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

ABSTRACT: OBJECTIVE:To 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. METHODS:Post 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. RESULTS:Overall, 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. CONCLUSION:Post hoc pooled analyses suggested that metformin reduced subsequent disease flares in patients with SLE with low disease activity, especially for serologically quiescent patients.

SUBMITTER: Sun F

PROVIDER: S-EPMC7583791 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Sun Fangfang F Geng Shikai S Wang Haiting H Wang Huijing H Liu Zhe Z Wang Xiaodong X Li Ting T Wan Weiguo W Lu Liangjing L Teng Xiangyu X Morel Laurence L Ye Shuang S

Lupus science & medicine 20201001 1

<h4>Objective</h4>To 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.<h4>Methods</h4>Post 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 ...[more]

PMID: 33093216

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Project description:ObjectiveTo investigate changes in B cell subsets in relation to disease flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with systemic lupus erythematosus (SLE).Patients and methodsUsing data from the BLISS-76, BLISS-SC and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) changes in peripheral B cell subsets, anti-dsDNA and complement levels with the occurrence of disease flares from week 24 through week 52 (Mann-Whitney U tests) or the entire study follow-up (Cox regression analysis), assessed using the SELENA-SLEDAI Flare Index.ResultsPatients on ST alone who flared displayed less prominent early decreases in CD19+CD20-CD138+ long-lived plasma cells (-16.1% versus -35.1%; P=0.012). In all arms combined, patients who developed severe flares showed less prominent early decreases in CD19+CD20-CD138+ long-lived plasma cells (-23.5% versus -39.4%; P=0.028) and CD19+CD27brightCD38bright SLE-associated plasma cells (-19.0% versus -27.8%; P=0.045). After adjustment for rapid changes, early increases in overall CD19+CD20+ B cells (HR: 1.81; 95% CI: 1.08-3.05; P=0.024) and early increases or no return after a rapid expansion in CD19+CD20+CD27+ memory B cells (HR: 1.58; 95% CI: 1.18-2.11; P=0.002) portended subsequent severe flares. Patients who developed flares of any severity showed no or less prominent rapid (0.0% versus -12.5%; P<0.001) or early (-1.9% versus -21.7%; P<0.001) decreases in anti-dsDNA levels, and patients who developed severe flares showed no or less prominent early decreases in anti-dsDNA levels (0.0% versus -13.3%; P=0.020). Changes in complement levels exhibited no ability to distinguish flaring from non-flaring patients.ConclusionsIncrease or lack of decrease in certain circulating B cell subsets or anti-dsDNA levels upon treatment initiation for active SLE heralded subsequent severe disease flares. A rapid expansion of memory B cells may signify sustained response to therapy when followed by a subsequent drop, while no return or delayed increases in memory B cells may portend flaring. Peripheral B cell and serological marker kinetics may help identify patients in whom therapeutic modifications could protect against flare development, and may hence prove a useful complement to traditional surveillance and early treatment evaluation in SLE.

Project description:ObjectiveEMBODY 1 (ClinicalTrials.gov identifier: NCT01262365) and EMBODY 2 (ClinicalTrials.gov identifier: NCT01261793) investigated the efficacy and safety of epratuzumab, a CD22-targeted humanized monoclonal IgG antibody, in patients with systemic lupus erythematosus (SLE). The studies showed no significant difference from placebo in primary or secondary clinical outcome measures but did demonstrate B cell-specific immunologic activity. The aim of this post hoc analysis was to determine whether epratuzumab had a different clinical efficacy profile in SLE patients with versus those without an associated diagnosis of Sjögren's syndrome (SS).MethodsThe efficacy and safety of epratuzumab were compared between 2 patient subpopulations randomized in EMBODY 1 and 2: SLE patients with and those without a diagnosis of associated SS. British Isles Lupus Assessment Group (BILAG) total score, BILAG-based Combined Lupus Assessment (BICLA) clinical response to treatment, biologic markers (including B cells, IgG, IgM, and IgA), and safety were assessed.ResultsA total of 1,584 patients were randomized in the EMBODY 1 and EMBODY 2 trials; 113 patients were anti-SSA positive and had a diagnosis of associated SS, and 1,375 patients (86.8%) had no diagnosis of associated SS (918 patients were randomized to receive epratuzumab and 457 to receive placebo). For patients with associated SS, but not those without associated SS, a higher proportion of patients receiving epratuzumab achieved a BICLA response and a reduction from baseline in BILAG total score. B cell reduction was faster in patients with associated SS. The sensitivity of B cells to epratuzumab as measured by the mean concentration producing 50% of the maximum B cell count depletion was lower for patients with associated SS (9.5 μg/ml) versus the total EMBODY population (87.1 μg/ml). No difference in the frequency of adverse events in those receiving placebo was reported.ConclusionPatients with SLE and associated SS treated with epratuzumab showed improvement in SLE disease activity, which was associated with bioactivity, such as decreases in B cell number and IgM level.

Project description:ObjectiveSystemic lupus erythematosus (SLE) is characterized by widespread organ inflammation. Metformin, commonly used for diabetes mellitus type 2, has been explored for its anti-inflammatory potential in SLE. This study investigates the association of metformin use on renal and cardiovascular outcomes in patients with SLE.MethodsThis is a retrospective study. We used the multicenter research network (TriNetX) database from 88 health care organizations globally. Patients with SLE aged 18 and above, admitted between January 1, 2014, and April 21, 2024, were included. Propensity score matching compared patients with SLE on metformin with those not on metformin, considering demographics, laboratory results, comorbidities, and baseline medication use. The study assessed outcomes, including lupus nephritis (LN), chronic kidney disease (CKD), and major adverse cardiovascular events (MACEs) at one and five years after SLE diagnosis.ResultsWe identified 9,178 patients with SLE on metformin and 78,983 patients with SLE not on metformin. After propensity score matching, patients with SLE on metformin had higher levels of hemoglobin A1C, whereas patients not on metformin had higher levels of urea nitrogen. When comparing both groups, the risk of developing LN (risk ratio [RR] = 1.70 [1.17-2.41]; P = 0.004), CKD (RR = 1.27 [1.07-1.52]; P = 0.007), and MACEs (RR = 1.21 [1.00-1.46]; P = 0.04) was significantly higher among patients not on metformin at one year after SLE diagnosis. After five years, the risk of LN and CKD was also higher in patients with SLE not on metformin. MACE risk was no longer significant after five years of diagnosis between both groups.ConclusionPatients with SLE not on metformin have a higher risk of developing LN, CKD, and MACEs compared with patients treated with metformin. Metformin's anti-inflammatory potential offers promise as a complementary therapy for SLE. Nonetheless, further research and clinical trials are needed to clarify its mechanisms, optimal dosage, and long-term effects.

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

Publications

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

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