A systematic review and meta-analysis evaluating the effect of methotrexate use on the development of type 2 diabetes in rheumatoid arthritis patients

Rheumatoid arthritis (RA) patients treated with methotrexate are at lower risk of developing type 2 diabetes when compared to RA patients not treated with methotrexate.

Rheumatoid arthritis (RA) is often associated with deformities in joint and extra-articular manifestations including the renal, respiratory and cardiovascular (CV) systems. CV disease is the most common and serious complication of RA, presenting excess risk of 48% CV morbidity and 60% CV mortality among RA patients. This potential burden of CV disease is increasing worldwide.

The risk of CV disease among RA patients was thought to be triggered by the coexistence of systemic inflammation, but there are no definite evidences to demonstrate the role of inflammation in increasing the risk of CV disease among RA patients. But, several studies had determined that risk of CV disease increases with presence of traditional risk factors such as high obesity, blood pressure, type 2 diabetes (T2D), hypercholesterolemia, physical inactivity and smoking. This association explains that CV disease among RA patients may occur due to presence of other CV risk factors. The findings of a previous systematic review also reported that the risk of CV disease increases in RA patients with various risk factors such as hypertension, T2D, smoking, hypercholesterolemia and obesity.

Several other studies have also evaluated the impact of T2D in increasing CV risk among RA patients. In comparison to non-diabetic RA patients, RA patients with diabetes presented twice the risk of developing CV disease. Moreover, diabetic RA patients are at an increased risk of CV events as compared to general population. There is no clear mechanism how T2D increase the risk of CV, however, emerging evidences suggest that a substantial increase in insulin resistance due to rheumatic disease can be a prominent factor. As per the recent randomized trials insulin resistance also decreases with the use of the conventional disease-modifying anti-rheumatic drugs (cDMARDs), mainly methotrexate (MTX) and infliximab. Another evidences suggested that MTX, in combination with B vitamin analogue and folic acid provide cardiovascular benefits in RA patients. Emerging evidences MTX not only lowered the CV risk but also risk of CV risk factors such as hypertension but there exist some inconsistencies in the effect of MTX on other CV risk factors such as T2D.

Rationale behind research:

Previous studies have shown a reduction in prevalence of T2D among patients treated with DMARDs but conclusive evidence about this protective effect is still lacking. Therefore, the present systematic review and meta analysis was conducted to determine the impact of MTX on development of T2D among RA patients.

Objective:

The present study aimed to evaluate the strength of the association between exposure to MTX and the rate of development of T2D in RA patients using systematic review of literature and a meta-analysis of eligible studies.

Literature search:

A systematic literature search was performed from Pre-Medline, Medline, Cochrane and Scopus databases until March 2020.  All the articles evaluating relationship between T2D and MTX in RA patients including abstracts published in English were searched. The search keywords used to identify articles were: ‘rheumatoid’ or the MeSH terms ‘rheumatoid arthritis’ in combination with ‘methotrexate’ or ‘anti-rheumatic’combined with ‘diabetes’ or ‘type 2 diabetes’. Additional articles were included from relevant articles hand searched from citation lists.

Inclusion criteria:

The meta-analysis included studies with:

• Adult patients diagnosed with RA as per a rheumatologist or current RA guidelines (the European League Against Rheumatism [EULAR]/ or the American College of Rheumatology [ACR])
• Documentation of MTX exposure
• Assessment of the outcome of interest (T2D), and reported raw count data

 The studies which did not fulfill inclusion criteria and had no information about MTX exposure, outcome (T2D) and the required raw count data were excluded.

Study selection:

RA patients which were on MTX monotherapy was the target participants. The exposure to MTX was defined as taking MTX for at least 8 weeks. The comparator group includes patients who did not receive MTX (either MTX naïve, taking other anti rheumatic drugs, i.e. cDMARDs, or biological disease-modifying antirheumatic drugs [bDMARDs]). The selected articles were assessed for eligibility by author and an independent assessor.

Data extraction:

The data extracted from each study was categorized according to participant characteristics,  study design, MTX exposure, assessment of non-MTX antirheumatic medications, evaluation of outcome, study quality score (Qi) and other traditional CV risk factors.

Quality assessment:

Studies with different study designs and a variety of methodological approaches were included; therefore it is essential to consider the quality of pooled studies. For evaluation of selected studies, a validated and reproducible checklist approach was used as it was feasible and effective in distinguishing research articles with high precision and less bias. It also includes a quality score assessment for each study.

The checklist approach evaluated the study quality using 14 questions which assessed the internal and external validity along with statistical analysis. The question in the checklist was given a quality assessment score. Among these questions, one question accounts for prognostic factors (question 9 in S4 Materials) tailored to accommodate the study requirements. To create a balance between indicators affecting T2D outcomes across exposure groups, a prognostic score was developed. The prognostic factors included sex, age, body mass index (BMI), hypertension, dyslipidemia, and family history of T2D and CV disease, duration of RA, physical inactivity, and use of other medications such as cDMARDs, bDMARDs, folic acid and corticosteroids.

A study balancing ≥5 of these indicators was given a score of 1. However, if the study reported 3 or 4 indicators, it was given a score of 0.5 and if the study balanced 1 or 2 of these factors or there was no evidence of any of these prognostic factors, it was given a score of 0. The total points were summed up to obtain a Qi score after assigning points for each question and critically reading of each study. A Qi score of ≤9 was defined as a low-quality score and ≥10 was defined as a high-quality score.

Statistical Analysis and Risk of Bias:

Meta analysis was conducted using MetaXL software version 5.3 to determine association between MTX exposure and development of T2D. Meta analysis was obtained using a quality-effects model (QE) whereas for comparison purpose random-effects model (RE) was used. The QE model also considers quality of studies by adjusting study level risk of bias as compared to the RE model.

The effect size and confidence intervals (CI) for the T2D outcome was calculated using raw counts for exposed and nonexposed, and event and nonevent RA groups. Statistical heterogeneity was evaluated using the I² statistical test. An I² value of 50% or more showed substantial level of heterogeneity. Publication bias was assessed using Egger’s test of the intercept and asymmetry assessment in the funnel plot. P values less than 0.05 and presence of asymmetry indicate statistically significant publication bias.

Study outcomes:

The primary outcome of study is evaluation of rate of T2D, described by presence or absence of T2D in RA patients. 

Outcomes

Study characteristics:

All the 16 studies included were observational studies. Among 16 studies, 8 studies were prospective cohorts, 4 were retrospective cohorts, 3 were cross-sectional and 1 had a nested case-control design. Differences occur between the included studies and country of publication differed between the included studies.

Study quality:

There was a variation in the methodological quality of included studies. This noticeable variation was observed with quality score (Qi score) ranging from 7-12.

Effect of intervention on outcome:

• There was a 52% reduction in risk of T2D among RA patients exposed to MTX when compared to RA patients not taking MTX in QE model risk reduction analysis
• Similar reduction of 87% was observed in risk of T2D among RA patients exposed to MTX when compared to RA patients not taking MTX in RE model risk reduction analysis

• Sensitivity analysis determined that RA patients receiving MTX had greater reduction in T2D development if they were older (>60 years); the duration of RA was shorter (≤2 years); the follow-up time was longer (>5 years); they had prevalent T2D and were reported in studies published before 2010; the RA disease activity was measured and adjusted in the study.

According to prior evidences, this study is the first to evaluate the association between the MTX exposure and the development of T2D in the RA population. A significant positive effect of drug has been determined in reducing the risk of T2D in RA patients. The findings of this study are consistent with the results of several studies indicating a reduction in prevalence of T2D among RA patients using other drugs such as cDMARDs and TNF inhibitors (TNFi). Along with a positive effect on T2D, MTX also affects other cardiovascular risk factors in RA population. In line with these findings the authors of this study has reported a reduction in vascular events in RA patients with use of low dose methotrexate in a previous observational study.

The potential factors influencing the results were also studied. A lower risk of T2D was observed in patients aged >60 years, compared to those ≤60 years of age, which might be due to the long term exposure of MTX in older RA patients. These findings are consistent with the findings of a prospective study that shows better survival outcomes and reduced cardiovascular mortality with MTX in older patients. Similar trends were also determined in patients with longer follow up periods. Additionally, it was also determined that adjusting disease activity and analysis might also influence the risk reduction of T2D in RA patients exposed to MTX. It may occur due to greater severity and disease activity in patients with long-standing RA associated with a higher risk of T2D. Among various countries, it was estimated that MTX exposure shows a greater T2D reduction in Latin America and Europe compared to Asia Pacific and North America (USA). These differences can be explained by differences and disparities in the social determinants of health affected by lifestyle, geography and epidemiology of chronic diseases such as obesity.

The exact mechanism of T2D reduction in RA patients receiving MTX is still debatable. However, it is shown that MTX shows beneficial metabolic effects beyond its anti-inflammatory properties. In the present study it was hypothesized that MTX induces the production of prostaglandins which inhibits 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase. The inhibition of this enzyme leads to accumulation of the substrate aminoimidazole carboxamide ribonucleotide (AICAR) which in turns blocks the activity of adenosine monophosphate (AMP) deaminase and adenosine deaminase. Subsequently the intracellular concentrations of AICAR-monophosphate (ZMP) and AMP increases leading to activation of the adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK activation ameliorates glucose homeostasis in T2D patients. Therefore, MTX may reduce glucose homeostasis and improves the level of HbA1c by promoting AMPK activation and ZMP accumulation. MTX also increase insulin sensitivity via the activation of AMPK and improves hepatic production and intestinal absorption of glucose.

In conclusion, long term exposure to MTX positively influences the development of T2D in RA patients.  The long as well as short term effects on MTX on reducing other cardiovascular risk factors are also explored. Also, the potential mechanisms by which MTX reduces the risk of T2D and generate cardio protective functions are explained. It is essential to underwent careful diagnosis and recognition of RA patients at a higher risk of T2D for proper management and risk reduction of T2D and associated CV factors.