medwireNews: A randomized controlled trial has demonstrated uncertain benefits of the antidiabetes drug metformin when added to standard therapy in patients with systemic lupus erythematosus (SLE), but the researchers believe that further investigation of the drug is warranted for the reduction of major flares.
In their phase 4 study, Shuang Ye (Renji Hospital South Campus, Shanghai, China) and co-investigators demonstrated no significant difference in the risk for major or mild-to-moderate lupus flares – defined according to the modified SELENA-SLEDAI Flare Index – among 67 Chinese patients with low-grade SLE who were randomly assigned to receive add-on metformin and their 73 counterparts given add-on placebo, with 1-year rates of 21% and 34%, respectively.
Metformin was administered orally at an initial dose of 0.5 g/day for 1 week, and the dose was gradually increased by 0.5 g each week to a maximum of 1.5 g/day given in two or three doses. All patients were free from diabetes, the majority (94%) were female, and the average SELENA-SLEDAI score was approximately 2.5 points at baseline. Standard therapy included hydroxychloroquine in 91% and 89% of patients in the metformin and placebo groups, respectively, while a corresponding 69% and 64% were taking immunosuppressive drugs.
Ye and team also report no significant prednisone-sparing effect of metformin, and while the evolution of SLEDAI score over the study period favored metformin, time-adjusted changes in this score were not significantly different in the metformin versus placebo arms during follow-up.
However, in an exploratory analysis of their data, the study authors identified a significant association between metformin treatment and a reduction in major flare risk, with rates of 13% in the metformin group versus 27% in the placebo arm and a risk ratio of 0.59.
They say that metformin had an acceptable safety profile in the trial, with a similar incidence of non-flare adverse events (AEs) in the metformin and placebo groups (1 vs 4%). Rates of gastrointestinal AEs were significantly higher among patients treated with metformin versus placebo (39 vs 15%), while infection rates were numerically lower (25 vs 44%).
The investigators caution that their study “recruited too few patients because of the relatively restrictive enrolment criteria and funding limitation of the trial,” and therefore it was “underpowered to draw a sound conclusion on the efficacy of metformin to reduce disease flares as an add-on treatment to standard care in patients with SLE.”
Nevertheless, Ye et al believe that “[c]onsidering the favourable safety profile of metformin and its low cost, this trial suggests a basis for future larger and longer multicentre trials in different ethnic populations.”
Writing in a comment accompanying the research published in The Lancet Rheumatology, Mandana Nikpour (University of Melbourne, Victoria, Australia) says that “the investigators should be commended for their effort to repurpose a drug such as metformin as adjunct therapy in patients with SLE.”
However, she stresses that “in a landscape of multiple competing trials of novel targeted therapies in patients with SLE and the substantial sample size requirements for what is likely to be a modest treatment effect, sufficient recruitment [for large-scale trials] might once again prove difficult.”
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Lancet Rheumatol 2020; doi:10.1016/S2665-9913(20)30004-7
Lancet Rheumatol 2020; doi:10.1016/S2665-9913(20)30040-0