Effects of metformin on metabolic and inflammatory markers in older people with sarcopenia and frailty: analysis from the MET-PREVENT randomised controlled trial

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Ihfaz Islam1, Jasmine Wilson1, Andrew Clegg2, Helen Hancock3, Carmen Martin-Ruiz4, Claire McDonald1, Avan Aihie Sayer1, Claire Steves5, Thomas von Zglinicki4, Miles D Witham1
1. AGE Research Group NIHR Newcastle Biomedical Research Centre 2. Academic Unit for Ageing & Stroke Research, Univ of Leeds 3. Newcastle Clinical Trials Unit 4. BioScreening Core Facility, Newcastle Univ 5. Dept of Twins Research, KCL
Scientific Research
SP - BMR (Bone
Sarcopenia

Abstract

Background

Chronic inflammation and metabolic dysfunction are posited to contribute to sarcopenia and physical frailty; both are targets for metformin therapy. We investigated correlations between physical performance measures and inflammatory and metabolic biomarkers in a group of older people with sarcopenia and frailty/prefrailty and investigated the effect of metformin treatment on this biomarker panel.

Methods

We analysed samples collected at baseline and follow-up (4 months) from the randomised controlled MET-PREVENT trial. MET-PREVENT recruited participants aged 65 and over with probable sarcopenia (EWGSOP2 guidelines) and 4m walk speed <0.8m/s. Participants received 500mg metformin 3x/day or matching placebo for 4 months. Blood sampling and physical performance measures (handgrip strength, 4m walk speed, six-minute walk distance, 5x sit to stand) were conducted at baseline and 4 months. Biomarkers were measured using ELISA and Luminex platforms for insulin, CRP, adiponectin, leptin, MCP-1, IL-1b, IL-6, IL-8, and TNF-a. Baseline correlations and correlations of changes between baseline and follow-up, were analysed using Spearman’s test; median change between baseline and follow-up in the metformin and placebo groups was compared using Mann-Whitney tests.

Results

Seventy-two participants were studied, mean age 80 years. Higher baseline IL-6 concentrations correlated with lower six-minute walk distance, (r=-0.40, p=0.008); other correlations were non-significant. Increased IL-1B and decreased adiponectin between baseline and 4 months were correlated with worsening grip strength (r=-0.25, p=0.04; r=0.29, p=0.016); increased TNFa and decreased MCP-1 were correlated with worsening 5x sit-to-stand time (r=0.38, p=0.02; r=-0.32, p=0.04). Metformin treatment reduced circulating insulin concentrations more than placebo (median change between baseline and 4 months: -178pg/ml [IQR -462, 180] vs 147pg/ml [IQR -89, 353]; between-group p=0.04) but did not significantly change other biomarkers compared with placebo.

Conclusions

In this trial population, only weak and inconsistent correlations were seen between physical performance and inflammatory/metabolic biomarkers, and metformin did not beneficially affect most biomarkers measured.

Comments

Interesting project, and something that is new to me with respect to metformin and sarcopenia. Did you find any negative effects of metformin use during this trial period, or were there just no benefits?

Submitted by allessiacooper_47905 on

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Thanks Allessia - there were a LOT of side effects in the metformin group; 40% had to discontinue the metformin due to GI side effects (although almost all still completed the trial assessments at 4 months). Thats despite the dose being low, and almost certainly reflects the marked degree of frailty that our study population were living with - much more frail than participants in previous trials of metformin in diabetes.

Very interesting. Was there any particular reason of choosing metformin ? While selecting the patients did you look for any particular comorbidities as well ?

Submitted by hindol.dasgupt… on

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Thanks Hindol. We chose metformin as it has multiple potential biological effects that might improve muscle function. We cover these in the main paper: Metformin and physical performance in older people with probable sarcopenia and physical prefrailty or frailty in England (MET-PREVENT): a double-blind, randomised, placebo-controlled trial - PubMed

We didnt seek out particular comorbidities (e.g. pre-diabetes, insulin resistance etc) although there are other trials underway with young-old people that are focussing on those subgroups

 

Really interesting area of research which I have not thought about and it seems a shame that there was no positive findings. It would have been useful to see whether there was adverse events and what these were. Really well thought out project though. 

Submitted by emma.abel@nhs.net on

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Thanks Emma. We didnt include the data on adverse events in this poster but we have presented on this previously and you can find the full results in the main paper: Metformin and physical performance in older people with probable sarcopenia and physical prefrailty or frailty in England (MET-PREVENT): a double-blind, randomised, placebo-controlled trial - PubMed

As you will see from that paper, there were a lot of adverse events with metformin and 40% had to discontinue it, mostly from GI side effects...

I wonder if once the sarcopenia is present if it’s too late perhaps? Were there any trends in patients with less frailty or sarcopenia?

Submitted by iainwilkinson1_13125 on

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Thanks Ian. Its possible, and as we argue in the main paper, the sweet spot might be prefrailty. Metformin blunts the effect of exercise training in healthy older people, so not a good choice there as a preventative for sarcopenia; there is one study in prefrail older adults from Indonesia that does seem to show benefit. I suspect for our study population, it is probably that any small physiological benefit is cancelled out by adverse effects. There was no difference in effect between those with a baseline walk speed > or < 0.6m/s (roughly the median) so no evidence from our study that people who were less frail would get benefit

Submitted by milesandjus_12967 on

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