Anderson M Pereira da Silva, Maria D V Santos do Nascimento, Giovana Menegucci, Gabriel Caruso Novaes Tudella, Lucas Silva Cabeça, Ocílio Ribeiro Gonçalves, Bernardo Vieira Nogueira, Julia Oliveira Franco, Diogo Haddad Santos, Filipe Silveira Duarte, George Perry, Eryvelton de Souza Franco, Maria Bernadete de Sousa Maia
Pioglitazone was not associated with consistent differences in global cognitive outcomes in individuals with mild cognitive impairment or Alzheimer disease. Safety outcomes were broadly comparable to placebo, although peripheral edema occurred more frequently.
BACKGROUND: Cognitive impairment is increasingly recognized among older adults with metabolic disorders, including type 2 diabetes. Metabolic dysfunction and insulin resistance have been implicated in neurodegenerative processes. Pioglitazone, an insulin-sensitizing agent widely used in the treatment of type 2 diabetes, has been investigated for potential effects on cognitive outcomes. This systematic review and meta-analysis evaluated the efficacy and safety of pioglitazone on cognitive outcomes in individuals with mild cognitive impairment or Alzheimer disease.
METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched through July 2025 for randomized controlled trials comparing pioglitazone with placebo in adults with mild Alzheimer disease or mild cognitive impairment. Cognitive outcomes included the Mini-Mental State Examination, the Wechsler Memory Scale-Revised, and the Alzheimer's Disease Assessment Scale-Cognitive subscale. Safety outcomes included adverse events, serious adverse events, treatment discontinuation, and peripheral edema. Random-effects meta-analyses were conducted using frequentist and Bayesian approaches.
RESULTS: Six randomized trials, including 3680 participants, were analyzed. Pioglitazone was not associated with differences in Mini-Mental State Examination or Wechsler Memory Scale-Revised scores compared with placebo. Alzheimer's Disease Assessment Scale-Cognitive subscale estimates modestly favored pioglitazone, although this finding was not consistent across other cognitive measures. Overall, adverse events and serious adverse events were similar between treatment groups. Treatment discontinuation occurred less frequently with pioglitazone. Peripheral edema was reported more frequently with pioglitazone, although estimates were based on a small number of events and wide CIs.
CONCLUSION: Pioglitazone was not associated with consistent differences in global cognitive outcomes in individuals with mild cognitive impairment or Alzheimer disease. Safety outcomes were broadly comparable to placebo, although peripheral edema occurred more frequently.