Safety and efficacy of metformin in systemic lupus erythematosus: a multicentre, randomised, double-blind, placebo-controlled trial.

Background: Immunometabolism is involved in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to repurpose metformin, an anti-diabetic drug that regulates systemic and cellular metabolism, and assess its effects in Chinese patients with SLE without diabetes.

Methods: We did a multicentre, randomised, double-blind, placebo-controlled trial in three hospitals in Shanghai, China. We enrolled adult patients with SLE, without diabetes, who had Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores no higher than 6; with no A score or no more than one B score on the British Isles Lupus Assessment Group (BILAG) scale at screening; who had had at least one lupus flare; and were treated with prednisone (≥20 mg per day) within the preceding 12 months. Patients were randomly assigned (1:1) in blocks of four by a computer algorithm to add metformin tablets (250 mg per tablet with a target dose of 0·5 g three times per day; metformin group) or placebo tablets (placebo group) to their standard therapy, for a maximum of 12 months. Patients, assessment staff, and statisticians were masked to group assignment. The primary endpoint was a composite index of major or mild-to-moderate disease flares (SELENA-SLEDAI Flare Index) at 12 months. The full analyses were done in all patients who received at least one dose of the study drug using the χ test. Adverse events were recorded during the 12-month follow-up. This study is registered with ClinicalTrials.gov, NCT02741960.

Findings: Between May 24, 2016, and Dec 13, 2017, 180 patients were screened, of whom 140 (78%) of them were enrolled. 31 (17%) did not meet the inclusion criteria and nine (5%) withdrew informed consent without treatment after randomisation. 67 patients were assigned to the metformin group and 73 to the placebo group. By 12 months of follow-up, there was no significant difference in the incidence of lupus flares, which occurred in 14 (21%) patients in the metformin group versus 25 (34%) in the placebo group (relative risk 0·68, 0·42-1·04, p=0·078). Patients receiving metformin experienced more gastrointestinal adverse events (three [4%] discontinued for this reason vs one [1%] for placebo; overall 26 [39%] vs 11 [15%], p=0·0015), but the incidence of non-flare serious adverse events was similar between groups (one [1%] vs three [4%], p=0·35). The frequency of infection events was significantly lower in patients in the metformin group than in the placebo group (17 [25%] vs 32 [44%], p=0·022). No patients died as a result of treatment.

Interpretation: This trial 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. Nonetheless, metformin had a favourable safety profile and our data present a basis for larger trials to investigate its potential effect on reducing the frequency of flares for patients with SLE with low-grade disease activity who are at risk of relapse.

Funding: Shanghai Shenkang Promoting Project and the National Key Research and Development Program of China.