Effect of metformin on infection event reduction in patients with systemic lupus erythematosus:a post-hoc analysis of a Met-Lupus Trial

doi:10.3969/j.issn.1674-8115.2021.04.009

Abstract

Abstract: Objective

·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).

Methods

·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.

Results

·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).

Conclusion

·Metformin may have a potential effect on infection event reduction in the SLE patients with moderate/low disease activity.

Key words: systemic lupus erythematosus (SLE), metformin, infection, randomized controlled study

CLC Number:

R593.24

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 JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(4): 473-478.

Figures/Tables 4

TrendMD

References 33

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Indicator	With infection （n=49）	Without infection （n=91）	P value
Female/n(%)	45 (91.8)	86 (94.5)	0.539
Age/year	35.1±12.8	32.1±10.9	0.255
Disease duration/year	5.2±5.3	4.5±3.7	0.779
BMI/(kg·m^－2)	23.5±4.0	22.7±3.5	0.221
Complication/n(%)	10 (20.4)	21 (23.1)	0.717
Lupus nephritis	6 (12.2)	16 (17.6)	0.408
Immune thrombocytopenia	2 (4.1)	3 (3.3)	0.811
Antiphospholipid syndrome	1 (2.0)	1 (1.1)	0.666
Pulmonary hypertension	1 (2.0)	1 (1.1)	0.666
SELENA-SLEDAI	2.4±1.8	2.7±1.6	0.481
Laboratory result
White blood cell/(×10⁹·L^－1)	6.0 (4.7, 8.0)	5.4 (4.2, 7.3)	0.270
Neutrophil/(×10⁹·L^－1)	4.2±2.2	3.9±1.9	0.428
Lymphocyte/(×10⁹·L^－1)	1.4 (1.0, 1.9)	1.5 (1.1, 2.0)	0.317
Hemoglobin/(g·L^－1)	127.3±14.0	125.6±21.7	0.810
Platelet/(×10⁹·L^－1)	223.5 (159.5, 270.0)	213.0 (162.8, 263.5)	0.814
ESR/(mm·h^－1)	11.0 (7.0, 28.0)	13.0 (5.3, 30.0)	0.641
CRP/(mg·L^－1)	2.5 (2.0, 4.3)	2.5 (1.0, 4.0)	0.694
GPT /(U·L^－1)	16.4±11.7	20.5±16.2	0.203
Serum creatinine/ (μmol·L^－1)	57.9±9.4	57.9±12.6	0.784
Anti-dsDNA antibody/ (IU·mL^－1)	22.0 (4.3, 53.1)	30.0 (14.7, 87.5)	0.176
Complement 3/(g·L^－1)	0.8±0.3	0.8±0.2	0.782
Complement 4/(g·L^－1)	0.2±0.0	0.1±0.1	0.161
IgG/(g·L^－1)	13.9±4.8	14.5±5.5	0.703
IgM/(g·L^－1)	0.7±1.3	0.5±0.6	0.856
IgA/(g·L^－1)	2.9±2.1	2.3±1.4	0.171
Medication
Prednisone/(mg·d^－1)	10.0 (7.5, 15.0)	10.0 (6.3, 15.0)	0.914
Hydroxychloroquine/n (%)	44 (89.8)	82 (90.1)	0.539
Immunosuppressants/n (%)	33 (67.4)	60 (65.9)	0.866
Azathioprine	2 (4.1)	7 (7.7)	0.406
Mycophenolate	18 (36.7)	29 (31.9)	0.561
Calcineurin inhibitor	4 (8.2)	6 (6.6)	0.731
Methotrexate	8 (16.3)	16 (17.6)	0.851
Leflunomide	1 (2.0)	2 (2.2)	0.951
Metformin/n(%)	17 (34.7)	50 (65.9)	0.022

Indicator	With infection （n=49）	Without infection （n=91）	P value
Female/n(%)	45 (91.8)	86 (94.5)	0.539
Age/year	35.1±12.8	32.1±10.9	0.255
Disease duration/year	5.2±5.3	4.5±3.7	0.779
BMI/(kg·m^－2)	23.5±4.0	22.7±3.5	0.221
Complication/n(%)	10 (20.4)	21 (23.1)	0.717
Lupus nephritis	6 (12.2)	16 (17.6)	0.408
Immune thrombocytopenia	2 (4.1)	3 (3.3)	0.811
Antiphospholipid syndrome	1 (2.0)	1 (1.1)	0.666
Pulmonary hypertension	1 (2.0)	1 (1.1)	0.666
SELENA-SLEDAI	2.4±1.8	2.7±1.6	0.481
Laboratory result
White blood cell/(×10⁹·L^－1)	6.0 (4.7, 8.0)	5.4 (4.2, 7.3)	0.270
Neutrophil/(×10⁹·L^－1)	4.2±2.2	3.9±1.9	0.428
Lymphocyte/(×10⁹·L^－1)	1.4 (1.0, 1.9)	1.5 (1.1, 2.0)	0.317
Hemoglobin/(g·L^－1)	127.3±14.0	125.6±21.7	0.810
Platelet/(×10⁹·L^－1)	223.5 (159.5, 270.0)	213.0 (162.8, 263.5)	0.814
ESR/(mm·h^－1)	11.0 (7.0, 28.0)	13.0 (5.3, 30.0)	0.641
CRP/(mg·L^－1)	2.5 (2.0, 4.3)	2.5 (1.0, 4.0)	0.694
GPT /(U·L^－1)	16.4±11.7	20.5±16.2	0.203
Serum creatinine/ (μmol·L^－1)	57.9±9.4	57.9±12.6	0.784
Anti-dsDNA antibody/ (IU·mL^－1)	22.0 (4.3, 53.1)	30.0 (14.7, 87.5)	0.176
Complement 3/(g·L^－1)	0.8±0.3	0.8±0.2	0.782
Complement 4/(g·L^－1)	0.2±0.0	0.1±0.1	0.161
IgG/(g·L^－1)	13.9±4.8	14.5±5.5	0.703
IgM/(g·L^－1)	0.7±1.3	0.5±0.6	0.856
IgA/(g·L^－1)	2.9±2.1	2.3±1.4	0.171
Medication
Prednisone/(mg·d^－1)	10.0 (7.5, 15.0)	10.0 (6.3, 15.0)	0.914
Hydroxychloroquine/n (%)	44 (89.8)	82 (90.1)	0.539
Immunosuppressants/n (%)	33 (67.4)	60 (65.9)	0.866
Azathioprine	2 (4.1)	7 (7.7)	0.406
Mycophenolate	18 (36.7)	29 (31.9)	0.561
Calcineurin inhibitor	4 (8.2)	6 (6.6)	0.731
Methotrexate	8 (16.3)	16 (17.6)	0.851
Leflunomide	1 (2.0)	2 (2.2)	0.951
Metformin/n(%)	17 (34.7)	50 (65.9)	0.022

Factor	β value	Standard error	Wald value	P value	OR (95%CI)
Gender	0.176	0.818	0.046	0.829	1.193 (0.240－5.930)
Age	0.018	0.017	1.123	0.289	1.018 (0.985－1.053)
SELENA-SLEDAI	0.125	0.133	0.876	0.349	1.133 (0.872－1.471)
Neutrophil	0.025	0.110	0.053	0.818	1.026 (0.827－1.272)
Prednisone	-0.022	0.035	0.381	0.537	0.979 (0.914－1.048)
Use of hydroxychloroquine	1.014	0.826	1.506	0.220	2.755 (0.546－13.905)
Use of metformin	-0.860	0.404	4.536	0.033	0.423 (0.192－0.934)

Factor	β value	Standard error	Wald value	P value	OR (95%CI)
Gender	0.176	0.818	0.046	0.829	1.193 (0.240－5.930)
Age	0.018	0.017	1.123	0.289	1.018 (0.985－1.053)
SELENA-SLEDAI	0.125	0.133	0.876	0.349	1.133 (0.872－1.471)
Neutrophil	0.025	0.110	0.053	0.818	1.026 (0.827－1.272)
Prednisone	-0.022	0.035	0.381	0.537	0.979 (0.914－1.048)
Use of hydroxychloroquine	1.014	0.826	1.506	0.220	2.755 (0.546－13.905)
Use of metformin	-0.860	0.404	4.536	0.033	0.423 (0.192－0.934)

Indicator	Metformin (n=17)	Placebo (n=32)	P value
Female/n(%)	15 (88.2)	30 (93.8)	0.502
Age/year	36.6±14.4	34.3±12.0	0.634
Disease duration/year	5.2±5.8	5.1±5.0	0.846
BMI/(kg·m^－2)	22.1±3.1	24.3±4.1	0.056
SELENA-SLEDAI	2.4±1.7	3.1±2.1	0.184
Laboratory result
White blood cell/ (×10⁹·L^－1)	5.9 (4.52, 7.5)	6.0 (4.5, 7.3)	0.852
Neutrophil/(×10⁹·L^－1)	4.7±2.3	5.5±1.9	0.446
Platelet/(×10⁹·L^－1)	223.5 (159.5, 267.3)	230.5 (176.5, 276.8)	0.582
ESR/(mm·h^－1)	25.5 (10.5, 44.5)	17.0 (7.3, 30.8)	0.185
CRP/(mg·L^－1)	2.5 (2.4, 6.4)	4.5 (2.5, 8.9)	0.075
Anti-dsDNA antibody/ (IU·mL^－1)	23.0 (4.5, 34.1)	22.0 (3.0, 62.2)	0.622
Complement 3/(g·L^－1)	0.9±0.3	0.8±0.2	0.087
Complement 4/(g·L^－1)	0.2±0.1	0.2±0.1	0.112
IgG/(g·L^－1)	3.3±1.9	2.9±2.5	0.997
IgM/(g·L^－1)	17.9±10.0	15.8±7.5	0.331
IgA/(g·L^－1)	1.2±0.6	1.0±0.4	0.746
Medication
Prednisone/(mg·d^－1)	5.0 (3.8, 7.5)	6.9 (5.0, 12.5)	0.084
Hydroxychloroquine/n (%)	15 (88.2)	29 (90.6)	0.793
Immunosuppressants/n (%)	13 (76.5)	20 (62.5)	0.321
Infection duration/d	7.0 (6.0, 11.8)	10.0 (7.0, 21.8)	0.034
Infection/n (%)			0.466
Severe infection	1 (5.9)	4 (12.5)
Mild infection	16 (94.1)	28 (87.5)