Glucocorticoid-induced diabetes and adrenal suppression: How to detect and manage them
ABSTRACTGlucocorticoids, commonly used to treat multiple inflammatory processes, can cause hyperglycemia, Cushing syndrome, adrenal suppression, and, when they are discontinued, adrenal insufficiency. Physicians must be aware of these adverse effects and be equipped to manage them.
KEY POINTS
- Nonfasting plasma glucose levels are more sensitive than fasting levels for detecting glucocorticoid-induced diabetes, and antidiabetic agents that have greater effects on random postprandial plasma glucose levels are more suitable than those that mostly affect fasting levels.
- Even those glucocorticoid formulations that are not intended to have systemic effects (eg, eye drops, inhaled corticosteroids, creams, intra-articular injections) can cause adrenal suppression and, therefore, if they are discontinued, steroid withdrawal and adrenal insufficiency.
- Needed are studies comparing antidiabetic regimens for glucocorticoid-induced hyperglycemia and studies comparing glucocorticoid tapering schedules for adrenal suppression to determine the best way to manage these adverse effects.
Steroid withdrawal vs adrenal insufficiency
Another phenomenon that can be confused with adrenal insufficiency or glucocorticoid insufficiency is steroid withdrawal, in which patients experience lethargy, muscle aches, nausea, vomiting, and postural hypotension as glucocorticoids are tapered and their effects wane.42 Increasing the glucocorticoid dose for presumed adrenal insufficiency may delay recovery of the adrenal function and would have to be weighed against the patient’s symptoms.
The following may help distinguish the two: if the patient is on supraphysiologic glucocorticoid doses, then he or she is not glucocorticoid-deficient and is likely suffering from steroid withdrawal. At this point, patients may just need reassurance, symptomatic treatment, or if necessary, a brief (1-week) increase of the previous lowest dose, followed by reevaluation.
With local glucocorticoid preparations that may be systemically absorbed, however, there is no good way of estimating dose equivalence. In these situations, the decision to simply reassure the patient or give symptomatic treatment—as opposed to giving low-dose oral glucocorticoids such as hydrocortisone 5 to 10 mg daily for a week followed by reevaluation— depends on the severity of symptoms and whether the patient has quick access to medical attention should he or she develop an intercurrent illness.
Identifying patients at risk of adrenal suppression
Patients presenting with weight gain or symptoms suggesting Cushing syndrome should be asked about steroid intake and should be prompted to recall possible nonoral routes. In addition, patients presenting with muscle aches and fatigue—symptoms of steroid withdrawal— may have received unrecognized local glucocorticoids that were systemically absorbed, now with diminishing effects.
The ACTH stimulation test for adrenal recovery
Testing can be done to see if the adrenal glands have recovered and glucocorticoid therapy can be discontinued (see Tapering from glucocorticoids, below).
The test most often used is the corticotropin (ACTH) stimulation test. Since the suppression is at the level of the hypothalamus and the pituitary gland, the ACTH stimulation test is an indirect method of assessing hypothalamic and pituitary function in the context of glucocorticoid-induced adrenal suppression. It has good correlation with the insulin tolerance test, the gold-standard test for an intact hypothalamic-pituitary-adrenal axis.
The synthetic ACTH cosyntropin (Cortrosyn) 250 μg is injected intravenously or intramuscularly, and a cortisol level is drawn at baseline and 30 and 60 minutes later. Other doses such as 1 μg or 10 μg have been reported but are not yet widely accepted. A cortisol level of greater than 18 to 20 μg/dL at any time point shows that the adrenals have regained function and the steroids may be discontinued.42 If adrenal suppression persists, weaning from steroids should continue.
In reality, it may not be possible or practical to do an ACTH stimulation test, as not all physicians’ offices have a supply of cosyntropin or the manpower to perform the test correctly. In these cases, weaning can progress with monitoring of symptoms.
Testing for synthetic glucocorticoids in the urine and serum can demonstrate systemic absorption and may be helpful in patients who do not recall receiving steroids.33
Tapering from glucocorticoids
Several tapering schedules have been suggested (although not necessarily validated). Whether and how to taper depend on how long the glucocorticoid has been taken.
If taken for less than 1 week, glucocorticoids can be stopped without tapering, regardless of the dose.
If taken for 1 to 3 weeks, the decision to taper depends on the clinician’s assessment of the patient’s general health or constitution and the illness for which the glucocorticoid was prescribed. For example, if the underlying disease is less likely to flare with a gradual dose reduction, then tapering would be suitable.44
If taken for more than 3 weeks, the practice has been a more rapid taper at the beginning until a physiologic dose is reached. How quickly to reduce the dose depends on whether the underlying illness is expected to flare up, or if the patient might experience steroid withdrawal symptoms.
One schedule is to lower the glucocorticoid dose by an amount equivalent to prednisolone 2.5 mg every 3 to 4 days when above the physiologic dose, then to taper more slowly by 1 mg every 2 to 4 weeks.44 Once the physiologic dose is reached, one can switch to the equivalent dose of hydrocortisone and decrease the dose by 2.5 mg a week until a daily dose of 10 mg a day is reached and maintained for 2 to 3 months, and then perform a test of adrenal function (see above).44 Passing the test implies that the adrenal glands have recovered and the glucocorticoid can be stopped.
Another option is to switch to alternate-day therapy once a physiologic dose is reached and to test 8:00 am cortisol levels, continuing the glucocorticoid and retesting in 4 to 6 weeks if the value is less than 3 μg/dL; stopping the glucocorticoid if the value is higher than 20 μg/dL; and performing an ACTH stimulation test for values in between.45
A review of other tapering regimens for chronic diseases, mostly pulmonary, did not find enough evidence to recommend one particular schedule over another.46 The tapering schedule may have to be adjusted to prevent disease flare and symptoms of steroid withdrawal.
Locally administered steroids. Since the equivalence of systemically absorbed local glucocorticoids is not known, these patients are likely to present when they have symptoms of steroid withdrawal. In this situation, testing adrenal function will help.
