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.
If the random or 1- to 2-hour post-meal plasma glucose is lower than 220 mg/dL
In this situation the choices are:
- Metformin
- Dipeptidyl peptidase-4 (DPP-4) inhibitors (“gliptins”)
- Meglitinides (“glinides”). The guidelines on new-onset diabetes after transplantation point out that meglitinides may be the safest agents apart from insulin in the renal transplant population, but does acknowledge that efficacies of different oral agents have not been compared in this group.20
- Glucagon-like protein-1 (GLP-1) agonists
- Sulfonylureas. However, the longer-acting forms such as glimepiride (Amaryl) are not suitable if the fasting plasma glucose is not affected.
We have not used thiazolidinediones (“glitazones”) routinely because they can cause weight gain and edema—problems that are already seen with the use of steroids—and have a slower onset of action.
If the random or 1- to 2-hour post-meal plasma glucose is 220 to 300 mg/dL
Often, a combination of drugs or insulin (see below) is needed. However, you can start with one agent and add a second agent within 2 or 3 months (as is recommended for type 2 diabetes).22,23 The following combinations of the agents listed above are supported by published guidelines for type 2 diabetes:
- Metformin plus a sulfonylurea22,23
- Metformin plus a glinide22
- Metformin plus a GLP-1 agonist23
- Metformin plus a DPP-4 inhibitor.22
If the random or 1- to 2-hour post-meal plasma glucose is higher than 300 mg/dL
In our experience, if their plasma glucose levels are this high, patients are experiencing frank symptoms of hyperglycemia.
Insulin addresses those symptoms and avoids the prolonged wait that often results from unsuccessfully starting one agent and then adding another. Of all the available drugs, insulin is the only one that can be used despite multiple underlying illnesses; it does not cause a lot of drug interactions, and the dose can be adjusted upward and downward in increments to fit the patient’s needs, especially when a larger glucocorticoid load is given up front and then is tapered either slowly or rapidly. However, it can cause hypoglycemia and weight gain.
The initial total daily dose of insulin can be based on the patient’s weight. A starting total daily dose of 0.15 to 0.3 U/kg is reasonable— on the lower end if only the postprandial glucose levels are elevated, and on the higher end if both fasting and postprandial glucose levels are affected.
If fasting glucose levels are not elevated, then Neutral Protamine Hagedorn insulin (which is intermediate-acting) or a premixed combination of an intermediate-acting plus a fast- or short-acting insulin can be given once a day before breakfast, or even before lunch if the glucose levels start to rise only after lunch.
If both the fasting and the postprandial glucose levels are elevated, regimens similar to those for type 1 or insulin-requiring type 2 diabetes can be used, except that the ratios of the doses are tilted more toward covering postprandial than fasting hyperglycemia:
- Long-acting insulin plus prandial insulin, in a ratio of 30:70 to 50:50. As glucocorticoids are tapered, the long-acting insulin may have to be discontinued while the prandial doses are continued, since the fasting glucose level decreases first.
- Premixed insulins, with one-half to two-thirds of the dose given before breakfast and the rest before the evening meal, with the possibility of a third injection before lunch. As glucocorticoids are tapered, the evening dose is tapered first.
- Intermediate-acting insulin plus short- or fast-acting insulin in the morning (these two will make up one-half to two-thirds of the total daily dose), short- or fast-acting insulin before the evening meal, and intermediate-acting insulin at bedtime. As glucocorticoids are tapered, the bedtime insulin is tapered first.
Capillary blood glucose (fingerstick) checks
The timing and frequency of fingerstick checks depend on the treatment.
Though postprandial testing is ideal, it is often not practical or convenient. Before lunch, before dinner, and at bedtime are good alternatives since they reflect the pattern of glucose rise throughout the day. For patients on diet and exercise with or without agents other than insulin, testing once or twice a day is reasonable, rotating times before meals (including fasting if this time is affected) and at bedtime.
For patients on insulin, checking two to four times a day initially would help match insulin doses with glucose excursions. For continued care, the American Diabetes Association recommends fingerstick checks three times daily in patients on multiple insulin injections, but it has no specific recommendations for those on once-a-day insulin.21 We have been recommending that our patients on once-daily insulin check at least twice a day.
Goal fingerstick glucose levels that we use are in accordance with the American Diabetes Association guidelines for diabetes in general21:
- Before meals 70 to 130 mg/dL or
- 1 to 2 hours after meals < 180 mg/dL.
During steroid taper, if the glucocorticoid dose is in the lower range (eg, a prednisone-equivalent dose of approximately 7.5 mg per day or less), the fingerstick glucose levels are at the lower end of the target range, and the patient is on a single antidiabetic agent that does not often cause hypoglycemia (eg, metformin), then it is reasonable to ask the patient to not take the antidiabetic medication for 3 to 7 days while continuing to check fingersticks to see if it needs to be resumed. Patients on agents that can cause hypoglycemia need to check more often during the 1 to 3 days after the glucocorticoid dose reduction, as it may take this much time for the glycemic effect to diminish and to adjust the diabetes medication to the appropriate dose.
STARTING GLUCOCORTICOIDS IN PATIENTS WITH KNOWN DIABETES
Fingerstick checks more often
Most patients will already have a glucose meter. They should be instructed to check as discussed above if they do not have a previous diagnosis of diabetes, or to continue as they are doing if they are already checking more often. Patients who have been checking only fasting levels should be instructed to check later in the day, either before or 1 to 2 hours after meals, as discussed above. Patients on oral medications may need additional oral agents or insulin.
