Methotrexate reduces HbA1c concentration but does not produce chronic accumulation of ZMP in patients with rheumatoid or psoriatic arthritis

Perdan-Pirkmajer, Katja; Pirkmajer, Sergej; Thevis, Mario; Thomas, Andreas; Praprotnik, Sonja; Hočevar, Alojzija; Rotar, Žiga; Gašperšič, N.; Sodin‐Šemrl, Snežna; Žibert, Janez; Omersel, Jasna; Chibalin, Alexander V.; Tomšič, Matija; Ambrožič, Aleš

doi:10.3109/03009742.2015.1105290

Cited by 14 publications

(12 citation statements)

References 26 publications

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“…These effects are not necessarily associated with direct actions on insulin resistance and/or pancreatic β cell function [24,25,27], but rather to a reduction of low-grade inflammation by inhibiting the inflammasome [28]. Methotrexate (MTX) also reduces glycosylated haemoglobin (HbA1c) levels and the risk for diabetes in patients with RA [29], likely independently of insulin sensitivity [30].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials

et al. 2020

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Background Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes. Methods Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes. Results Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was − 0.28 (− 0.40, − 0.16; nominal p < 0.0001) and − 0.42 (− 0.54, − 0.31; nominal p < 0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40 mg at week 24 was − 0.13 (− 0.22, − 0.04; nominal p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA. Conclusions In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings. Trial registration ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.

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Section: Introductionmentioning

confidence: 99%

Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials

et al. 2020

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“…Although it is now well established that insulin resistance (IR) represents the pathophysiological hallmark of MS [ 9 ], the mechanism leading to IR/MS in PsA patients is only partially explained by the abnormal metabolic phenotype [ 10 ] and could be accounted for also by the negative impact of TNF-α and other inflammatory cytokines on insulin signaling [ 11 ] and altered balance in adipocytokines [ 12 ]. The so-called “inflammatory” hypothesis is supported by the evidence that disease-modifying antirheumatic drugs (DMARDs) [ 13 ] and biologic agents [ 14 – 18 ] have been demonstrated to improve insulin sensitivity in inflammatory arthritis patients.…”

Section: Introductionmentioning

confidence: 99%

Complement C3 Is the Strongest Predictor of Whole-Body Insulin Sensitivity in Psoriatic Arthritis

et al. 2016

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ObjectivesTo evaluate the correlation between inflammatory measures and whole-body insulin sensitivity in psoriatic arthritis (PsA) patients.MethodsFor the present study, 40 nondiabetic PsA patients were recruited. A standard oral glucose tolerance test (OGTT) was performed. The insulin sensitivity index (ISI), insulinogenic index (IGI) and oral disposition index (ODI) were calculated from dynamic values of glucose and insulin obtained during OGTT.ResultsIn our study population, mean ISI was 3.5 ± 2.5, median IGI was 1.2 (0.7–1.8), mean ODI 4.5 ± 4.5. In univariate correlation analysis, ISI correlated inversely with systolic blood pressure (sBP) (R = -0.52, p = 0.001), diastolic blood pressure (dBP) (R = -0.45, p = 0.004) and complement C3 (R = -0.43, p = 0.006) and ODI correlated inversely with sBP (R = -0.38, p = 0.02), dBP (R = -0.35, p = 0.03) and complement C3 (R = -0.37, p = 0.02). No significant correlations were found between analyzed variables and IGI. In a stepwise multiple regression, only complement C3 entered in the regression equation and accounted for approximately 50% of the variance of ISI. Using a receiver operating characteristic (ROC) curve we identified the best cut-off for complement C3 of 1.32 g/L that yielded a sensitivity of 56% and a specificity of 96% for classification of insulin resistant patients.ConclusionsIn conclusion, our data suggest that serum complement C3 could represent a useful marker of whole-body insulin sensitivity in PsA patients.

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“…However, in a large retrospective study of patients with RA or psoriasis, use of a TNFi was associated with a decreased risk for diabetes whereas use of methotrexate was not [ 25 ]. In other studies, significant decreases were not seen in the HOMA-IR index with initiation of MTX [ 23 , 24 , 26 ].…”

Section: Introductionmentioning

confidence: 76%

“…Little is known about the role of MTX in insulin resistance and existing studies have conflicting messages. One study observed decreases in HbA1c in RA and PsA patients without diabetes taking MTX [ 23 ]. In addition, the prevalence of metabolic syndrome in patients with RA was found to be lower among patients using methotrexate, though this data may be confounded by the steatohepatitis leading to discontinuation of methotrexate [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of tumor necrosis factor inhibitors and methotrexate on diabetes mellitus among patients with inflammatory arthritis

et al. 2020

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Background To determine whether initiation of a tumor necrosis factor inhibitor (TNFi) or methotrexate improves hemoglobin A1c in patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), or ankylosing spondylitis (AS) who also have diabetes mellitus (DM). Methods A retrospective cohort study was conducted in Optum’s de-identified Clinformatics® Data Mart Database, an administrative claims database, using data from 2000 to 2014. Patients with PsA, RA, or AS, with DM (defined by ICD-9-CM codes) and/or HbA1c ≥7%, who newly initiated either a TNFi, MTX, or metformin (positive control) were identified. The change in HbA1c after drug initiation was calculated. Statistical differences in the change in HbA1c between drugs were assessed using the Wilcoxon rank sum test and linear regression models adjusting for potential confounders. Results Among 10,389 drug initiations in 9541 patients with PsA, RA, or AS, and available HbA1c values, HbA1c was ≥7 at baseline in 254 (35%) TNFi initiations, 361(37%) MTX initiations, and 2144 (50%) metformin initiations. Median HbA1c change was − 0.35 (IQR -1.10, 0.30) after TNFi initiation, − 0.40 (IQR -1.20, 0.30) after MTX initiation, and − 0.80 (IQR -1.60, − 0.10) after metformin initiation. In adjusted analyses, TNFi initiators had less of a decrease in HbA1c compared to MTX initiators (β 0.22, 95% CI: 0.004, 0.43), p = 0.046. Metformin initiators had a significantly greater decrease in HbA1c than MTX, β − 0.38 (95% CI: − 0.52, − 0.23), p < 0.001. Glucocorticoid use was not accounted for in the models. Conclusion HbA1c decreased with TNFi initiation or MTX initiation. Reductions in HbA1c after initiation of a TNFi or MTX are about half ( ~ 0.4 units) the decrease observed after initiation of metformin.

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Methotrexate reduces HbA1c concentration but does not produce chronic accumulation of ZMP in patients with rheumatoid or psoriatic arthritis

Abstract: MTX therapy probably does not produce a chronic increase in erythrocyte ZMP or urinary AICAR concentrations. Collectively, our data do not support the hypothesis that MTX improves glucose homeostasis through chronic accumulation of ZMP.

Cited by 14 publications

References 26 publications

Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials

Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials

Complement C3 Is the Strongest Predictor of Whole-Body Insulin Sensitivity in Psoriatic Arthritis

Impact of tumor necrosis factor inhibitors and methotrexate on diabetes mellitus among patients with inflammatory arthritis

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