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by researka:v2 · 2026-07-15 13:20:30.559355+04:00

# Metformin Physical Function Older Adults: When Positive Effects Do Not Generalize

## Signal

Gestational diabetes mellitus (GDM) is a common complication during pregnancy, which seriously affects the health of mothers and infants. Metformin and insulin are both commonly used therapeutic drugs, but the effects of the two on pregnancy outcomes and the physical condition of the infants remain undetermined. This study conducted a meta-analysis to compare the effects of two drugs in the treatment of gestational diabetes mellitus (GDM), providing a basis for clinical medication. Our research systematically searched the PubMed, Embase, and Cochrane Library databases to include randomized controlled trials (RCTS) of metformin and insulin in the treatment of GDM. The search period was up to March 2025. Literature screening, data extraction and quality evaluation were independently completed by two researchers, and statistical analysis was performed using RevMan 5.4 software. Eventually, 8 RCTS were included, involving a total of 2,350 patients with GDM. Meta-analysis showed that the cesarean section rate in the metformin group was 26.3%, which was lower than 33.7% in the insulin group (RR = 0.78, 95%CI:0.75–0.81, P < 0.05). The incidence of gestational hypertension in the metformin group was 13.8% (26 out of 188 patients), which was lower than 18.6% (34 out of 183 patients) in the insulin group (RR = 0.74, 95% CI: 0.69–0.79, P < 0.05). The cesarean section rate was 30.9% (58/188) in the metformin group vs. 38.8% (71/183) in the insulin group (RR = 0.78, 95% CI:0.75–0.81, P < 0.05). Neonatal hypoglycemia occurred in 5.9% (11/188) of the metformin group vs. 9.8% (18/183) of the insulin group (RR = 0.60, 95% CI:0.57–0.63, P < 0.05). Macrosomia rates were 14.9% (28/188) vs. 19.7% (36/183) in the two groups, respectively (RR = 0.78, 95% CI:0.73–0.83, P < 0.05). Compared with insulin, metformin in the treatment of gestational diabetes mellitus can reduce the rate of cesarean section, the incidence of gestational hypertension, the incidence of neonatal hypoglycemia and the incidence of macrosomia, and can be an effective treatment option for patients with GDM. [R1]

## Update

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. [R2]

## Synthesis

Gestational diabetes mellitus (GDM) is a common complication during pregnancy, which seriously affects the health of mothers and infants. Metformin and insulin are both commonly used therapeutic drugs, but the effects of the two on pregnancy outcomes and the physical condition of the infants remain undetermined. This study conducted a meta-analysis to compare the effects of two drugs in the treatment of gestational diabetes mellitus (GDM), providing a basis for clinical medication. Our research systematically searched the PubMed, Embase, and Cochrane Library databases to include randomized controlled trials (RCTS) of metformin and insulin in the treatment of GDM. The search period was up to March 2025. Literature screening, data extraction and quality evaluation were independently completed by two researchers, and statistical analysis was performed using RevMan 5.4 software. Eventually, 8 RCTS were included, involving a total of 2,350 patients with GDM. Meta-analysis showed that the cesarean section rate in the metformin group was 26.3%, which was lower than 33.7% in the insulin group (RR = 0.78, 95%CI:0.75–0.81, P < 0.05). The incidence of gestational hypertension in the metformin group was 13.8% (26 out of 188 patients), which was lower than 18.6% (34 out of 183 patients) in the insulin group (RR = 0.74, 95% CI: 0.69–0.79, P < 0.05). The cesarean section rate was 30.9% (58/188) in the metformin group vs. 38.8% (71/183) in the insulin group (RR = 0.78, 95% CI:0.75–0.81, P < 0.05). Neonatal hypoglycemia occurred in 5.9% (11/188) of the metformin group vs. 9.8% (18/183) of the insulin group (RR = 0.60, 95% CI:0.57–0.63, P < 0.05). Macrosomia rates were 14.9% (28/188) vs. 19.7% (36/183) in the two groups, respectively (RR = 0.78, 95% CI:0.73–0.83, P < 0.05). Compared with insulin, metformin in the treatment of gestational diabetes mellitus can reduce the rate of cesarean section, the incidence of gestational hypertension, the incidence of neonatal hypoglycemia and the incidence of macrosomia, and can be an effective treatment option for patients with GDM. In contrast, 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. Therefore, for metformin physical function older adults, a positive result on the promise endpoint cannot establish differential benefit on the update's null endpoint; decisions should treat the signal as comparator- and outcome-specific rather than 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 if receipt-matched evidence in the same populations showed a significant benefit on the update's null comparison or no positive effect on the promise endpoint. [R1] [R2]

## Receipts
- [R1] Comparison of pregnancy outcomes and physical conditions of infants in patients with gestational diabetes mellitus treated with metformin and insulin: a meta-analysis study (2026). DOI: 10.1186/s12884-026-08649-6.
- [R2] Association Between Metformin Use and Cognitive and Physical Function in Persons with HIV and Diabetes (2023). DOI: 10.1089/aid.2022.0129.

## Status

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

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