The results of this multicenter, retrospective cohort study indicate that the risk of hyperglycemia requiring treatment with hypoglycemic medications is approximately 4.4-fold higher following initiation of systemic corticosteroids in patients being treated for inflammatory eye diseases, with higher doses being associated with higher risk. Even so, the absolute risk is low (an attributable risk of 1.18% within one year of treatment). The risk of hyperglycemia also increased monotonically with age and was nearly 3-fold higher amongst African-Americans than among other races (mostly Caucasians). The majority of patients requiring hypoglycemic medications subsequently stopped them within one year, usually in association with tapering of corticosteroids.
The incidence of corticosteroid-induced hyperglycemia in our study is much lower than reported in previous small clinical series of patients with systemic diseases. Uzu 2008 reported that 41% of 42 patients with primary renal disease being treated with corticosteroids subsequently developed diabetes. Patients in this study were treated with both oral and occasionally very high dose intravenous corticosteroids. Age and body mass index were the only other identifiable significant risk factors. Information regarding body mass index was not available in our database. Similarly Iwamoto 2004 reported that 52% of 25 patients with various neurologic diseases being treated with oral and intravenous corticosteroids developed corticosteroid-induced diabetes. Age and serum cholesterol level after corticosteroid therapy were the only significant risk factors for hyperglycemia in this study. Dose and duration of corticosteroid therapy were not found to be significant risk factors. Panthakalam 2004 reported that 8.8% of 102 patients with rheumatoid arthritis developed corticosteroid-induced diabetes and that 6 of 6 patients with pre-existing diabetes experienced worsening of their disease. Our study did not evaluate the risk of worsening diabetes amongst those already known to be diabetic.
Although the risk of developing diabetes appears much lower in our study, the results of these studies cannot be directly compared to ours, because they diagnosed diabetes based on blood glucose levels, whereas our study only examined the initiation of hypoglycemic medication. It is likely that several patients in our study developed hyperglycemia that would have met the criteria used for diabetes diagnosis used in the other studies had they been screened repeatedly for hyperglycemia in the hospitalized setting, but which never came to clinical attention in the outpatient setting, or else was not judged to require hypoglycemic medication because of an expectation of improvement with tapering of systemic corticosteroids. Moreover, corticosteroid treatment for patients with ocular inflammatory diseases may be less intensive than the approach used for other illnesses, which may have reduced the risk of corticosteroid-induced diabetes. Because ocular inflammation is not life-threatening, and often can be addressed with topical and periocular corticosteroids in addition to systemic corticosteroid-sparing therapies, clinicians would have had greater freedom to taper corticosteroids and may have been able to avert corticosteroid-induced hyperglycemia requiring hypoglycemic medications for many cases. Additionally, the study centers were chosen for the study based on their frequent use of corticosteroid-sparing immunosuppressive therapy for ocular inflammatory diseases, and frequent recourse to such therapy (in approximately 25% of patients) also may have reduced the risk of corticosteroid-induced diabetes12,13
Using a retrospective, case-control approach to this question, Gurwitz et al examined a random sample of 11,855 patients enrolled in the New Jersey Medicaid Program aged 35 years or older over a 10 year period who had recently initiated a hypoglycemic medication (event)11
. The odds ratio for development of hyperglycemia requiring treatment was 2.23 (95% CI = 1.92 – 2.59) compared to those not taking corticosteroids, a value more similar to that obtained in our study, though somewhat lower. Risk increased with average daily corticosteroid dose, African-American race, and nursing home residence, but (in contrast to our results) age was not found to be a significant risk factor. Indications for corticosteroid therapy were unavailable in the study. Our study instead looked at patients with a unifying diagnoses and examined them over time to see which patients with the exposure (corticosteroid use) subsequently developed the event (initiation of hyperglycemic mediation). The data obtained from our study are based upon office visits, in which all relevant changes to the medical history are available, whereas the Gurwitz study may have missed patients who were on hypoglycemic medications or corticosteroids, but did not receive them from Medicaid.
There are several limitations to this study. Our absolute risk results should be interpreted as reflecting the risk of hyperglycemia of a degree sufficient to come to clinical attention and require therapy; temporary elevations in blood glucose that did not cause clinical symptoms would be missed with this approach. Relative risk estimates associated with risk factors would be less affected by this limitation than absolute risk estimates. Also, as a retrospective study, patients were considered to have had an event only if hypoglycemic therapy was initiated between the initial visit for ocular inflammation and sustained until a follow-up visit. Furthermore, it is possible that some patients already had diabetes and/or were already on hypoglycemic therapy at the initial visit, but that this information was missing from the medical record. Such errors would tend to inflate estimates of the absolute risk of hyperglycemia, and to blunt risk factor associations (since the errors would affect both groups), leading to underestimates of risk ratios, rather than creating spurious associations. However, because the practices involved are run in a manner resembling rheumatology practices, such omissions likely would be infrequent, as also is suggested by the low absolute risk observed. Conversely, because patients not requiring oral corticosteroids may have been followed less frequently, episodes of hypoglycemic therapy may have been missed more frequently in the untreated group, which would tend to inflate the relative risk of hyperglycemia following corticosteroid therapy. The data available did not provide the opportunity to adjust for some reported risk factors, such as body mass index, cholesterol level, or family history of diabetes. If these factors were distributed unevenly between groups, unrecognized confounding could have affected the associations observed. However, given the likelihood that risk factors for corticosteroid-induced diabetes would have tended to deter use of systemic corticosteroids, unmeasured confounding would have been more likely to reduce the relative risk of hyperglycemia with corticosteroid therapy rather than produce spurious associations. It is reassuring that the other risk factors implicated in this analysis generally were consistent with those seen in prior reports8–11
. Most patients receiving treatment were free of systemic morbidity and were relatively young, so the relatively favorable results observed may reflect a lesser risk of corticosteroid-induced hyperglycemia in such patients than in patients with systemic diseases studied in other reports. The participating centers also pioneered corticosteroid-sparing approaches to the management of ocular inflammatory diseases, so the results reflect an approach which minimizes the dose and duration of systemic corticosteroids.
In summary, patients with inflammatory eye diseases managed at tertiary uveitis centers experienced in the use of corticosteroid and corticosteroid-sparing therapy had a low absolute risk of developing hyperglycemia requiring treatment following oral corticosteroid treatment (attributable risk of ~1% within 12 months). However, the relative risk for hyperglycemia that required treatment was 4.4 times greater with systemic corticosteroid therapy, and higher initial doses tended to be associated with higher risk, confirming that there is a heightened risk of hyperglycemia with this approach.. The risk of hyperglycemia was increased further with increasing age and African-American race. Ophthalmologists managing ocular inflammation patients with systemic corticosteroids should be aware that corticosteroid therapy increases the risk for clinically important hyperglycemia—especially among patients whose older age and African-American descent put them at higher risk. Clinicians managing systemic corticosteroid therapy in such patients should include monitoring for hyperglycemia (via questioning patients for hyperglycemic symptoms and laboratory testing when indicated) and/or seek medical consultation when appropriate. However, given the low absolute risk, routine laboratory monitoring or medical consultation for low risk patients may not be necessary.