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.
Adjust medications if glucose is not at goal
Patients with type 2 diabetes treated with diet and exercise alone can be started on the medications discussed above if their fingerstick readings are not at goal.
If they are already on insulin, we advise them to increase the short- or fast-acting insulins and the morning intermediate-acting insulin by at least 10% to 20% as soon as an elevation in glucose is detected. Long-acting insulin or nighttime intermediate-acting insulin should be increased if fasting glucose levels are affected.
Insulin requirements can double depending on the glucocorticoid dose. In patients with type 1 diabetes who were given prednisone 60 mg orally for 3 days, mean blood glucose levels increased from a baseline of 110 mg/dL at baseline to 149 mg/dL on the days on prednisone.6 The average blood glucose level remained elevated at 141 mg/dL on the day after the last dose of prednisone. The insulin dose increased by 31% to 102% (mean 69%).
CUSHING SYNDROME AND ADRENAL SUPPRESSION
Unlike glucocorticoid-induced diabetes, in which the dilemma is often when to initiate antidiabetic treatment, the question for patients in whom Cushing syndrome or adrenal suppression has developed is when to discontinue glucocorticoids.
Adrenal suppression for the most part goes hand in hand with exogenous Cushing syndrome. If cushingoid features develop, we can infer that the dose of exogenous glucocorticoid exceeds the physiologic needs. This supraphysiologic dosing also leads to suppression of endogenous cortisol production. The suppression occurs at the level of the hypothalamus and pituitary gland, with subsequent atrophy of the part of the adrenal cortex that produces endogenous glucocorticoids.
To understand further the concept of supraphysiologic dosing, the following interconversion of systemic glucocorticoid effects is helpful24,25:
However, there is not much information on interconversion for the local preparations (intra-articular, epidural, inhaled, topical).
Moreover, the definition of supraphysiologic dosing seems to be evolving. Though a total hydrocortisone-equivalent dose of 30 mg/day is still often touted as physiologic replacement, many patients require less. Several studies in the early 1990s, mostly in children and adolescents, showed the mean daily cortisol production rate to be 4.8 to 6.8 mg/m2/day, or closer to 10 to 15 mg/day.26–28 For purposes of this discussion, a physiologic dose will be defined as up to 30 mg hydrocortisone per day or its equivalent.
Adrenal suppression vs insufficiency
Adrenal suppression is often confused with adrenal insufficiency.
Adrenal suppression occurs when cortisol production is decreased because of the presence of exogenous glucocorticoids or other drugs, such as megestrol acetate (Megace), that act on the glucocorticoid receptor. Another situation beyond the scope of this review is excess endogenous cortisol production by an adrenal adenoma or adrenal carcinoma that causes suppression of the contralateral adrenal gland.29
In contrast, adrenal insufficiency is caused by failure of the adrenal gland to produce cortisol as a result of an innate disorder of the adrenal gland (eg, Addison disease) or pituitary gland (eg, pituitary surgery).
Hence, endogenous cortisol production in a patient taking supraphysiologic doses of exogenous glucocorticoids may be suppressed. Recovery of endogenous cortisol production is expected after stopping the exogenous glucocorticoid, though the time to recovery can vary and the patient can be adrenally insufficient if the glucocorticoid is stopped abruptly.
In addition, during times of intercurrent illness, a patient with adrenal suppression may be relatively adrenally insufficient and may need larger doses (“stress doses”) of glucocorticoids, since the adrenal glands may be unable to mount a stress response.29
Local steroids can suppress the adrenal glands
Glucocorticoids are the most common cause of Cushing syndrome. Oral formulations such as dexamethasone, prednisone, and hydrocortisone taken in supraphysiologic doses and for prolonged durations are easily recognized as obvious causes of Cushing syndrome. However, intra-articular, epidural, inhaled, nasal, ocular, and topical steroids—so-called local preparations—have also been linked to Cushing syndrome, and physicians are less likely to recognize them as causes.30–38
In a study in 16 pediatric patients with asthma and 48 controls, inhaled beclomethasone dipropionate (Qvar) 300 to 500 μg daily resulted in adrenal suppression in 100% of patients after 6 to 42 months, as determined by an insulin tolerance test.30
The topical steroid betamethasone (Diprosone) carries a warning that systemic absorption of topical steroids can cause adrenal suppression.39 Intra-articular, intranasal, epidural, and ocular routes are also reported to cause adrenal suppression.32–38
When is adrenal suppression more likely?
Adrenal suppression is more likely in the following situations:
- Longer duration of treatment. Studies have shown that exposure to supraphysiologic steroid doses for 2 weeks or less might already suppress the adrenal glands, but the clinical significance of this is unclear since some recovery already occurs a few days after the glucocorticoids are discontinued.31,40
- Supraphysiologic doses, stronger formulations, longer-acting formulations.41
When is adrenal suppression less likely?
Adrenal suppression is less likely in the following situations:
- Regimens that mimic the diurnal rhythm of cortisol (higher dose in the morning, lower dose in the afternoon)42
- Alternate-day dosing of steroids.43
