Cleveland Clinic Journal of Medicine

For many of those long-term effects, such as osteoporosis, cushingoid features, skin fragility, and cataracts, all we can do is hope that they don’t occur, since there is little we can do to screen for or prevent them. We have previously discussed steroid-associated osteoporosis in the Journal,¹ and strategies for preventing it have been proposed by specialty societies.² For other complications such as hypertension, weight gain, and glucose intolerance, we can offer common-sense protective suggestions, monitor for them, and intervene if they occur.

In this issue, Dr. M. Cecilia Lansang and Ms. Leighanne Kramer Hustak³ discuss the management of steroid-induced adrenal suppression and diabetes. They offer practical management suggestions but also point out that the evidence base for our treatment decisions is surprisingly limited.

Nearly all patients chronically receiving high-dose glucocorticoid therapy develop glucose intolerance, but knowing when that is happening is not always easy. In patients destined to develop type 2 diabetes, the laboratory or clinical signs of hyperglycemia appear only when the pancreas can no longer maintain the insulin production necessary to overcome peripheral insulin resistance. Steroid-induced diabetes is characterized by increased gluconeogenesis, insulin resistance, and excessive postprandial surges, so fasting glucose levels are not sensitive for this clinical syndrome.

The degree and duration of the chronic hyperinsulinemia and hyperglycemia dictates the risk of microvascular complications and thus will be linked to duration of steroid therapy (unless the steroid is unmasking preexisting mild diabetes). Although issues surrounding tight control of blood glucose levels in the acute setting remain unresolved, I believe that even short-term significant steroid-induced hyperglycemia should be prevented when reasonably possible, at the least keeping in mind the additive ill effects of hyperglycemia and steroid therapy on the risk of nuisance infections such as oral and vaginal candidiasis and urinary tract infections that, in the setting of high-dose steroid therapy, can rapidly turn nasty.

For many of those long-term effects, such as osteoporosis, cushingoid features, skin fragility, and cataracts, all we can do is hope that they don’t occur, since there is little we can do to screen for or prevent them. We have previously discussed steroid-associated osteoporosis in the Journal,¹ and strategies for preventing it have been proposed by specialty societies.² For other complications such as hypertension, weight gain, and glucose intolerance, we can offer common-sense protective suggestions, monitor for them, and intervene if they occur.

In this issue, Dr. M. Cecilia Lansang and Ms. Leighanne Kramer Hustak³ discuss the management of steroid-induced adrenal suppression and diabetes. They offer practical management suggestions but also point out that the evidence base for our treatment decisions is surprisingly limited.

Nearly all patients chronically receiving high-dose glucocorticoid therapy develop glucose intolerance, but knowing when that is happening is not always easy. In patients destined to develop type 2 diabetes, the laboratory or clinical signs of hyperglycemia appear only when the pancreas can no longer maintain the insulin production necessary to overcome peripheral insulin resistance. Steroid-induced diabetes is characterized by increased gluconeogenesis, insulin resistance, and excessive postprandial surges, so fasting glucose levels are not sensitive for this clinical syndrome.

The degree and duration of the chronic hyperinsulinemia and hyperglycemia dictates the risk of microvascular complications and thus will be linked to duration of steroid therapy (unless the steroid is unmasking preexisting mild diabetes). Although issues surrounding tight control of blood glucose levels in the acute setting remain unresolved, I believe that even short-term significant steroid-induced hyperglycemia should be prevented when reasonably possible, at the least keeping in mind the additive ill effects of hyperglycemia and steroid therapy on the risk of nuisance infections such as oral and vaginal candidiasis and urinary tract infections that, in the setting of high-dose steroid therapy, can rapidly turn nasty.

For many of those long-term effects, such as osteoporosis, cushingoid features, skin fragility, and cataracts, all we can do is hope that they don’t occur, since there is little we can do to screen for or prevent them. We have previously discussed steroid-associated osteoporosis in the Journal,¹ and strategies for preventing it have been proposed by specialty societies.² For other complications such as hypertension, weight gain, and glucose intolerance, we can offer common-sense protective suggestions, monitor for them, and intervene if they occur.

In this issue, Dr. M. Cecilia Lansang and Ms. Leighanne Kramer Hustak³ discuss the management of steroid-induced adrenal suppression and diabetes. They offer practical management suggestions but also point out that the evidence base for our treatment decisions is surprisingly limited.

Nearly all patients chronically receiving high-dose glucocorticoid therapy develop glucose intolerance, but knowing when that is happening is not always easy. In patients destined to develop type 2 diabetes, the laboratory or clinical signs of hyperglycemia appear only when the pancreas can no longer maintain the insulin production necessary to overcome peripheral insulin resistance. Steroid-induced diabetes is characterized by increased gluconeogenesis, insulin resistance, and excessive postprandial surges, so fasting glucose levels are not sensitive for this clinical syndrome.

The degree and duration of the chronic hyperinsulinemia and hyperglycemia dictates the risk of microvascular complications and thus will be linked to duration of steroid therapy (unless the steroid is unmasking preexisting mild diabetes). Although issues surrounding tight control of blood glucose levels in the acute setting remain unresolved, I believe that even short-term significant steroid-induced hyperglycemia should be prevented when reasonably possible, at the least keeping in mind the additive ill effects of hyperglycemia and steroid therapy on the risk of nuisance infections such as oral and vaginal candidiasis and urinary tract infections that, in the setting of high-dose steroid therapy, can rapidly turn nasty.

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.

Nocturia is common, but elderly patients infrequently volunteer this complaint, and even when they do, some clinicians may dismiss it as simply a part of aging. Nevertheless, nocturia causes significant distress and impairment of quality of life. It is associated with very serious consequences such as depression, social isolation, and a higher risk of death.

In this article, we review the concepts behind frequent nighttime voiding in older adults. We will start with two case scenarios to aid in understanding these concepts; near the end of the article, we will discuss the most appropriate management strategies for these two patients.

CASE SCENARIOS

Case 1: An 82-year-old man with fatigue

An 82-year-old obese white man with a history of hypertension, diabetes, and benign prostatic hyperplasia comes in to see his primary care provider, complaining of fatigue. He wakes up tired and has difficulty completing his daytime tasks. He gets up every 1 to 2 hours at night to urinate and has slow urinary flow and a feeling of incomplete bladder emptying.

See related patient education material

He says his wife has been increasingly bothered by his loud snoring. Recently, he had a car accident when he fell asleep while driving.

Case 2: An 85-year-old woman with incontinence

An 85-year-old white woman is in her family physician’s office with a primary complaint of waking up at least four times at night to urinate, and often ends up soaking her bed or adult diapers. She is bothered by urinary urgency and frequency during the day as well. She denies dysuria and hematuria.

She has a history of hypertension and urinary incontinence, and she has seven children. Her current medications are diltiazem (Cardizem), metoprolol (Toprol), and oxybutynin (Ditropan).

In these two cases, what would account for the nocturia? What would be the best way to help these patients?

THE NORM, NOT THE EXCEPTION

Although nocturia is defined as an awakening by the need to urinate even once in a night, many experts consider that it begins to be clinically significant only when the patient voids at least twice during the night.¹

In older adults, nocturia is the norm rather than the exception. Studies done between 1990 and 2009 found that 68.9% to 93% of men age 70 and older get up at least once a night to void. The prevalence in women is somewhat lower, at 74.1% to 77.1%.² Clinically significant nocturia is present in a majority of the elderly: more than 60% of both men and women.³

An Austrian study⁴ reported that elderly men got up to urinate a mean of 2.8 times per night, while women got up significantly more often—3.1 times. Women were also bothered more by this symptom, and their quality of life was significantly more decreased.

In another study,⁵ whites had a significantly higher nocturia ratio (ratio of nighttime urine volume to the 24-hour urine volume) than Asians. Asians, on the other hand, had a significantly higher nocturnal bladder capacity index than whites. (See below for definitions of the various indices of nocturia.) This information implies that nocturia may be a more prominent problem for elderly whites than for other racial groups.

In an epidemiologic study in Sweden,⁶ the death rate was as much as twice as high in both men and women who had three or more nocturnal voids, even after taking into account the influence of cardiac disease, diabetes mellitus, and stroke.

If nocturia is not addressed in the physician-patient encounter, patients may try to “self-manage” it by restricting their fluid intake or by limiting their social exposure,⁷ with limited success and with unwanted social isolation.

WHAT CAUSES NOCTURIA?

Advancing age is primary among these factors. Age-related structural changes in the urinary system include decreased functional bladder capacity, a decreased maximum urinary flow rate,⁶ a decreased ability to postpone urination,⁸ and an age-related increase in postvoiding residual urine volume.⁹ The aging kidney is also less able to concentrate urine. Also implicated are histologic changes in the detrusor muscle¹⁰ that lead to diminished bladder compliance and, together with detrusor overactivity, result in increased urinary frequency.

Nocturnal polyuria or nocturnal urine overproduction is common in patients with nocturia.¹¹

Although the pathophysiology of nocturnal polyuria is still unclear, some investigators believe that low levels of antidiuretic hormone (ADH) at night are involved, reflecting an alteration in the circadian rhythm seen in diurnal plasma arginine vasopressin levels.¹² In patients with nocturnal polyuria, ADH levels drop to very low or undetectable levels at night, which increases nocturnal urine output. In some extreme cases, the low to absent levels of ADH increase nocturnal voiding to 85% of the total 24-hour urine volume.¹³

Other causes of nocturnal polyuria include mobilization of fluids in patients with edema,¹⁴ and autonomic dysfunction. Other biochemical changes that contribute to nocturia include a decrease in nighttime plasma melatonin levels, an increase in nighttime plasma catecholamine levels, an increase in nighttime plasma natriuretic peptide levels, an increase in blood pressure, and an increase in total urine volume.¹⁵

A decreased ability to store urine also leads to nocturia. This is caused by decreased nocturnal bladder capacity, more irritative symptoms, and comorbid conditions such as overactive bladder, pelvic floor laxity resulting in pelvic organ prolapse, and, in men, benign prostatic hyperplasia.

Neural inputs to the bladder can also be impaired, as in patients who have diabetes mellitus or spinal stenosis, leading to chronic urinary retention, detrusor dysfunction, nocturia, and incontinence.

WHICH PATIENTS ARE AT RISK?

Obesity is associated with a higher incidence of moderate to severe nocturia.¹⁵ Studies have shown that the higher the body mass index, the greater the number of nighttime voids, especially in women.¹⁶

Habitually eating at night, with poor daytime appetite, is shown to be associated with increased nighttime diuresis.

Obstructive sleep apnea¹⁷ and untreated depressive symptoms such as frequent napping¹⁸ are also associated with moderate to severe nocturia.¹⁹

Higher systolic blood pressures are associated with more urine production at night. Plasma ADH regulation is also altered, which contributes to nocturnal polyuria.²¹

Other comorbid conditions associated with nocturia include recurrent cystitis, lung disease, congestive heart failure, neurodegenerative conditions (eg, Alzheimer disease and parkinsonism), and chronic kidney disease.²¹

Drugs associated with nocturia include cholinesterase inhibitors (for dementia),²² beta-blockers,²³ and calcium channel blockers.²⁴

Lifestyle factors. Alcohol and coffee have shown either no or only a mild diuretic effect. Smoking has not been shown to be associated with nocturia.¹⁵

Seasonal differences also exist, with increased frequency of nocturia in the winter.²⁵

WHAT ARE THE CLINICAL CONSEQUENCES OF NOCTURIA?

Quality of life can be profoundly affected, and if nocturia is left untreated, it may lead to morbidity and even death. Elderly patients may feel simultaneously debilitated, frustrated, distressed, and puzzled. Nocturia may also increase their fear of falling and may negatively affect personal relationships.²⁶

Falls, injuries. Nocturia exposes elderly patients to injuries such as hip fractures due to falling, significantly increasing the incidence of this injury.²⁶ This occurs as elderly patients get up from bed and walk to the bathroom to void.²⁷ In addition, during the day, superficial and fragmented sleep leads to daytime sleepiness and impaired perception and balance, also increasing the risk of falls.²⁸ The complications of immobility and the need for surgery in many cases lead to debility, increased risk of infections, decubitus ulcers, and death. The risk of hip fractures can lead elderly patients with nocturia to associate this symptom with a fear of falling and can alter their concept of their own age (“Nocturia makes me feel old”),²⁹ further diminishing quality of life.

The estimated medical cost of nocturia-associated falls in the elderly is about $1.5 billion per year, part of the $61 billion in lost productivity due to nocturia in adults.³⁰

Long-term complications (eg, debilitation, poor sleep, obesity, decreased energy), increase the overall mortality rate, especially in patients who report voiding more than three times per night.²⁹ Elderly patients with nocturia also have a greater need for emergency care.³¹

Nocturia also complicates other comorbid conditions, such as dementia, which increases the risk of urinary incontinence.³² In patients who have had a stroke, nocturia is the most frequent lower urinary tract symptom, and represents a major impact on daily life.³³

Sleep disturbance is another important consequence. In one survey,³⁴ nocturia was cited as a cause of poor sleep four times more often than the cause cited next most often, ie, pain. Because the elderly patient is awakened from sleep numerous times throughout the night, nocturia leads to more fatigue,³⁵ lower energy levels, and poorer quality of sleep.³⁶ Depression may be linked to poor sleep, as men with two or more nocturnal episodes were shown to be six times more likely to experience depression.

The patient is not the only person who loses sleep: so do the patient’s family members or sleeping partner.⁷ It is therefore not surprising that sleep disruption caused by nocturia has been cited as a principal reason for admitting older relatives to care homes.³⁷

The risk of death is higher for elderly patients with coronary heart disease if they have nocturia. The causative link is the hemodynamic changes (increases in blood pressure and heart rate) that accompany awakening and arising, which may cause cardiovascular strain and lead to cardiovascular events. The 12-year survival rate has been shown to be significantly lower in patients with nighttime voiding, making nocturia a highly significant independent predictor of death in coronary heart disease patients.³⁸

HOW TO EVALUATE AN OLDER ADULT WHO PRESENTS WITH NOCTURIA

A thorough history and physical examination are crucial in diagnosing nocturia. The goal is to identify any treatable underlying condition, such as diabetes mellitus, obstructive sleep apnea, diabetes insipidus, overactive bladder, benign prostatic hyperplasia, urinary tract infection, and congestive heart failure. Laboratory tests and imaging studies can help rule out these underlying conditions.

Other important facets in the history that must be elicited are medication use, patterns of fluid intake, and a history of other urinary complaints.³⁹

A voiding diary and indices of nocturia

A voiding diary is extremely useful and should be used whenever possible. Episodes of incontinence, time of voids, volume voided, and frequency and volume of fluid intake are recorded. From the raw data, one can determine the following:

Total nocturnal urine volume, ie, the sum volume of the nighttime voids

Maximum voided volume, ie, the largest single recorded volume voided in a 24-hour period

Nocturia index, ie, the total nocturnal urine volume divided by the maximum voided volume. A nocturia index greater than 1 shows that nocturnal urine production is greater than the functional bladder capacity. Clinically significant nocturia is observed in patients with a nocturia index of 2.1 or greater.

Nocturnal polyuria index, ie, total nocturnal urine volume divided by the 24-hour urine output. A nocturnal polyuria index higher than 33% implies nocturnal polyuria.⁴⁰

Nocturnal bladder capacity index, ie, the actual number of nightly voids minus the predicted number of nightly voids, which in turn is calculated as the nocturia index minus 1.

It is especially important to encourage patients to make a voiding diary, as some patients may find this cumbersome, and compliance can be low unless its importance is emphasized. A diary over 7 days usually gives meaningful data. The results from the diary typically confirm the presence of nocturnal polyuria or a decrease in bladder capacity, influencing management.⁴¹

WHAT ARE THE TREATMENT OPTIONS?

Therapy must be directed at the primary cause, addressing any underlying conditions that can contribute to nocturia. Examples³⁹:

• Tight control of blood sugar for patients with diabetes mellitus
• Treatment of diabetes insipidus
• Referral for patients with primary polydipsia
• Management of hypercalcemia and hypokalemia
• A survey of medications
• Treatment of infections.

Nonpharmacologic measures

Tailored behavioral therapy can also be instituted, but the patient needs to have realistic expectations, as these measures are rarely effective alone.

Avoiding nighttime fluid intake, including alcohol and caffeine, has shown promise.

Wearing compression stockings and elevating the legs in the afternoon decrease the retention of fluid that otherwise would return to the circulation at night.

Identifying and eliminating nighttime influences that disturb sleep has variable efficacy. The use of continuous positive airway pressure helps to treat sleep apnea. Moderate exercise, reducing nonsleep time spent in bed,⁴² and sleeping in a warm bed⁴³ to decrease cold diuresis have also been shown to improve sleep quality.⁴⁴ Patients with nocturia may have a disrupted circadian rhythm, and phototherapy may help resynchronize the diurnal rhythm and melatonin secretion.

Pharmacotherapy

Pharmacotherapy of nocturia includes desmopressin (DDAVP) to manage nocturnal polyuria and antimuscarinic agents to manage the patient’s decreased ability to store urine. Alpha-blockers such as tamsulosin (Flomax) and 5-alpha-reductase inhibitors such as finasteride (Proscar) are used for men with benign prostatic hyperplasia. Novel and second-line therapies include diuretics such as furosemide (Lasix), cyclooxygenase-2 inhibitors, as well as botulinum toxin injected directly into the detrusor muscle for overactive bladder.⁴⁵

Desmopressin in a low oral dose (0.1–0.4 mg) at bedtime can be initiated and the response assessed. Patients with nocturnal polyuria and disorders of the vasopressin system have been found to be more sensitive to desmopressin therapy.⁴⁶ Fluid retention and hyponatremia can complicate therapy, and desmopressin must be avoided in patients with liver cirrhosis, renal failure, or congestive heart failure.⁴⁷

Antimuscarinic agents are effective for patients who have lower urinary tract symptoms and for those with a diminished ability to store urine. They act by decreasing both voluntary and involuntary bladder contractions by blocking muscarinic receptors on the detrusor muscle. This reduces the bladder’s ability to contract and the urge to urinate, thereby increasing bladder capacity.⁴⁸ These agents include oxybutynin (Ditropan), tolterodine (Detrol), solifenacin (Vesicare), and propiverine (not available in the United States).

Diuretics are being used as second-line agents or for patients who cannot tolerate desmopressin.⁴⁹ Hydrochlorothiazide is taken 8 hours before bedtime to prevent water accumulation before the early sleeping hours.⁵⁰ Furosemide has also led to a reduction in the mean number of nocturnal voids.⁵¹ The effect of these drugs on nocturia are especially beneficial to patients with concomitant hypertension or cardiovascular disease.

Cyclo-oxygenase-2 inhibitors such as celecoxib (Celebrex)⁵² and other nonsteroidal anti-inflammatory drugs such as diclofenac (Voltaren, others)⁵³ and loxoprofen (not available in the United States)⁵⁴ have been shown to decrease urine production, detrusor muscle tone, and inflammation, especially in men with benign prostatic hyperplasia.

Botulinum toxin has been used, usually in patients refractory to first-line treatment.⁴⁴

Table 4 summarizes the treatment strategies for nocturia.

CASES REVISITED

The first patient described above has nocturia caused by several concomitant diseases, ie, hypertension, diabetes, benign prostatic hyperplasia, and obstructive sleep apnea. In addition to controlling his blood pressure and blood sugar, his primary care provider referred him to a pulmonologist, who confirmed obstructive sleep apnea with polysomnography and prescribed nightly use of a continuous positive airway pressure apparatus. A few weeks later, the patient’s nocturia had improved significantly, and his level of fatigue had decreased.

Apart from hypertension, the second patient’s nocturia was mostly attributed to her existing urinary incontinence. Recognizing that her current antihypertensive regimen may worsen nocturia, her family physician changed it to enalapril (Vasotec) and doxazosin (Cardura) and counseled her to restrict her fluid intake 2 hours before bedtime. She was also referred to a gynecologist, who found a moderate degree of cystocele and treated her with a collagen injection. Her nocturia improved significantly.