Systemic lupus erythematosus, a chronic autoimmune disease is difficult to treat despite advancements in this field. Three questions that are always pose a challenge while considering treatment goals of this disease are, ‘How to control active disease?’, ‘How to minimise accrual organ damage?’ and ‘How to prevent disease flares?’. Of these , the last question is burdensome. Due to the intrinsic immuno-metabolic abnormalities of this disease, metformin, a commonly used oral hypoglycemic agent, add-on to standard therapy appears a promising metabolic approach for preventing flares.

To confirm that metformin prevents flares in patients with systemic lupus erythematosus with low disease activity, the researchers conducted a post hoc analysis combining 2previous randomised trials: the open-labelled proof-of-concept trial involving 113 patients and placebo-controlled Met Lupus trial with 140 patients. These trials compared the effectiveness of metformin with placebo/nil add-on to standard therapy in patients with systemic lupus erythematosus with low disease activity (SELENA-SLEDAI ≤4). SELENA-SLEDAI Flare Index was used to define the primary endpoint at 12-month follow-up. A subgroup analysis was done. In this study, a total of 201 eligible patients were included. Of these, 99 were allocated to metformin group and 102 to the placebo/nil group. By 12 months of follow-up, only 21 patients (21.2%) flared in the metformin group, while the figure was 36 (35.3%) in the placebo/nil group (p=0.027, risk ratio=0.68, 95% CI 0.46 to 0.96). It is noteworthy that patients who took metformin had less major flares (12.1% vs 23.5%, p=0.035, RR 0.63, 95% CI 0.38 to 0.97). On analysing flare-free and major flare-free survival, it was seen that metformin reduced disease flares by 45% (adjusted HR 0.55, 95% CI 0.32 to 0.94) and major flares by 51% (adjusted HR 0.49, 95% CI 0.25 to 0.99) within an year. Subgroup analysis showed better response to metforminin patients who had negative anti-ds DNA antibody and normal complement, disease duration less than 5 years and used to take hydroxychloroquine.

The researchers of this study suggested possible efficacy of metformin in patients with systemic lupus erythematosus with low disease activity in regard to preventing disease flares, especially for serologically quiescent patients. Furthermore, they mentioned that metformin may have a synergic effect with hydroxychloroquine. However, no such effect was observed with other immune suppressants, like mycophenolate mofetil. Metformin also indirectly blocks mammalian target of rapamycin (mTOR), which is a canonical target of sirolimus, an immunosuppressant used in the treatment of systemic lupus erythematosus.

Reference

1. Sun F, Geng S, Wang H, et al. Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials. Lupus Sci Med. 2020 Oct;7(1):e000429.