Risk of hyperglycemia from glucocorticoids

A 65 year old patient with COPD sees his primary care provider for worsening shortness of breath over the past week.  His current medications include tiotropium and albuterol.  He has no other significant past medical history but has a family history of diabetes.  His current labs include a fasting plasma glucose of 96 mg/dL, HbA1c of 6.1%, Scr = 0.8 mg/dL.  His primary care provider determines that the patient is having a COPD exacerbation and is opting to initiate a 5 day course of prednisone 40 mg orally daily (click here for more on a 5 days course versus longer steroid courses for COPD exacerbations).  What are some of the risk factors, the time-course, and the mechanism for developing hyperglycemia in a situation like this?


The development of hyperglycemia secondary to glucocorticoids is thought to be a common occurrence that has been reported in up to 65.6% of patients using glucocorticoids.1  It is difficult to determine with accuracy the incidence of glucocorticoid-induced hyperglycemia for some of the following reasons:

• 'Steroids' with varying glucocorticoid potencies are used at a wide range of doses and durations for different conditions
• Definitions of glucocorticoid-induced hyperglycemia and diabetes vary among studies
• Specific screening methodology varies.  This is important because glucocorticoid-induced hyperglycemia is not uniform throughout the day.  It predominates in the postprandial hours (one study specifically found that 2-hours post lunch was the highest concentration over the course of the day and if this screening time was not chosen, many cases would have been missed).²

Steroid-related risk factors

A large case-control study of nearly 12,000 patients in each group was used to determine the risk factors associated with needing a new hypoglycemic agent.  The authors looked at the average corticosteroid dose and found that there was a higher risk for hypoglycemia therapy as doses increase [see table below where doses are based on hydrocortisone equivalents (click here to see how to convert corticosteroid potencies)].The authors also found that recency of steroid use was significant, with more recent prescriptions being associated with higher risk of hypoglycemic agent use (within up to 90 days was significant).  Here are the odds ratios for these risk factors.3

Hydrocortisone dose	Odds ratio
1-39 mg	1.77 (95% CI, 1.54-2.02)
40-79 mg	3.02 (95% CI, 2.09-4.37)
80-119 mg	5.82 (95% CI, 2.74-12.35)
≥120 mg	10.34 (95% CI, 3.16-33.90)
Recency of steroid
1-45 days	2.23 (95% CI, 1.92-2.59)
46-90 days	1.64 (95% CI, 1.31-2.05)
>90 days	1.23 (95% CI, 0.87-1.74)

Other risk factors

It has not been fully established whether traditional risk factors for diabetes mellitus are also risk factors for glucocorticoid-induced diabetes mellitus.  One study found that glucocorticoid-induced diabetes mellitus generally developed within 4 weeks of therapy and identified the following risk factors:1

• Age ≥65
• HbA1c ≥6%
• eGFR <40

Fasting plasma glucose, hypertension, and BMI ≥25 kg/m2 were not found to be risk factors and a family history of diabetes mellitus was found to be much less of a factor in another study.

Mechanism

The mechanism for glucocorticoid-induced hyperglycemia is a combination of effects at both the beta cells and insulin's target tissues.

• At the beta cells glucocorticoids acutely cause beta cell dysfunction, but with chronic use the beta cell may partly recover.  Based on animal studies, beta cell endoplasmic reticulum homeostasis may be disrupted by glucocorticoids.
• In the liver, glucocorticoids affect an enzyme (PEPCK) causing an increased release of fatty acids into the blood.  This causes insulin resistance and decreased glucose utilization, chiefly in the skeletal muscles (where the majority of insulin-mediated glucose uptake occurs).

Back to the patient case

Our patient (who was correctly prescribed the GOLD guideline-recommended regimen of prednisone 40 mg daily for 5 days) has multiple risk factors for developing hyperglycemia from this glucocorticoid regimen.  His age and HbA1c are risk factors, though his family history is probably less significant.  His prednisone 40 mg is roughly equivalent to hydrocortisone 160 mg daily, revealing a very high odds ratio (>10 according to the chart above) for risk of requiring a hypoglycemic agent (again, click here if you want to see how to convert among glucocorticoid potencies).  If he does develop hyperglycemia, it can occur within the first few days but will likely resolve a few days after his short course of steroids is completed.  If you did want to monitor for hyperglycemia, you would more likely detect it after lunch or other postprandial times of the day, not when he is fasting.

Take home points

• Hyperglycemia secondary to glucocorticoids is primarily postprandial, occurs within hours, and is largely dose-dependent
• Patients with traditional risk factors for diabetes mellitus are likely at increased risk for this adverse effect, though not all risk factors carry equal weight

References
1.  Katsuyama T, Sada K, Namba S, et al.  Risk factors for the development of glucocorticoid-induced diabetes mellitus. Diabetes Res Clin Pract  2015  http://dx.doi.org/10.1016/j.diabres.2015.02.010
2.  Iwamoto T, Kagawa Y, Naito Y, et al.  Steroid-induced diabetes mellitus and related risk factors in patients with neurologic diseases.  Pharmacotherapy  2004;24(4):508-14.
3.  Gurwitz JH, Bohn RL, Glynn RJ, et al.  Glucocorticoids and the risk for initiation of hypoglycemic therapy.  Arch Intern Med  1994;154(1):97-101.

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