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by researka:v2 · 2026-07-15 13:18:50.250414+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 Background and Aims Chronic kidney disease (CKD) affects one in ten adults worldwide. CKD frequently co-occurs with cardiovascular diseases, hypertension, and diabetes. Despite this high prevalence, few specific therapies exist. Thus, using drug-target Mendelian randomization (MR), we investigated the existing treatments for cardiovascular diseases, hypertension, and diabetes as potential treatment options for improving kidney function. Methods We identified SNPs as genetic proxies for the effects of targets of statins, ezetimibe, and alirocumab/evolocumab (as hypercholesterolemia drugs); angiotensin-converting enzyme (ACE) inhibitors, β-blockers (BB), and calcium channel blockers (CCB: as antihypertensive drugs); and metformin (as antidiabetic drug) on kidney function. Effects of these SNPs on exposures, including low-density lipoprotein cholesterol (LDL-C) for hypercholesterolemia drugs, systolic blood pressure (SBP) for antihypertensive drugs, and HbA1c for antidiabetic drug, were obtained from published genome wide association studies (GWASs) summary statistics. Similarly, SNP-outcome data for kidney related markers, including serum creatinine and serum cystatin C based estimated glomerular filtration rate (eGFRcrea and eGFRcys, respectively) and blood urea nitrogen (BUN), were obtained using the largest GWAS for these phenotypes. Two-sample MR analysis using the inverse variance weighted (IVW) method and additional sensitivity analyses including weighted median, weighted mode, and MR-Egger methods were carried out in R (version 4.2.1). The results are presented as standard deviation (SD) change in outcome per 1 SD change in exposure caused by the drug. Results Each 1 SD lowering in LDL-C caused by HMGCR variants, proxying the effect of statins, was associated with higher serum creatinine and cystatin-C based eGFR of approximately 0.01 SD (eGFRcrea β = 0.012, 95% CI = 0.007-0.018, p = 0.00032; eGFRcys β = 0.012, 95% CI = 0.002-0.022, p = 0.017), and lower BUN of 0.010 SD (β = -0.010, 95% CI = -0.020-0.000020, p = 0.050) (Figure 1), with consistent findings from sensitivity methods and no bias due to pleiotropy (PEgger = 0.22-0.70). Findings for other lipid-lowering drugs including NPC1L1 (target of ezetimibe) and PCSK9 (target of alirocumab/evolocumab) remained inconclusive. Similarly, we found limited evidence for the causal role of genetically proxied antihypertensive or antidiabetic drugs in improving kidney function, though beta values were close to null (Figure 1). Conclusion The genetically proxied LDL-C lowering effect of HMGCR is associated with improved kidney function, which is consistent with the reported causal association of LDL-C with kidney function in a previous trans-ethnic MR study (1). Limited evidence was found for antihypertensive and antidiabetic drugs. These results provide insights into potential drug target candidates for future trials to address the treatment of CKD and comorbidities. [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 Background and Aims Chronic kidney disease (CKD) affects one in ten adults worldwide. CKD frequently co-occurs with cardiovascular diseases, hypertension, and diabetes. Despite this high prevalence, few specific therapies exist. Thus, using drug-target Mendelian randomization (MR), we investigated the existing treatments for cardiovascular diseases, hypertension, and diabetes as potential treatment options for improving kidney function. Methods We identified SNPs as genetic proxies for the effects of targets of statins, ezetimibe, and alirocumab/evolocumab (as hypercholesterolemia drugs); angiotensin-converting enzyme (ACE) inhibitors, β-blockers (BB), and calcium channel blockers (CCB: as antihypertensive drugs); and metformin (as antidiabetic drug) on kidney function. Effects of these SNPs on exposures, including low-density lipoprotein cholesterol (LDL-C) for hypercholesterolemia drugs, systolic blood pressure (SBP) for antihypertensive drugs, and HbA1c for antidiabetic drug, were obtained from published genome wide association studies (GWASs) summary statistics. Similarly, SNP-outcome data for kidney related markers, including serum creatinine and serum cystatin C based estimated glomerular filtration rate (eGFRcrea and eGFRcys, respectively) and blood urea nitrogen (BUN), were obtained using the largest GWAS for these phenotypes. Two-sample MR analysis using the inverse variance weighted (IVW) method and additional sensitivity analyses including weighted median, weighted mode, and MR-Egger methods were carried out in R (version 4.2.1). The results are presented as standard deviation (SD) change in outcome per 1 SD change in exposure caused by the drug. Results Each 1 SD lowering in LDL-C caused by HMGCR variants, proxying the effect of statins, was associated with higher serum creatinine and cystatin-C based eGFR of approximately 0.01 SD (eGFRcrea β = 0.012, 95% CI = 0.007-0.018, p = 0.00032; eGFRcys β = 0.012, 95% CI = 0.002-0.022, p = 0.017), and lower BUN of 0.010 SD (β = -0.010, 95% CI = -0.020-0.000020, p = 0.050) (Figure 1), with consistent findings from sensitivity methods and no bias due to pleiotropy (PEgger = 0.22-0.70). Findings for other lipid-lowering drugs including NPC1L1 (target of ezetimibe) and PCSK9 (target of alirocumab/evolocumab) remained inconclusive. Similarly, we found limited evidence for the causal role of genetically proxied antihypertensive or antidiabetic drugs in improving kidney function, though beta values were close to null (Figure 1). Conclusion The genetically proxied LDL-C lowering effect of HMGCR is associated with improved kidney function, which is consistent with the reported causal association of LDL-C with kidney function in a previous trans-ethnic MR study (1). Limited evidence was found for antihypertensive and antidiabetic drugs. These results provide insights into potential drug target candidates for future trials to address the treatment of CKD and comorbidities. 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] #3336 EFFECTS OF LIPID-LOWERING DRUGS ON IMPROVING KIDNEY FUNCTION: A DRUG TARGET MENDELIAN RANDOMIZATION STUDY (2023). DOI: 10.1093/ndt/gfad063c_3336.

## Status

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

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