Metformin could mitigate glucocorticoid-related complications
medwireNews: Findings from a proof-of-concept phase 2 study suggest that treatment with the antidiabetes drug metformin could help minimize some metabolic complications and improve clinical outcomes for patients taking systemic glucocorticoid therapy.
The trial included 53 participants without diabetes treated for an inflammatory disease with continuous prednisolone (≥20 mg/day for ≥4 weeks and ≥10 mg/day for the following 12 weeks, or cumulative dose-equivalent). They were randomly assigned to receive an escalating dose of oral metformin (850 mg/day on days 1–5, 850 mg twice daily on days 6–10, and 850 mg three times daily thereafter) or placebo for 12 weeks.
The most common rheumatic disease in the study population was vasculitis, affecting 18.9% of participants, followed by systemic lupus erythematosus in 16.9%, myositis in 7.5%, and rheumatoid arthritis in 5.7%. Asthma was the main indication for glucocorticoid therapy overall, reported in 30.2% of patients.
Márta Korbonits (Queen Mary University of London, UK) and co-investigators report in The Lancet Diabetes & Endocrinology that the primary outcome of change in the visceral-to-subcutaneous fat area ratio over 12 weeks was not significantly different among the 26 patients given metformin and the 27 in the placebo group, with average changes of 0.08 versus –0.03.
However, people in the metformin arm experienced significantly greater truncal subcutaneous fat loss, losing an average of 2035 mm2 from baseline to week 12, compared with a gain of 1799 mm2 in the placebo group. Patients given metformin also had significantly greater improvements in markers of glycemic control than those in the placebo arm, which the researchers say is “clinically relevant given the cohort’s propensity to diabetes.”
Mean levels of high-sensitivity C-reactive protein, a marker of inflammation, decreased by 0.010 mg/L among patients in the metformin group and increased by 0.003 mg/L in the placebo group, and average visual analog scale global disease activity scores improved to a greater degree in the metformin arm, but the between-group differences did not reach statistical significance for these endpoints.
In the safety analysis, there were significantly more cases of diarrhea (18 vs eight) but significantly fewer cases of moderate-to-severe infections (two vs 11), pneumonia (one vs seven), and hospital admission due to adverse events (one vs nine) among patients treated with metformin versus placebo.
“Although warranting an exploration in a larger study, these results point to up to a 30% absolute risk reduction of moderate-to-severe infections or all-cause hospital admissions, which corresponds to treating three patients with metformin to prevent one case,” say Korbonits and team.
Writing in an accompanying comment, Martin Reincke (Ludwig Maximilian University of Munich, Germany) says that “[t]he stunning efficacy of metformin” demonstrated in the phase 2 trial “might call for immediate action.”
He asks: “[I]f metformin is capable of reversing the side-effects of glucocorticoids, why not prophylactically treat every patient exposed to excess glucocorticoids with this drug?”
However, he cautions that the trial had limited patient numbers, and “[f]or a common problem affecting millions of patients, only a phase 3 trial will be considered sufficient to change clinical practice.” He also notes that “the study’s duration was short and not powered to investigate meaningful endpoints such as cardiovascular events and osteoporotic fractures.”
And Reincke concludes: “Until further evidence is available, doctors might consider metformin for patients at high risk for glucocorticoid side-effects on an individual basis and with compassionate use.”
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