Retrospective Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Feb 15, 2018; 9(2): 53-58
Published online Feb 15, 2018. doi: 10.4239/wjd.v9.i2.53
Blood glucose changes surrounding initiation of tumor-necrosis factor inhibitors and conventional disease-modifying anti-rheumatic drugs in veterans with rheumatoid arthritis
Patrick R Wood, Evan Manning, Joshua F Baker, Bryant England, Lisa Davis, Grant W Cannon, Ted R Mikuls, Liron Caplan
Patrick R Wood, Evan Manning, Liron Caplan, Denver Veterans Affairs Medical Center, Division of Rheumatology, University of Colorado, Aurora, CO 80045, United States
Joshua F Baker, Philadelphia Veterans Affairs Medical Center, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, United States
Bryant England, Ted R Mikuls, Omaha Veterans Affairs Medical Center, Division of Rheumatology, University of Nebraska, Omaha, NE 68198, United States
Lisa Davis, Denver Health and Hospital, Division of Rheumatology, University of Colorado, Aurora, CO 80045, United States
Grant W Cannon, George Wahlen Veterans Affairs Medical Center, Division of Rheumatology, University of Utah, Salt Lake City, UT 84148, United States
Author contributions: All authors helped to perform the research and reviewed and edited the final manuscript; Wood PR and Caplan L contributed to writing the manuscript, conception and design; Wood PR, Manning E and Caplan L contributed to data analysis.
Supported by VA HSR&D MERIT Award IIR, No. 14-048-3 for Dr Caplan; and Dr. Wood is supported by a VA GME Enhancement Award.
Institutional review board statement: This study was approved by local IRBs (Colorado Multiple Institutional Review Board #06-0956) and the Scientific and Ethical Advisory Board of the VARA registry for analysis of VARA and VA administrative data.
Informed consent statement: All patients provided written consent prior to enrollment in the VARA registry.
Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Liron Caplan, MD, PhD, Associate Professor, Denver Veterans Affairs Medical Center, Division of Rheumatology, University of Colorado, POB 6511, B115, Aurora, CO 80045, United States.
Telephone: +1-720-8575103 Fax: +1-720-8575992
Received: January 8, 2018
Peer-review started: January 8, 2018
First decision: February 9, 2018
Revised: February 13, 2018
Accepted: February 14, 2018
Article in press: February 14, 2018
Published online: February 15, 2018

To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study.


Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi’s, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti-rheumatic drugs (DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics.


Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events (-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events (+5.85 mg/dL, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events (-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (β = -0.58, P = 0.01) and hydroxychloroquine (β = -5.78, P = 0.01) use as predictors of lower post-medication-initiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication-initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure (β = 4.69, P = 0.03) was predictive for higher post-initiation RBG values among all medication-initiation events.


No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects.

Keywords: Disease modifying anti-rheumatic drugs, Drug toxicity, Glucocorticoids, Rheumatoid arthritis, Tumor necrosis factor inhibitors

Core tip: Clinicians should be cognizant of the potential for rare hypoglycemic effects of the conventional disease-modifying anti-rheumatic drugs hydroxychloroquine and sulfasalazine, in addition to the well-known hyperglycemic effects of glucocorticoids. Although case reports describe dramatic sporadic hypoglycemic events with the initiation of tumor necrosis factor inhibitors, these effects were not confirmed in our large retrospective study.