Effect of multivitamin-mineral supplementation versus placebo on cognitive function: results from the clinic sub-cohort of the COSMOS randomized clinical trial and meta-analysis of three cognitive studies within COSMOS

BACKGROUND: Longer effects of multivitamin‐mineral (MVM) supplementation on late‐life cognitive function remain untested using in‐person, detailed neuropsychological assessments. Furthermore, insufficient evidence exists for healthcare providers to recommend daily MVM supplements to prevent cognitive decline. OBJECTIVES: To: 1) test MVM effects on cognitive change using in‐person, detailed neuropsychological assessments; 2) conduct a meta‐analysis within COSMOS (COcoa Supplement and Multivitamin Outcomes Study) cognitive sub‐studies for a robust evaluation of MVM effects on cognition. DESIGN: COSMOS is a 2x2 factorial trial of cocoa extract [500 mg flavanols/day] and/or a daily multivitamin‐mineral supplement for cardiovascular disease and cancer prevention among 21,442 US adults aged ≥60 years. There were 573 participants in the clinic sub‐cohort of COSMOS (i.e., COSMOS‐Clinic) who completed all cognitive tests administered at baseline. For meta‐analysis, we included non‐overlapping participants across three COSMOS cognitive sub‐studies: COSMOS‐Clinic (n=573); COSMOS‐Mind (n=2158); COSMOS‐Web (n=2472). RESULTS: In COSMOS‐Clinic, we observed a modest benefit of MVM, compared to placebo, on global cognition over 2 years [mean difference (95% confidence interval (CI))=0.06 standard deviation units (SU) (‐0.003, 0.13)], with a significantly more favorable change in episodic memory [mean difference (95% CI)=0.12 SU (0.002, 0.23)] but not in executive function/attention [mean difference (95% CI)=0.04 SU (‐0.04, 0.11)]. Meta‐analysis of COSMOS sub‐studies showed clear evidence of MVM benefits on global cognition [mean difference (95% CI)=0.07 SU (0.03, 0.11); p=0.0009] and episodic memory [mean difference (95% CI)=0.06 SU (0.03, 0.10); p=0.0007]; magnitude of effect on global cognition was equivalent to reducing cognitive aging by 2 years. CONCLUSIONS: In COSMOS‐Clinic, daily MVM supplementation led to a significantly more favorable 2‐year change in episodic memory. The meta‐analysis within COSMOS cognitive sub‐studies indicated that daily MVM significantly benefited both global cognition and episodic memory. These findings within the COSMOS trial support the benefits of a daily MVM in preventing cognitive decline among older adults. TRIAL REGISTRATION: i) COSMOS ‐ ClinicalTrials.gov identifier: NCT02422745, URL: https://www. CLINICALTRIALS: gov/study/NCT02422745; ii) COSMOS‐Mind ‐ ClinicalTrials.gov identifier: NCT03035201, URL: https://clinicaltrials.gov/study/NCT03035201; iii) COSMOS‐Web ‐ ClinicalTrials.gov identifier: NCT04582617, URL: https://clinicaltrials.gov/study/NCT04582617.