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by researka:v2 · 2026-07-15 13:17:50.054813+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

Abstract Introduction: Metformin is a glucose-lowering medication that has anti-inflammatory properties, as does physical activity. Both have been suggested as beneficial for lung function; however, there are no prior randomized trials testing whether these interventions prevent chronic lung disease. Methods: The Diabetes Prevention Program (DPP) was a 3 year trial that randomized 3,234 individuals at risk for diabetes to metformin, lifestyle intervention or placebo. After the DPP, 88% of participants enrolled in the DPP Outcomes Study (DPPOS) that offered lifestyle intervention to all and open-label continuation of metformin. Spirometry was performed in DPPOS years 15 and 18. The forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC were compared in an intention-to-treat (ITT) analysis by original randomization group. An obstructive deficit was defined as FEV1/FVC <70% and a restrictive pattern as FVC <LLN and FEV1/FVC ≥70%. Results: At the time of first spirometry the 1,888 participants were a mean (±SD) age of 68.2±9.3 years, 70% were female, 6% currently smoked cigarettes and 33% had smoked in the past, and self-reported race/ethnicity was: 52% non-Hispanic white, 20% non-Hispanic Black, 16% Hispanic, 7% American Indian and 5% Asian American or Pacific Islander. Mean follow-up time was 19.0±0.8 years. The mean FEV1 was 2.14±0.60 L, FVC 2.74±0.74 L, FEV1/FVC 78.4±6.4%, mean body mass index (BMI) was 32.4±6.7 kg/m2 and 58% had diabetes. In both unadjusted and adjusted ITT analyses, randomization group was not associated with FEV1, FVC or FEV1/FVC (Table). The unadjusted results for FEV1 were: placebo 2.08 L (95% CI: 2.03, 2.13), lifestyle intervention 2.12 L (95% CI: 2.07, 2.16), metformin: 2.11 L (95% CI: 2.07, 2.16), P-value=0.469. There were no differences in rates of obstructive deficit or restrictive deficit across original randomization group in unadjusted or adjusted analyses. Conclusions: In this long-term follow-up after a randomized trial, there were no significant associations between randomization to metformin or lifestyle change and any measure of lung function measured 15 years after study completion. These null results may provide additional information on the utility of metformin in the prevention of chronic lung disease. [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, Abstract Introduction: Metformin is a glucose-lowering medication that has anti-inflammatory properties, as does physical activity. Both have been suggested as beneficial for lung function; however, there are no prior randomized trials testing whether these interventions prevent chronic lung disease. Methods: The Diabetes Prevention Program (DPP) was a 3 year trial that randomized 3,234 individuals at risk for diabetes to metformin, lifestyle intervention or placebo. After the DPP, 88% of participants enrolled in the DPP Outcomes Study (DPPOS) that offered lifestyle intervention to all and open-label continuation of metformin. Spirometry was performed in DPPOS years 15 and 18. The forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC were compared in an intention-to-treat (ITT) analysis by original randomization group. An obstructive deficit was defined as FEV1/FVC <70% and a restrictive pattern as FVC <LLN and FEV1/FVC ≥70%. Results: At the time of first spirometry the 1,888 participants were a mean (±SD) age of 68.2±9.3 years, 70% were female, 6% currently smoked cigarettes and 33% had smoked in the past, and self-reported race/ethnicity was: 52% non-Hispanic white, 20% non-Hispanic Black, 16% Hispanic, 7% American Indian and 5% Asian American or Pacific Islander. Mean follow-up time was 19.0±0.8 years. The mean FEV1 was 2.14±0.60 L, FVC 2.74±0.74 L, FEV1/FVC 78.4±6.4%, mean body mass index (BMI) was 32.4±6.7 kg/m2 and 58% had diabetes. In both unadjusted and adjusted ITT analyses, randomization group was not associated with FEV1, FVC or FEV1/FVC (Table). The unadjusted results for FEV1 were: placebo 2.08 L (95% CI: 2.03, 2.13), lifestyle intervention 2.12 L (95% CI: 2.07, 2.16), metformin: 2.11 L (95% CI: 2.07, 2.16), P-value=0.469. There were no differences in rates of obstructive deficit or restrictive deficit across original randomization group in unadjusted or adjusted analyses. Conclusions: In this long-term follow-up after a randomized trial, there were no significant associations between randomization to metformin or lifestyle change and any measure of lung function measured 15 years after study completion. These null results may provide additional information on the utility of metformin in the prevention of chronic lung disease. 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] Lung Function After Randomization to Metformin, Lifestyle Intervention or Placebo in the Diabetes Prevention Program Outcome Study (DPPOS) (2025). DOI: 10.1164/ajrccm.2025.211.abstracts.a4220.

## Status

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

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