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

Sun, Fangfang; Wang, Hui Jing; Liu, Zhe; Geng, Shikai; Wang, Hai Ting; Wang, Xiaodong; Li, Ting; Morel, Laurence; Wan, Weiguo; Lu, Liangjing; Teng, Xiangyu; Ye, Shuang

doi:10.1016/s2665-9913(20)30004-7

Cited by 44 publications

(31 citation statements)

References 28 publications

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“…The primary endpoint of reducing disease flares within 12 months was unmet, although a lower frequency was observed (metformin: 20.9% vs placebo: 34.2%, p=0.08). 3 Nevertheless, the safety profile of metformin was consistently good in these two trials. To further address the lupus flare prevention outcome, we carried out a post hoc analysis by combining the aforementioned two trials, which were the only two existing and similarly designed.…”

Section: Introductionmentioning

confidence: 87%

“… 1 Thus, we initiated a multicentre, randomised, double-blind placebo-controlled trial (‘Met Lupus’ Trial) to further evaluate the efficacy and safety of metformin in low-grade activity (baseline SELENA-SLEDAI ≤6, prednisone ≤20 mg/day) Chinese patients with SLE at risk of flares (with documented flare within 12 months before screening). 3 However, this trial was under-recruited to draw a definite conclusion. The primary endpoint of reducing disease flares within 12 months was unmet, although a lower frequency was observed (metformin: 20.9% vs placebo: 34.2%, p=0.08).…”

Section: Introductionmentioning

confidence: 99%

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Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials

et al. 2020

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ObjectiveTo confirm that metformin prevents flares in patients with SLE with low disease activity, we performed a post hoc analysis combining our previous two randomised trials.MethodsPost hoc analyses were performed on data from the open-labelled proof-of-concept trial (n=113, ChiCTR-TRC-12002419) and placebo-controlled ‘Met Lupus’ trial (n=140, NCT02741960) comparing the efficacy of metformin versus placebo/nil add-on to standard therapy in patients with SLE with low disease activity (SELENA-SLEDAI ≤4). The primary endpoint was defined by the SELENA-SLEDAI Flare Index at 12-month follow-up. A subgroup analysis was performed.ResultsOverall, 201 eligible patients were included, with 99 allocated to metformin group and 102 allocated to the placebo/nil group. By 12 months of follow-up, 21 patients (21.2%) flared in the metformin group, as compared with 36 (35.3%) in the placebo/nil group (p=0.027, risk ratio=0.68, 95% CI 0.46 to 0.96). Subgroup analysis showed that patients with negative anti-dsDNA antibody and normal complement at baseline, and a disease duration <5 years with concomitant use of hydroxychloroquine had a better response to metformin.ConclusionPost hoc pooled analyses suggested that metformin reduced subsequent disease flares in patients with SLE with low disease activity, especially for serologically quiescent patients.

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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials

et al. 2020

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“…This means that while the data may seem contradictory it is more likely that there is a complex feedback network regulating IFN signaling and mitochondrial oxidative stress in SLE. Along with the clinical progress of repurposing metabolic modulators, such as metformin, in the management of SLE [ 8 , 32 , 33 ], our data may offer additional insight into the immunometabolism of SLE.…”

Section: Discussionmentioning

confidence: 90%

“…There is a growing belief that metabolic modulators (metformin and/or 2-Deoxy-D-glucose) could restore their cellular function and reverse certain disease phenotypes, this theory is supported by several studies using mouse models of lupus [ 4 , 6 , 7 ]. In addition, our recent clinical trials suggest that the addition of metformin to the standard of care for these patients may reduce the risk of a lupus flare [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

tRNA derived fragment (tRF)-3009 participates in modulation of IFN-α-induced CD4+ T cell oxidative phosphorylation in lupus patients

et al. 2021

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Background Accumulating evidence suggests tRNA-derived fragments (tRFs) play important roles in cellular homeostasis. Here we aimed to explore aberrant expression of tRFs in CD4+ T cells from patients with systemic lupus erythematosus (SLE) and their potential function in the SLE pathogenesis. Methods First, small RNA sequencing was performed on CD4+ T cells from four SLE patients and three healthy controls (HCs). Candidate tRFs were then validated in CD4+ T cells from 97 SLE patients and their relevant disease controls using qRT-PCR. Then sequencing was used to investigate the profiles of HC-derived CD4+ T cells transfected with tRF-3009. Lastly, tRF-3009 siRNA or tRF-3009 mimics were transfected into CD4+ T cells with/without IFN-α. Changes in oxygen consumption rate (OCR), ATP, and ROS production were analyzed. Results We identified 482 differentially expressed tRFs from SLE CD4+ T cells and chose tRF-3009 for further analysis due to its upregulation and the positive correlations between its expression and SLEDAI, active lupus nephritis and serum IFN-α levels. In vitro, tRF-3009 over-expressing CD4+ T cell profiling and putative analysis linked this product to the type I IFN and oxidative phosphorylation (OXPHOS) pathways. Interestingly, IFN-α is capable of inducing ROS and ATP production in CD4+ T cells, while knockdown of tRF-3009 reversed this process. Overexpression of tRF-3009 in CD4+ T cells alone was sufficient to upregulate OCR, ROS, and ATP production. Conclusions Our study is the first to link aberrant tRF expression and SLE. tRF-3009 may participate in metabolic modulation of IFN-α-induced CD4+ T cell OXPHOS in lupus.

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“…In a separate study, metformin given alongside the glycolytic inhibitor 2-DG was shown to ameliorate autoimmune pathology in lupus-prone mice (134). A recent clinical trial into the efficacy of metformin in SLE patients found no efficacy in reducing the incidence of disease flares, although pooled analysis with a previous trial suggested a modest reduction in flare incidence was achieved, warranting further investigation (135,136).…”

Section: B Cell Metabolism and Autophagy As Therapeutic Targetsmentioning

confidence: 99%

B Cell Metabolism and Autophagy in Autoimmunity

Raza

Clarke

2021

Front. Immunol.

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B cells are central to the pathogenesis of multiple autoimmune diseases, through antigen presentation, cytokine secretion, and the production of autoantibodies. During development and differentiation, B cells undergo drastic changes in their physiology. It is emerging that these are accompanied by equally significant shifts in metabolic phenotype, which may themselves also drive and enforce the functional properties of the cell. The dysfunction of B cells during autoimmunity is characterised by the breaching of tolerogenic checkpoints, and there is developing evidence that the metabolic state of B cells may contribute to this. Determining the metabolic phenotype of B cells in autoimmunity is an area of active study, and is important because intervention by metabolism-altering therapeutic approaches may represent an attractive treatment target.

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

Cited by 44 publications

References 28 publications

Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials

Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials

tRNA derived fragment (tRF)-3009 participates in modulation of IFN-α-induced CD4+ T cell oxidative phosphorylation in lupus patients

B Cell Metabolism and Autophagy in Autoimmunity

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