failure in depressive patients compared to DPP-4i [ROR95=0.66 vs 0.86 in FAERS and ROR95=0.92 vs 1.06 in VigiBase, respectively]. Conclusions: GLP-1 analogues may offer more substantial clinical benefits. Regarding metformin, there is insufficient evidence of its cognitive benefits. Further research is necessary to confirm these findings and explore their clinical significance.
glucose-lowering agent, cognitive disfunction, drug repurposing, Settore BIOS-11/A - Farmacologia
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