Journal of Shanghai Jiao Tong University (Medical Science) >
Effect of metformin on infection event reduction in patients with systemic lupus erythematosus:a post-hoc analysis of a Met-Lupus Trial
Received date: 2020-05-28
Online published: 2021-05-14
Supported by
National Key Research and Development Program of China(2016YFC0903902);Three-year Action Plan of Shanghai Shenkang Hospital Development Center(16CR1013A);Youth Program of National Natural Science Foundation of China(71804109);Shanghai Health and Family Planning Commission Scientific Research Project for Youth(20174Y0040);National Natural Science Foundation Cultivation Project for Youth of Renji Hospital South Campus, Shanghai Jiao Tong University School of Medicine(2017PYQA08)
·To evaluate the effect of metformin on reducing infection events in the systemic lupus erythematosus (SLE) patients with moderate/low disease activity based on a multicenter, randomized, double-blind, placebo-controlled clinical study (Met-Lupus Trial).
·The 140 participants in the Met-Lupus Trial were randomly divided into the metformin group (67 cases) and the placebo group (73 cases). The metformin tablets or placebo tablets were added to their standard therapy with target dose of 1 500 mg/d, three times per day. The infection events during the 12 months' follow-up of the patients were recorded, including the types of infection events, infection duration, infection severity, and laboratory results during infection. The clinical characteristics between the patients with or without infection as well as between the infected patients treated with metformin or placebo were compared. Multivariate Logistic regression analysis was used to analyze the correlation between metformin and infection events, and survival analysis was used to compare the infection-free survival time between the metformin group and the placebo group.
·By 12 months of follow-up, the exposure rate of metformin in the patients without infection (65.9%) was significantly higher than that in the patients with infection (34.7%, P=0.022), while other clinical parameters were comparable. Multivariate Logistic regression analysis suggested that the use of metformin was an independent protective factor against infection in the SLE patients (OR=0.423, P=0.033). In the infected patients, the severe infection incidence in the metformin group was numerically lower than that in the placebo group, but there was no significant difference (5.9% vs 12.5%, P=0.466). Further analysis showed that the infection duration [7.0 (6.0, 11.8) d] of the metformin group was significantly lower than that of the placebo group [10.0 (7.0, 21.8) d] (P=0.034); meanwhile, the C-reactive protein in the metformin group [2.5 (2.4, 6.4) mg/L] was also lower than that in the placebo group [4.5 (2.5, 8.9) mg/L] without significant difference (P=0.075). Survival analysis showed that infection-free survival of the metformin group was significantly longer than that of the placebo group (HR=0.527, 95%CI 0.294?0.945, P=0.036).
·Metformin may have a potential effect on infection event reduction in the SLE patients with moderate/low disease activity.
Shi-kai GENG , Le ZHANG , Hui-jing WANG , Liang-jing Lü , Wei-guo WAN , Fang-fang SUN , Shuang YE . Effect of metformin on infection event reduction in patients with systemic lupus erythematosus:a post-hoc analysis of a Met-Lupus Trial[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2021 , 41(4) : 473 -478 . DOI: 10.3969/j.issn.1674-8115.2021.04.009
1 | Tsokos GC. Systemic lupus erythematosus[J]. N Engl J Med, 2011, 365(22): 2110-2121. |
2 | Zucchi D, Elefante E, Calabresi E, et al. One year in review 2019: systemic lupus erythematosus[J]. Clin Exp Rheumatol, 2019, 37(5): 715-722. |
3 | 刘喆, 叶霜. 代谢与免疫: 解析系统性红斑狼疮的新视角[J]. 中华风湿病学杂志, 2016, 20(8): 505-507. |
4 | Hahn BH. Belimumab for systemic lupus erythematosus[J]. N Engl J Med, 2013, 368(16): 1528-1535. |
5 | Lai ZW, Kelly R, Winans T, et al. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial[J]. Lancet, 2018, 391(10126): 1186-1196. |
6 | Schneider M. Target therapy in SLE[J]. Autoimmun Rev, 2019, 18(1): 21-24. |
7 | Barber C, Gold WL, Fortin PR. Infections in the lupus patient: perspectives on prevention[J]. Curr Opin Rheumatol, 2011, 23(4): 358-365. |
8 | Danza A, Ruiz-Irastorza G. Infection risk in systemic lupus erythematosus patients: susceptibility factors and preventive strategies[J]. Lupus, 2013, 22(12): 1286-1294. |
9 | Morel L. Immunometabolism in systemic lupus erythematosus[J]. Nat Rev Rheumatol, 2017, 13(5): 280-290. |
10 | Sharabi A, Tsokos GC. T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy[J]. Nat Rev Rheumatol, 2020, 16(2): 100-112. |
11 | Teng X, Brown J, Choi SC, et al. Metabolic determinants of lupus pathogenesis[J]. Immunol Rev, 2020, 295(1): 167-186. |
12 | Teng X, Cornaby C, Li W, et al. Metabolic regulation of pathogenic autoimmunity: therapeutic targeting[J]. Curr Opin Immunol, 2019, 61: 10-16. |
13 | Yin Y, Choi SC, Xu Z, et al. Normalization of CD4+ T cell metabolism reverses lupus[J]. Sci Transl Med, 2015, 7(274): 274ra18. |
14 | Chen FC, Kung CT, Cheng HH, et al. Metformin affects serum lactate levels in predicting mortality of patients with sepsis and bacteremia[J]. J Clin Med, 2019, 8(3):318. |
15 | Pernicova I, Kelly S, Ajodha S, et al. Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial[J]. Lancet Diabetes Endocrinol, 2020, 8(4): 278-291. |
16 | Wang H, Li T, Chen S, et al. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin[J]. Arthritis Rheumatol, 2015, 67(12): 3190-3200. |
17 | Singhal A, Jie L, Kumar P, et al. Metformin as adjunct antituberculosis therapy[J]. Sci Transl Med, 2014, 6(263): 263ra159. |
18 | Marupuru S, Senapati P, Pathadka S, et al. Protective effect of metformin against tuberculosis infections in diabetic patients: an observational study of south Indian tertiary healthcare facility[J]. Braz J Infect Dis, 2017, 21(3): 312-316. |
19 | Malik F, Mehdi SF, Ali H, et al. Is metformin poised for a second career as an antimicrobial?[J]. Diabetes Metab Res Rev, 2018, 34(4): e2975. |
20 | Tsoyi K, Jang HJ, Nizamutdinova IT, et al. Metformin inhibits HMGB1 release in LPS-treated RAW264.7 cells and increases survival rate of endotoxaemic mice[J]. Br J Pharmacol, 2011, 162(7): 1498-1508. |
21 | Kim J, Kwak HJ, Cha JY, et al. Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction[J]. J Biol Chem, 2014, 289(33): 23246-23255. |
22 | Sun F, Wang HJ, Liu Z, et al. Safety and efficacy of metformin in systemic lupus erythematosus: a multicentre, randomised, double-blind, placebo-controlled trial[J]. Lancet Rheumatol, 2020, 2(4): e210-e216. |
23 | Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus[J]. Ann Rheum Dis, 2019, 78(6): 736-745. |
24 | Jorge A, McCormick N, Lu N, et al. Hydroxychloroquine and mortality among patients with systemic lupus erythematosus in the general population[J]. Arthritis Care Res (Hoboken), 2020. DOI: 10.1002/acr.24255. |
25 | Wu W, Ma J, Zhou Y, et al. Mortality risk prediction in lupus patients complicated with invasive infection in the emergency department: LUPHAS score[J]. Ther Adv Musculoskelet Dis, 2019, 11: 1759720X1988555. |
26 | Zhang L, Geng S, Qian L, et al. Multidisciplinary care in patients with systemic lupus erythematosus: a randomized controlled trial in China[J]. Int J Clin Pharm, 2019, 41(5): 1247-1255. |
27 | Garnett JP, Baker EH, Naik S, et al. Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose[J]. Thorax, 2013, 68(9): 835-845. |
28 | Lin SY, Tu HP, Lu PL, et al. Metformin is associated with a lower risk of active tuberculosis in patients with type 2 diabetes[J]. Respirology, 2018(23): 1063-1073. |
29 | Xun YH, Zhang YJ, Pan QC, et al. Metformin inhibits hepatitis B virus protein production and replication in human hepatoma cells[J]. J Viral Hepat, 2014, 21(8): 597-603. |
30 | Patkee WR, Carr G, Baker EH, et al. Metformin prevents the effects of Pseudomonas aeruginosa on airway epithelial tight junctions and restricts hyperglycaemia-induced bacterial growth[J]. J Cell Mol Med, 2016, 20(4): 758-764. |
31 | Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin[J]. Science, 2005, 310(5754): 1642-1646. |
32 | Zhang CS, Li M, Ma T, et al. Metformin activates AMPK through the lysosomal pathway[J]. Cell Metab, 2016, 24(4): 521-522. |
33 | Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action[J]. J Clin Invest, 2001, 108(8): 1167-1174. |
/
〈 |
|
〉 |