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by researka:v2 · 2026-07-15 13:22:02.525627+04:00

# Metformin Physical Function Older Adults: Two Null Signals, One Bounded Conclusion

## Signal

Older persons with HIV (PWH) experience high rates of cognitive impairment and frailty, and accelerated decline in physical function compared with the general population. Metformin use has been associated with beneficial effects on cognitive and physical function among older adults without HIV. The relationship between metformin use on these outcomes in PWH has not been evaluated. AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH with annual assessments for cognition and frailty, including measures of physical function (e.g., gait speed and grip strength). Participants with diabetes who were prescribed antihyperglycemic medications were included in this analysis to evaluate the association between metformin and functional outcomes. Cross-sectional, longitudinal, and time-to-event models were used to evaluate the relationship between metformin exposure with cognitive, physical function, and frailty outcomes. Ninety-eight PWH met inclusion criteria and were included in at least one model. No significant associations between metformin use, frailty, physical, or cognitive function were noted in unadjusted or adjusted cross-sectional, longitudinal, or time-to-event models ( p > .1 for all models). This study is the first to examine the association between metformin use on functional outcomes among older PWH. Although it did not ascertain significant associations between metformin use and functional outcomes, our small sample size, restriction to persons with diabetes, and lack of randomization to metformin therapy were limitations. Larger randomized studies are needed to determine whether metformin use has beneficial effects on cognitive or physical function in PWH. Clinical Trial Registration numbers: 02570672, 04221750, 00620191, and 03733132. [R1]

## Update

Aims: Metformin uptake is transporter-dependent. Observational data indicates that reduced-function variants in organic cation transporter 1 (OCT1) and OCT1-inhibiting drugs increase risk of metformin intolerance. The ImpOCT study investigated impact of OCT1 genotype and use of omeprazole (an OCT1-inhibiting drug) on an individual’s metformin tolerance. Methods: This recruit-by-genotype, double-blind, randomised, placebo-controlled, crossover study recruited 61 nondiabetic individuals with homozygous reduced-function (null) or wild type (WT) OCT1 genotype. During two 4-week treatment periods, participants received metformin and concurrent omeprazole or placebo. Metformin was titrated weekly according to tolerance, assessed by interview and symptom severity scoring. The primary outcome was maximum tolerated dose of metformin (MTD) in each treatment period. Results were analysed using mixed effects modelling, assessing effect of genotype, treatment and gene x drug interaction on MTD. Results: Participants were well matched for age and gender. Median BMI was higher in OCT1 null (26.3 [IQR 24.1 - 28.1] vs. 29 [IQR 26.5 - 31.8], p<0.001), though these OCT1 variants are not associated with obesity. Frequency of tolerance was comparable (WT 60% vs. null 64.5%, p=0.7). We identified a significant gene x drug interaction (p=0.04) - OCT1 WT individuals have improved MTD whilst taking omeprazole, compared to placebo, p=0.008, whereas OCT1 null individuals show no improvement in MTD with omeprazole compared to placebo, p=0.87. BMI was not significant in the model of MTD, p=0.27. Conclusions: Reduced function SNPs in OCT1 are relatively common and can affect transporter efficacy. This study identified a gene x drug interaction, between OCT1, metformin and omeprazole. Our data indicates that OCT1 WT individuals may benefit from PPI treatment to improve symptoms of metformin intolerance - this benefit is lost in those with reduced OCT1 function. Disclosure L.J. McCreight: None. S.M. Hapca: None. E. Pearson: None. Funding UK Wellcome Trust (to E.P.) [R2]

## Synthesis

Older persons with HIV (PWH) experience high rates of cognitive impairment and frailty, and accelerated decline in physical function compared with the general population. Metformin use has been associated with beneficial effects on cognitive and physical function among older adults without HIV. The relationship between metformin use on these outcomes in PWH has not been evaluated. AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH with annual assessments for cognition and frailty, including measures of physical function (e.g., gait speed and grip strength). Participants with diabetes who were prescribed antihyperglycemic medications were included in this analysis to evaluate the association between metformin and functional outcomes. Cross-sectional, longitudinal, and time-to-event models were used to evaluate the relationship between metformin exposure with cognitive, physical function, and frailty outcomes. Ninety-eight PWH met inclusion criteria and were included in at least one model. No significant associations between metformin use, frailty, physical, or cognitive function were noted in unadjusted or adjusted cross-sectional, longitudinal, or time-to-event models ( p > .1 for all models). This study is the first to examine the association between metformin use on functional outcomes among older PWH. Although it did not ascertain significant associations between metformin use and functional outcomes, our small sample size, restriction to persons with diabetes, and lack of randomization to metformin therapy were limitations. Larger randomized studies are needed to determine whether metformin use has beneficial effects on cognitive or physical function in PWH. Clinical Trial Registration numbers: 02570672, 04221750, 00620191, and 03733132. Separately, Aims: Metformin uptake is transporter-dependent. Observational data indicates that reduced-function variants in organic cation transporter 1 (OCT1) and OCT1-inhibiting drugs increase risk of metformin intolerance. The ImpOCT study investigated impact of OCT1 genotype and use of omeprazole (an OCT1-inhibiting drug) on an individual’s metformin tolerance. Methods: This recruit-by-genotype, double-blind, randomised, placebo-controlled, crossover study recruited 61 nondiabetic individuals with homozygous reduced-function (null) or wild type (WT) OCT1 genotype. During two 4-week treatment periods, participants received metformin and concurrent omeprazole or placebo. Metformin was titrated weekly according to tolerance, assessed by interview and symptom severity scoring. The primary outcome was maximum tolerated dose of metformin (MTD) in each treatment period. Results were analysed using mixed effects modelling, assessing effect of genotype, treatment and gene x drug interaction on MTD. Results: Participants were well matched for age and gender. Median BMI was higher in OCT1 null (26.3 [IQR 24.1 - 28.1] vs. 29 [IQR 26.5 - 31.8], p<0.001), though these OCT1 variants are not associated with obesity. Frequency of tolerance was comparable (WT 60% vs. null 64.5%, p=0.7). We identified a significant gene x drug interaction (p=0.04) - OCT1 WT individuals have improved MTD whilst taking omeprazole, compared to placebo, p=0.008, whereas OCT1 null individuals show no improvement in MTD with omeprazole compared to placebo, p=0.87. BMI was not significant in the model of MTD, p=0.27. Conclusions: Reduced function SNPs in OCT1 are relatively common and can affect transporter efficacy. This study identified a gene x drug interaction, between OCT1, metformin and omeprazole. Our data indicates that OCT1 WT individuals may benefit from PPI treatment to improve symptoms of metformin intolerance - this benefit is lost in those with reduced OCT1 function. Disclosure L.J. McCreight: None. S.M. Hapca: None. E. Pearson: None. Funding UK Wellcome Trust (to E.P.) Therefore, for metformin physical function older adults, these two null results cannot establish benefit beyond their measured populations and outcomes; they support an outcome-specific boundary, not a uniform intervention effect. [R1] [R2]

## Limitations

The two receipts concern different populations, comparators, and outcomes; without a head-to-head comparison, they cannot establish that one intervention is uniformly superior or harmonize dose, duration, and endpoint aggregation. [R1] [R2]

## Falsifier

This boundary would be overturned by receipt-matched, adequately powered evidence in the same populations showing a significant benefit on either measured outcome. [R1] [R2]

## Receipts
- [R1] Association Between Metformin Use and Cognitive and Physical Function in Persons with HIV and Diabetes (2023). DOI: 10.1089/aid.2022.0129.
- [R2] 1121-P: Metformin Intolerance, Proton Pump Inhibitors, and OCT1 Variation: A Recruit-by-Genotype, Randomised Controlled Trial (ImpOCT) (2019). DOI: 10.2337/db19-1121-p.

## Status

Receipt-bound alpha memo. Every factual claim is source-bound; the falsifier is a test, not evidence.

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