BACKGROUND
Graves’ disease is the most common cause of hyperthyroidism. Graves’ disease is an autoimmune disease where the body produces an antibody that attacks and turns on the thyroid. If the antibody decreases or goes away, Graves’ disease can go into remission. Antithyroid drugs (ATDs) are often the first-line therapy for the treatment of Graves’ disease in the United States. The goal of ATD treatment is to control the Graves’ disease in preparation for surgery or radioactive iodine therapy or to treat long term until the Graves’ disease goes into remission. Unfortunately, the risk of relapse (recurrence of hyperthyroidism) after withdrawing ATDs is as high as 30 to 70%.

Vitamin D is an important vitamin for bone formation and calcium regulation. There are also some studies that show a decrease in the number of patients developing autoimmune disease with vitamin D supplementation. Studies investigating the role of vitamin D in Graves’ disease outcomes have been mixed and limited by short trial durations, small groups of patients and not looked at relapse as the primary outcome. To this end, researchers in Denmark examined whether supplementation with vitamin D in patients with newly diagnosed Graves’ disease would decrease the relapse rate of the disease after stopping ATDs.

THE FULL ARTICLE TITLE
Grove-Laugesen D et al 2023 Effect of vitamin D supplementation on Graves’ disease: The DAGMAR trial. Thyroid. Epub 2023 May 23. PMID: 37218433.

SUMMARY OF THE STUDY
This study included patients ages 18 to 80 years with new-onset Graves’ disease who were evaluated at Danish outpatient endocrinology clinics between March 2015 and December 2017. A diagnosis of Graves’ disease was confirmed biochemically based on suppressed levels of thyroid stimulating hormone (TSH), elevated levels of triiodothyronine (T3) and/or thyroxine (T4) and a positive thyrotropin receptor antibody (TRAb) test. Patients were excluded if they had been previously received an ATD for more than 3 months or were already receiving vitamin D supplementation.

All patients were treated with a usual course of ATDs for around 12 to 18 months, but the decision on when to stop therapy was ultimately left to the clinicians. In addition to this standard treatment, participants were randomly assigned to either supplementation with Vitamin D (cholecalciferol) 2800 IU per day or no Vitamin D that was begun when the patient started ATDs. This intervention was continued for an average of 12±1 months after ATD discontinuation or occurrence of one of three study outcomes.

At baseline, the 9-month mark, and the end of the study, participants provided blood samples for thyroid laboratory testing and completed questionnaires on quality of life, adherence, and side effects. A subset of patients had vitamin D levels assessed. The primary outcome was the number of participants who did not enter into or sustain remission. Researchers also studied a secondary outcome (risk of relapse) for its association with age, sex, vitamin D status, and smoking status and its effect on quality of life.

The study group was composed of 278 patients who were randomly assigned to either vitamin D supplementation (n = 140) or no Vitamin D (n = 138). Baseline characteristics of the two groups were similar, as were the dropout rates. The average age was 44 years, and 79% were female. There were 35% of participants who were vitamin D– deficient at baseline. The risk of failure to enter and sustain remission in conjunction with ATD use was 42% in the vitamin D group and 32% in the placebo group. There was a slightly higher proportion of smokers in the group who received vitamin D supplementation, but this did not reach statistical significance.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This randomized study showed that in patients with Graves’ disease, use of 2800 units of vitamin D supplementation along with ATD had no effect on the risk of relapse following stopping the ATD. At this point, the use of Vitamin D to decrease relapse of Graves’ disease after stopping ATDs cannot be recommended, although this study does not rule out whether higher doses of Vitamin D would have an effect. However, the use of Vitamin D supplementation should be reserved for those patients with Graves’ disease who are Vitamin D deficient.

— Alan P. Farwell, MD

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