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.
PATIENTS WITHOUT A PREVIOUS DIAGNOSIS OF DIABETES
Be alert for new-onset diabetes
For most diseases treated with glucocorticoids, clinicians can estimate in advance how long the patient will need to take the drug. We can arbitrarily classify the projected exposure as either short-term (3 to 4 weeks or less, such as a 6-day course of methylprednisolone for allergic conditions) or long-term (such as in transplant recipients to prevent rejection or to treat graft-vs-host disease). Hyperglycemia is a potential concern with both short-term and long-term treatment. However, guidelines on checking blood sugar levels, as opposed to relying on symptoms alone, are available only for long-term glucocorticoid treatment.
Patients beginning treatment should be warned of typical diabetes symptoms such as thirst and increased urination and, should these occur, to seek medical attention to have their blood glucose level checked. It is also reasonable to have them return in a week for a random postprandial plasma glucose test in the mid-afternoon.
Why this timing? In most once-daily regimens, glucocorticoids are given in the morning to prevent adrenal suppression (discussed below). In our experience, glucose levels start to rise mid-morning and continue to increase until bedtime. Measuring glucose levels 1 to 2 hours after lunch allows for both the glucocorticoid action and the carbohydrate absorption from lunch to reach their peaks. If hyperglycemia is going to happen, it should be detectable by then. A glucose level of 200 mg/dL or higher should prompt the practitioner to pursue this further.
If glucocorticoid treatment is to continue beyond 3 to 4 weeks, the only population for which there are published guidelines on managing glucocorticoid-related diabetes is transplant recipients. International consensus guidelines, published in 2003, suggest checking the fasting plasma glucose level once a week for the first 4 weeks after transplantation, then at 3 months, at 6 months, and then once a year.20
Though practical, this suggestion does not reflect the fact that glucocorticoids often do not affect fasting plasma glucose, especially if given once daily in the morning at doses of 30 mg or less of prednisone or its equivalent. These guidelines thus may not be applicable to other populations with glucocorticoid-induced diabetes.
The transplant guidelines do mention that an oral glucose tolerance test may be more sensitive, but this is often cumbersome to perform. We believe that checking random postprandial plasma glucose levels is helpful in this regard.
If the patient was at risk of developing diabetes even before receiving a glucocorticoid (for example, if he or she is overweight, has a family history of diabetes, or had a previous hemoglobin A1c of 5.7% or higher), then a fasting plasma glucose level of 126 mg/dL or higher or a hemoglobin A1c of 6.5% or higher might suffice to diagnose diabetes. Results should be confirmed on a separate day in the absence of unequivocal hyperglycemia. Fasting hyperglycemia can also be seen in patients receiving higher once-daily glucocorticoid doses—in our experience, an equivalent of prednisone 40 mg once a day in the morning— or twice-daily dosing.
A hemoglobin A1c checked less than 2 to 3 months after starting glucocorticoid treatment will not be sensitive in picking up glucocorticoid-induced diabetes if the patient did not have underlying diabetes.
Diet and exercise may not be practical
Though diet and exercise are important in managing diabetes, the condition for which the patient is receiving a glucocorticoid may prevent him or her from exercising, at least in the acute phase of the illness.
In addition, though the exact mechanism is not known, glucocorticoids increase hunger, and so decreasing food intake is not easy either. Nonetheless, patients should be familiarized with what carbohydrates are and should be advised to reduce their intake of them.
For suspected type 1 diabetes, start insulin
If type 1 diabetes is suspected, for example, in patients who are lean, younger than 30 years, or who had presented with diabetic ketoacidosis, then insulin should be started. In equivocal cases, insulin therapy can commence while testing is done for C-peptide, glutamic acid decarboxylase antibodies, islet cell antibodies, and insulinoma-associated protein antibodies.
Starting oral antidiabetic drugs
Some patients may have contraindications to specific drugs. For example, metformin (Glucophage) is contraindicated if the serum creatinine level is elevated, an abnormality that renal transplant patients may continue to have.
If the patient has no such contraindications, we have found the following medications suitable in view of their efficacy, low risk of hypoglycemia, or lack of distressing side effects. They will often lower glucose levels enough to achieve capillary blood glucose or fingerstick goals (discussed below). None of them has been specifically approved by the US Food and Drug Administration for glucocorticoid-induced diabetes, but they are approved for type 2 diabetes.
Guidelines from the American Association of Clinical Endocrinologists for type 2 diabetes call for starting monotherapy if the hemoglobin A1c is 6.5% to 7.5%, dual therapy if it is 7.6% to 9%, triple therapy if it is higher than 9% and the patient has no symptoms, and insulin if it is higher than 9% and the patient does have symptoms.22
In terms of estimated average glucose levels, these categories correspond to 140 to 169 mg/dL for monotherapy, 171 to 212 mg/dL for dual therapy, and higher than 212 mg/dL for triple therapy or insulin. Since estimated average levels also include fasting glucose levels (which are lower in glucocorticoid-induced diabetes compared with nonfasting levels), and because we use the American Diabetes Association general hemoglobin A1c goal of less than 7%, we believe that our suggestions below are reasonable.
We divide our recommendations according to initial random (ideally, 1- to 2-hour postprandial) plasma glucose levels.
