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Glucocorticoid-induced diabetes and adrenal suppression: How to detect and manage them

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ABSTRACTGlucocorticoids, commonly used to treat multiple inflammatory processes, can cause hyperglycemia, Cushing syndrome, adrenal suppression, and, when they are discontinued, adrenal insufficiency. Physicians must be aware of these adverse effects and be equipped to manage them.

KEY POINTS

  • Nonfasting plasma glucose levels are more sensitive than fasting levels for detecting glucocorticoid-induced diabetes, and antidiabetic agents that have greater effects on random postprandial plasma glucose levels are more suitable than those that mostly affect fasting levels.
  • Even those glucocorticoid formulations that are not intended to have systemic effects (eg, eye drops, inhaled corticosteroids, creams, intra-articular injections) can cause adrenal suppression and, therefore, if they are discontinued, steroid withdrawal and adrenal insufficiency.
  • Needed are studies comparing antidiabetic regimens for glucocorticoid-induced hyperglycemia and studies comparing glucocorticoid tapering schedules for adrenal suppression to determine the best way to manage these adverse effects.


 

References

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

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