Continuous Subcutaneous Hydrocortisone Infusion In Addison's Disease and Type 1 Diabetes

Treatment of Addison's disease includes glucocorticoid and mineralocorticoid replacement. Despite optimized therapy with these steroids, many patients suffer from impaired quality of life and increased mortality. The etiology of the premature death is complicated and may include a combination of inadequate treatment of adrenal crisis, patient non-compliance, and undetected hypoglycemia, in addition to being associated with increased cardiovascular, malignant, and infectious disease deaths. The relative risk of death for patients with Type 1 Diabetes is 3.8 in Sweden. Having Type 1 diabetes and Addison's disease significantly increased the risk of death when compared with having adrenal insufficiency alone. The risk for premature death in patients with the combination of Type 1 diabetes and Addison's disease has not been extensively studied and appears to contribute to a small portion of the increased mortality seen in patients with Addison's disease.

Cortisol has particularly potent effects on blood glucose levels, otherwise Addison's disease affects the production of cortisol, an important counterregulatory hormone for hypoglycaemia. Lack of cortisol might increase the risk of hypoglycemic episodes, whereas over-replacement might cause hyperglycemia. Because steroid replacement may cause significant insulin resistance, it is challenging to adjust insulin doses to maintain optimal glycemic control. Little is known about the effects of unphysiological glucocorticoid replacement therapy on glucose and lipid metabolism, but there has been concern about long-term metabolic consequence. Current glucocorticoid replacement results in large fluctuations in the cortisol levels directly influencing glucose homeostasis and, consequently, making accompanying insulin treatment difficult to manage. Different types, regimens and doses of glucocorticoids are now used in adrenal insufficiency, but none approximate the physiological rhythm. Hydrocortisone administration via a subcutaneous pump is a novel strategy that restores circadian cortisol rhythm in most patients.

The study will be open-labelled, cross-over designed, with comparison of two glucocorticoid replacement modalities to glycemic events in randomised order within each patient, as illustrated in figure.

Treatment A is optimised oral hydrocortisone ( Cortef 5 mg) replacement according to Mah et al, and treatment B is continuous subcutaneous hydrocortisone infusion therapy. The patients will be assigned a participation number and randomised to any of two treatment sequences (A-B or B-A). Should the need for an extra glucocorticoid dose occur (intercurrent illness, exercises) during the study, for safety reasons, the patients should administer their previous glucocorticoid and insulin replacement. If the dose of insulin is changed, new testing by self-monitoring of blood glucose and continuous glucose monitor system should be done.

The period of dose adjustments for insulin treatment during both glucocorticoids replacement modalities will take 2 weeks for each and 6 weeks assessment of glycemic control by continuous glucose monitor system, followed by a minimal of one month during which the patients use their previous glucocorticoid replacement and previous insulin therapy (wash-out period).