PITTSBURGH, July 10 - Far fewer rheumatoid arthritis patients treated with the drug hydroxychloroquine (HCQ) went on to develop diabetes compared to those who never took the drug, according to a 20-plus-year University of Pittsburgh School of Medicine-led study reported today in the Journal of the American Medical Association. In addition, those using HCQ who did develop diabetes were less likely to take medications to manage their disease after diagnosis.
The multi-center observational study of 4,905 adults with rheumatoid arthritis (RA) found that relative risk progressively declined by as much as 77 percent after four years of treatment with HCQ, a common antimalarial medication that also is used for rheumatoid arthritis and other autoimmune disorders.
Additional participating centers in the study are Stanford University, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), one of the National Institutes of Health (NIH) and the University of Cincinnati. Co-investigators at Stanford have directed the project database since its inception with support from the NIH.
"This reduction in risk persisted even after adjusting for other diabetes risk factors among these patients, such as body-mass index, degree of disability and use of corticosteroids," said rheumatologist Mary Chester M. Wasko, M.D., M.Sc., associate professor of medicine, University of Pittsburgh School of Medicine. Because people with RA tend to be less active and take corticosteroids that can cause weight gain, they are often considered to be at higher risk for developing diabetes, a disease in which blood sugar levels become abnormally high because of the body's inability to use or produce the hormone insulin.
"Another interesting finding was that the rheumatoid arthritis patients who developed diabetes were less likely to need blood sugar-lowering medication to manage their disease," said Dr. Wasko, whose clinical research has focused on long-term health improvement in patients with RA. "However, it is most exciting to consider that this drug might be appropriate for people with pre-diabetes as a preventive therapy - much in the same way as a daily baby aspirin is suggested for people at high risk for heart disease."
Nationally, diabetes is the fifth leading cause of death, according to the American Diabetes Association. Many people first become aware of the disease when confronted with one of its life-threatening complications such as heart disease, blindness, high blood pressure, stroke, kidney disease or circulatory problems that can lead to amputation.
Results show that HCQ's association with reduction in diabetes risk is comparable or superior to that of a number of other drugs studied in clinical trials for diabetes prevention and treatment, including rosiglitazone, hormones, metformin, acarbose and ramipril. And recent questions have arisen concerning rosiglitazone, marketed as Avandia, and a reported increased risk of heart attack.
Although HCQ is not without side effects - nausea, headache and dizziness, for example - the drug has a long history of being generally safe and well-tolerated. In addition, Dr. Wasko and her colleagues observed no apparent negative interactions between HCQ and other drugs commonly used by RA patients, such as methotrexate and prednisone. An important limitation of the study, however, is that investigators used self-report information from patients collected in follow-up twice yearly that did not include confirmation by laboratory tests.
Other studies of the blood sugar-lowering effects of HCQ have shown minimal use for the drug as a treatment for people with established diabetes, Dr. Wasko continued, stressing the treatment's real promise may be prevention.
"HCQ already has a role in long-term treatment for RA, potentially moderating lipids and having a weak anti-clotting effect. But, optimistically speaking, endocrinologists can identify people who are at high risk for diabetes, due to obesity, family history, lipid profile or other characteristics. HCQ may also have a role in delaying onset of diabetes," Dr. Wasko said. "More research is needed to verify our findings in people with RA, and also to determine how this medicine works. But my ultimate hope is that this relatively inexpensive, safe drug will be studied as a way to reduce diabetes risk for people who do not have RA."
In addition to Dr. Wasko, study authors are Helen B. Hubert, M.P.H., Ph.D., James F. Fries, M.D., and Vijaya Bharathi Lingala, Ph.D., all of Stanford University Medical Center; Jennifer R. Elliott, M.D., University of Pittsburgh School of Medicine; Michael E. Luggen, M.D., University of Cincinnati; and Michael M. Ward, M.D., M.P.H., Intramural Research Program, NIAMS. The study was conducted with support from the Arthritis Foundation of Western Pennsylvania, NIAMS and the Intramural Research Program, NIAMS.
Financial disclosure: Dr. Wasko is a consultant to Centocor in cardiovascular outcomes in ongoing rheumatoid arthritis clinical trials and has been a co-investigator in a Merck-sponsored study of blood clot markers in rheumatoid arthritis and osteoarthritis. She also has received payment as site principal investigator for clinical trials for rheumatoid arthritis drugs sponsored by Sanofi-Aventis (ending in 2002), Centocor, Roche, Novartis and Human Genome Sciences. Hydroxychloroquine, marketed as Plaquenil ® is manufactured by Sanofi-Aventis. In its generic form, the drug has multiple manufacturers.