Glucocorticoids remain a cornerstone of therapy for many inflammatory diseases despite being associated with significant adverse effects, among which are hyperglycemia and diabetes mellitus.  A recent study published by clinicians from Massachusetts General Hospital (MGH) and Harvard Medical School has shown that early use of steroid-sparing medications reduces glucose metabolism dysfunction and lowers the associated risk of developing diabetes mellitus [1].

Previous studies have estimated that patients who receive oral glucocorticoids are at twice the risk of developing diabetes compared to those not receiving them. While the increased risks of developing diabetes for patients taking glucocorticoids are well known, the association between tapering medication and the potential for improvement in glucose metabolism has not been described.

In order to understand the impact of a glucocorticoid taper on glucose metabolism, the Harvard team, led by Professor John Stone, the Edward A. Fox Chair of Medicine at MGH, analyzed data from a randomized, double-blind, placebo-controlled trial. The trial, known as GiACTA, evaluated the use of tocilizumab in giant cell arteritis (GCA). In the trial design, patients were randomized to receive either a prednisone taper, or a prednisone taper in combination with tocilizumab.

During the study, glucose metabolism was measured using the hemoglobin A_1c (HbA_1c) biomarker, a measure commonly used to estimate the degree of blood glucose level over the preceding few months. The HbA_1c has been the gold standard for assessing patients’ risk of developing diabetes. The regular measurement of HbA_1c and red blood cell counts during the 1-year follow-up period provided the researchers with a unique opportunity to understand the effects of both tocilizumab and glucocorticoid tapering on changes in HbA_1c over time.

At the start of the trial, 22% were determined to have diabetes based on their HbA_1c levels and 54% were prediabetic. Thus, only 24% of the patients had normal glucose tolerance at baseline – at the point of needing to embark upon a long course of glucocorticoids. Over the 52 weeks of the trial, HbA_1c levels declined substantially faster in the group that received tocilizumab compared to the group receiving the prednisone taper alone. 

42.5% of patients in the tocilizumab arm experienced a decline in their HbA_1c levels that was sufficient enough to reclassify them from prediabetes to normal. In contrast, only 12.5% of the glucocorticoid taper arm achieved this same mark.

This change led to 64% of the patients in the glucocorticoid-only group having HbA_1c levels in the prediabetes or diabetes range, compared to only 33% of those treated with tocilizumab. In the prednisone-only group, 50% of the patients concluded the trial in the prediabetic range, and 14% had diabetes, compared with only 29% (prediabetic) and 4% (diabetes) in the tocilizumab group.

The team postulates a key reason for this is the greater glucocorticoid burden endured in the group receiving the prednisone taper alone. The patients receiving prednisone alone were also more likely to experience disease flares, leading to the requirement for increased doses of prednisone and worse glucose metabolism control.

The team does highlight the difference in HbA_1c levels observed between the two arms of the study is potentially larger than can be explained by the glucocorticoid taper alone. They suggest some of the difference may be explained by "non-glycemic" effects of tocilizumab, such as improved red blood cell survival that also alters HbA_1c levels. Further investigation of this point is needed.

In summary, this analysis of the GiACTA trial data highlights the early use of a steroid-sparing medication and swift tapering of glucocorticoids is essential if patients are to avoid glucose metabolism damage and the heightened risk of diabetes mellitus associated with glucocorticoid use.

References

1. Patel NJ, Tozzo V, Higgins JM, Stone JH. The Effects of Daily Prednisone and Tocilizumab on Hemoglobin A_1c During the Treatment of Giant Cell Arteritis. Arthritis Rheumatol. 2022 Nov 16. doi: 10.1002/art.42405.