How Do DMARDs Alter Diabetes Risk in Rheumatoid Arthritis?

Hydroxychloroquine use was associated with a duration-dependent reduction in risk of developing diabetes.
Hydroxychloroquine use was associated with a duration-dependent reduction in risk of developing diabetes.

WASHINGTON, DC — In patients with rheumatoid arthritis (RA), risk for diabetes appears to differ with different drug therapies, researchers reported at the American College of Rheumatology/Association of Rheumatology

“Ever since Wasko's groundbreaking study in 2007, we've been interested in better understanding the impact of hydroxychloroquine on developing diabetes as well as better understanding the impact of RA and RA activity and how treatments for it may affect both,” study researcher Kaleb Michaud, PhD, associate professor in the division of rheumatology and immunology at the University of Nebraska Medical Center and co-director of the National Data Bank for Rheumatic Diseases, told Rheumatology Advisor. “Confounding influences make this analysis in observational cohorts more challenging.”

To learn more, researchers evaluated patients with RA with no comorbid diabetes at baseline who had participated for at least 1 year in the National Data Bank for Rheumatic Diseases from 2000 to 2015. They included 4 categories of disease-modifying antirheumatic drugs (DMARDs) in their analysis: methotrexate monotherapy (reference), abatecept with or without methotrexate, any other DMARD with methotrexate, all other DMARDs prescribed without methotrexate. Concurrent use of statins, glucocorticoids, ord HCQ was then evaluated as possible modifying variables.

Over a median follow-up of 4.6 years, 1139 incident cases of diabetes—determined via self-report or initiation of diabetes medications—occurred in 13,669 patients with RA. Crude and standardized incidence rates od diabetes was higher among patients with RA compared with the general US adult population (age- and sex-adjusted standardized incidence ratio: 1.37; 95% CI, 1.29-1.45).

Researchers noted significant differences in diabetes risk according to treatment. For HCQ and abatacept, diabetes risk was reduced by 33% (adjusted hazard ratio [HR]: 0.67; 95% CI, 0.57-0.80; P <.001) and 48% (adjusted HR: 0.52; 95% CI, 0.31-0.89; P =.017), respectively.

In contrast, glucocorticoid use increased risk of developing diabetes by 31% (adjusted HR: 1.31; 95% CI, 1.15-1.49; P <.001) and statins increased risk by 56% (adjusted HR: 1.56; 95% CI, 1.36-1.78).

There were no significant differences in diabetes risk for other synthetic or biologic DMARDs evaluated. For any other DMARD plus methotrextate, risk was reduced by 13% (adjusted HR: 0.87; 95% CI, 0.72-1.05; P =.152), while risk increased by 11% for other or no DMARDs (adjusted HR: 1.11; 95% CI, 1.36-1.78; P =.190).

For HCQ, the reduction in diabetes risk started 2 years after medication initiation (adjusted HR: 0.76; 95% CI, 0.58-1.00) and declined with longer treatment (longer than 4 years, HR: 0.69; 95% CI, 0.58-0.81).

Risk for diabetes was also reduced for HCQ doses of less than 400 mg/d (adjusted HR: 0.71; 95% CI, 0.52-0.96) as well as doses of 400 mg/d or more (adjusted HR: 0.66; 95% CI, 0.55-0.81). Risk was also reduced, though nonsignificantly, among patients who initiated and then discontinued HCQ (n=342) vs those who never used HCQ by 35% for at least 3 months (adjusted HR: 0.65; 95% CI, 0.21-2.0) and 12% for at least 6 months (adjusted HR: 0.88; 95% CI, 0.28-2.75). Risk was increased by 27% (adjusted HR: 1.72; 95% CI, 0.31-5.10) for at least 1 year off HCQ.  

The researchers also found that the increased risk seen with glucocorticoids and statins was eliminated when used with HCQ.

Dr Michaud noted that the researchers were hesitatnt about reporting the findings, “primarily because of the likely impact of confounding and treatment channeling bias.” However, he explained they were careful in their analysis of the data.

“We spent months conducting additional analyses to ensure these findings weren't just spurious,” Dr Michaud said. “We also felt that methotrexate monotherapy was a better reference comparison group, and doing so, we no longer saw significant associations with diabetes and most biologics as shown by others previously. We suspect having better control of disease activity helps, but that use of HCQ and abatacept stood out as being significantly associated with decreased risk of getting diabetes.”

These results are important, explained Dr Michaud, because rheumatologists require a complete picture of the patient's health status.

“There are so many additional conditions that rheumatologists have to be concerned about when treating their patients with RA,” he said. “Our work highlights the need to be concerned about developing diabetes due to RA activity and that use of HCQ could help bring this risk back to general US population levels.”

Moving forward, Dr Michaud highlighted several directions for future research.

“We are interested to learn more about our findings with change in risk of diabetes with use of abatacept and statins, either through additional analyses in other observational cohorts or revisiting prior clinical trial work,” he said.

Disclosures

The researchers report no relevant financial disclosures.

Reference

Ozen G, Pedro S, Holmqvist M, Wolfe F, Michaud K. Risk of incident diabetes mellitus and its association with disease-modifying antirheumatic drugs and statins in rheumatoid arthritis. Presented at: the 2016 American College of Rheumatology/ Association of Rheumatology Health Professionals (ACR/ARHP) Annual Meeting. November 11-16, 2016; Washington, DC. Abstract #1991


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