Leighanne Kramer Hustak, DNP, BC-FNP, CDE

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

Glucocorticoids are commonly prescribed by primary care physicians and specialists alike for multiple medical problems, acute as well as chronic.

However, these useful drugs have adverse effects on multiple endocrine systems, effects that include diabetes (or worsening of hyperglycemia in those with known diabetes), Cushing syndrome, adrenal suppression, osteoporosis (reviewed in the Cleveland Clinic Journal of Medicine in August 2010),¹ and dyslipidemia. In addition, suppression of gonadotropins, growth hormone, and, acutely, thyrotropin can ensue.

The focus of this review is on the diabetogenic and adrenal suppressive effects of glucocorticoids and their management. We describe the rationale for choosing specific drugs to counter hyperglycemia, tests for determining adrenal suppression and systemic glucocorticoid absorption, and how and why to taper these drugs.

WIDELY USED DRUGS

Although glucocorticoids (often simply called steroids or corticosteroids, although not all steroids are corticosteroids, and not all corticosteroids are glucocorticoids) are the core treatment for adrenal insufficiency, in most cases they are prescribed for their anti-inflammatory effects. They act through multiple pathways at the cellular and molecular levels, suppressing the cascades that would otherwise result in inflammation and promoting pathways that produce anti-inflammatory proteins.²

In addition to formulations that are intended to have systemic effects, other, “local” formulations are made for specific conditions, such as intra-articular injections for arthritis, epidural injections for lumbar disk pain, eye drops for uveitis, nasal sprays for allergic rhinitis, inhalers for asthma, and topical ointments and creams for eczema. However, as we will discuss, even these preparations can have systemic effects.

GLUCOCORTICOID-INDUCED DIABETES IS COMMON

Glucocorticoids are the most common cause of drug-induced diabetes. Though the exact prevalence is not known, a few observations suggest that glucocorticoid-induced diabetes or hyperglycemia is common:

• In patients with rheumatoid arthritis, mean age 62 years, nearly 9% developed diabetes in the 2 years after starting glucocorticoid treatment, which was a higher rate than expected.³
• In nondiabetic patients with primary renal disease treated with prednisolone 0.75 mg/kg/day, 42% were found to have 2-hour post-lunch plasma glucose concentrations higher than 200 mg/dL but normal fasting glucose levels.⁴
• In a case-control study, the odds ratio of starting an oral hypoglycemic agent or insulin was 1.77 for patients receiving a hydrocortisone-equivalent dose of 1 to 39 mg/day, 3.02 for 40 to 79 mg/day, 5.82 for 80 to 119 mg/day, and 10.34 for 120 mg/day or more.⁵ (For a full discussion of glucocorticoid equivalents, see the section below on Cushing syndrome and adrenal suppression.)
• In patients with type 1 diabetes, prednisone 60 mg/day raised the blood glucose levels starting 6 hours after the prednisone dose.⁶
• Diabetic ketoacidosis and hyperosmolar nonketotic syndrome have been reported as a result of glucocorticoid treatment.^7–9

GLUCOCORTICOIDS CAUSE DIABETES MAINLY VIA INSULIN RESISTANCE

The mechanism by which glucocorticoids cause diabetes predominantly involves insulin resistance rather than decreased insulin production. In fact, in a study in healthy volunteers, ¹⁰ hydrocortisone infusion resulted in higher insulin production than saline infusion did. (In high doses, however, glucocorticoids have been shown to decrease insulin secretion.¹¹)

Normally, in response to insulin, the liver decreases its output of glucose. Glucocorticoids decrease the liver’s sensitivity to insulin, thereby increasing hepatic glucose output.¹² They also inhibit glucose uptake in muscle and fat, reducing insulin sensitivity as much as 60% in healthy volunteers. This seems primarily due to a postreceptor effect, ie, inhibition of glucose transport.^13–15

THE PEAK EFFECT OCCURS 4 TO 6 HOURS AFTER DOSING

To understand the optimal time for checking plasma glucose and to apply appropriate treatment, we should consider the pharmacokinetic profile of glucocorticoids.

Studied using the whole-blood lymphocyte proliferation technique, prednisone shows a peak effect at about 4 to 6 hours and a duration of action of 13 to 16 hours.¹⁶ This closely resembles what we see in terms of glucose excursion with this drug.¹⁷ Two studies of intravenous dexamethasone 10 mg showed that glucose levels rose within 4 hours of injection, but did not pursue this beyond that time frame.^18,19

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 A_1c of 5.7% or higher), then a fasting plasma glucose level of 126 mg/dL or higher or a hemoglobin A_1c 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 A_1c 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 A_1c 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 A_1c 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.

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 sulfonylurea^22,23
• 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.

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 helpful^24,25:

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

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.

Glucocorticoids are commonly prescribed by primary care physicians and specialists alike for multiple medical problems, acute as well as chronic.

However, these useful drugs have adverse effects on multiple endocrine systems, effects that include diabetes (or worsening of hyperglycemia in those with known diabetes), Cushing syndrome, adrenal suppression, osteoporosis (reviewed in the Cleveland Clinic Journal of Medicine in August 2010),¹ and dyslipidemia. In addition, suppression of gonadotropins, growth hormone, and, acutely, thyrotropin can ensue.

The focus of this review is on the diabetogenic and adrenal suppressive effects of glucocorticoids and their management. We describe the rationale for choosing specific drugs to counter hyperglycemia, tests for determining adrenal suppression and systemic glucocorticoid absorption, and how and why to taper these drugs.

WIDELY USED DRUGS

Although glucocorticoids (often simply called steroids or corticosteroids, although not all steroids are corticosteroids, and not all corticosteroids are glucocorticoids) are the core treatment for adrenal insufficiency, in most cases they are prescribed for their anti-inflammatory effects. They act through multiple pathways at the cellular and molecular levels, suppressing the cascades that would otherwise result in inflammation and promoting pathways that produce anti-inflammatory proteins.²

In addition to formulations that are intended to have systemic effects, other, “local” formulations are made for specific conditions, such as intra-articular injections for arthritis, epidural injections for lumbar disk pain, eye drops for uveitis, nasal sprays for allergic rhinitis, inhalers for asthma, and topical ointments and creams for eczema. However, as we will discuss, even these preparations can have systemic effects.

GLUCOCORTICOID-INDUCED DIABETES IS COMMON

Glucocorticoids are the most common cause of drug-induced diabetes. Though the exact prevalence is not known, a few observations suggest that glucocorticoid-induced diabetes or hyperglycemia is common:

• In patients with rheumatoid arthritis, mean age 62 years, nearly 9% developed diabetes in the 2 years after starting glucocorticoid treatment, which was a higher rate than expected.³
• In nondiabetic patients with primary renal disease treated with prednisolone 0.75 mg/kg/day, 42% were found to have 2-hour post-lunch plasma glucose concentrations higher than 200 mg/dL but normal fasting glucose levels.⁴
• In a case-control study, the odds ratio of starting an oral hypoglycemic agent or insulin was 1.77 for patients receiving a hydrocortisone-equivalent dose of 1 to 39 mg/day, 3.02 for 40 to 79 mg/day, 5.82 for 80 to 119 mg/day, and 10.34 for 120 mg/day or more.⁵ (For a full discussion of glucocorticoid equivalents, see the section below on Cushing syndrome and adrenal suppression.)
• In patients with type 1 diabetes, prednisone 60 mg/day raised the blood glucose levels starting 6 hours after the prednisone dose.⁶
• Diabetic ketoacidosis and hyperosmolar nonketotic syndrome have been reported as a result of glucocorticoid treatment.^7–9

GLUCOCORTICOIDS CAUSE DIABETES MAINLY VIA INSULIN RESISTANCE

The mechanism by which glucocorticoids cause diabetes predominantly involves insulin resistance rather than decreased insulin production. In fact, in a study in healthy volunteers, ¹⁰ hydrocortisone infusion resulted in higher insulin production than saline infusion did. (In high doses, however, glucocorticoids have been shown to decrease insulin secretion.¹¹)

Normally, in response to insulin, the liver decreases its output of glucose. Glucocorticoids decrease the liver’s sensitivity to insulin, thereby increasing hepatic glucose output.¹² They also inhibit glucose uptake in muscle and fat, reducing insulin sensitivity as much as 60% in healthy volunteers. This seems primarily due to a postreceptor effect, ie, inhibition of glucose transport.^13–15

THE PEAK EFFECT OCCURS 4 TO 6 HOURS AFTER DOSING

To understand the optimal time for checking plasma glucose and to apply appropriate treatment, we should consider the pharmacokinetic profile of glucocorticoids.

Studied using the whole-blood lymphocyte proliferation technique, prednisone shows a peak effect at about 4 to 6 hours and a duration of action of 13 to 16 hours.¹⁶ This closely resembles what we see in terms of glucose excursion with this drug.¹⁷ Two studies of intravenous dexamethasone 10 mg showed that glucose levels rose within 4 hours of injection, but did not pursue this beyond that time frame.^18,19

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 A_1c of 5.7% or higher), then a fasting plasma glucose level of 126 mg/dL or higher or a hemoglobin A_1c 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 A_1c 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 A_1c 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 A_1c 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.

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 sulfonylurea^22,23
• 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.

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 helpful^24,25:

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

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.

Glucocorticoids are commonly prescribed by primary care physicians and specialists alike for multiple medical problems, acute as well as chronic.

However, these useful drugs have adverse effects on multiple endocrine systems, effects that include diabetes (or worsening of hyperglycemia in those with known diabetes), Cushing syndrome, adrenal suppression, osteoporosis (reviewed in the Cleveland Clinic Journal of Medicine in August 2010),¹ and dyslipidemia. In addition, suppression of gonadotropins, growth hormone, and, acutely, thyrotropin can ensue.

The focus of this review is on the diabetogenic and adrenal suppressive effects of glucocorticoids and their management. We describe the rationale for choosing specific drugs to counter hyperglycemia, tests for determining adrenal suppression and systemic glucocorticoid absorption, and how and why to taper these drugs.

WIDELY USED DRUGS

Although glucocorticoids (often simply called steroids or corticosteroids, although not all steroids are corticosteroids, and not all corticosteroids are glucocorticoids) are the core treatment for adrenal insufficiency, in most cases they are prescribed for their anti-inflammatory effects. They act through multiple pathways at the cellular and molecular levels, suppressing the cascades that would otherwise result in inflammation and promoting pathways that produce anti-inflammatory proteins.²

In addition to formulations that are intended to have systemic effects, other, “local” formulations are made for specific conditions, such as intra-articular injections for arthritis, epidural injections for lumbar disk pain, eye drops for uveitis, nasal sprays for allergic rhinitis, inhalers for asthma, and topical ointments and creams for eczema. However, as we will discuss, even these preparations can have systemic effects.

GLUCOCORTICOID-INDUCED DIABETES IS COMMON

Glucocorticoids are the most common cause of drug-induced diabetes. Though the exact prevalence is not known, a few observations suggest that glucocorticoid-induced diabetes or hyperglycemia is common:

• In patients with rheumatoid arthritis, mean age 62 years, nearly 9% developed diabetes in the 2 years after starting glucocorticoid treatment, which was a higher rate than expected.³
• In nondiabetic patients with primary renal disease treated with prednisolone 0.75 mg/kg/day, 42% were found to have 2-hour post-lunch plasma glucose concentrations higher than 200 mg/dL but normal fasting glucose levels.⁴
• In a case-control study, the odds ratio of starting an oral hypoglycemic agent or insulin was 1.77 for patients receiving a hydrocortisone-equivalent dose of 1 to 39 mg/day, 3.02 for 40 to 79 mg/day, 5.82 for 80 to 119 mg/day, and 10.34 for 120 mg/day or more.⁵ (For a full discussion of glucocorticoid equivalents, see the section below on Cushing syndrome and adrenal suppression.)
• In patients with type 1 diabetes, prednisone 60 mg/day raised the blood glucose levels starting 6 hours after the prednisone dose.⁶
• Diabetic ketoacidosis and hyperosmolar nonketotic syndrome have been reported as a result of glucocorticoid treatment.^7–9

GLUCOCORTICOIDS CAUSE DIABETES MAINLY VIA INSULIN RESISTANCE

The mechanism by which glucocorticoids cause diabetes predominantly involves insulin resistance rather than decreased insulin production. In fact, in a study in healthy volunteers, ¹⁰ hydrocortisone infusion resulted in higher insulin production than saline infusion did. (In high doses, however, glucocorticoids have been shown to decrease insulin secretion.¹¹)

Normally, in response to insulin, the liver decreases its output of glucose. Glucocorticoids decrease the liver’s sensitivity to insulin, thereby increasing hepatic glucose output.¹² They also inhibit glucose uptake in muscle and fat, reducing insulin sensitivity as much as 60% in healthy volunteers. This seems primarily due to a postreceptor effect, ie, inhibition of glucose transport.^13–15

THE PEAK EFFECT OCCURS 4 TO 6 HOURS AFTER DOSING

To understand the optimal time for checking plasma glucose and to apply appropriate treatment, we should consider the pharmacokinetic profile of glucocorticoids.

Studied using the whole-blood lymphocyte proliferation technique, prednisone shows a peak effect at about 4 to 6 hours and a duration of action of 13 to 16 hours.¹⁶ This closely resembles what we see in terms of glucose excursion with this drug.¹⁷ Two studies of intravenous dexamethasone 10 mg showed that glucose levels rose within 4 hours of injection, but did not pursue this beyond that time frame.^18,19

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 A_1c of 5.7% or higher), then a fasting plasma glucose level of 126 mg/dL or higher or a hemoglobin A_1c 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 A_1c 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 A_1c 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 A_1c 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.

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 sulfonylurea^22,23
• 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.

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 helpful^24,25:

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

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.