Hyperglycemia Associated with Non-oral and Locally Injected Corticosteroids

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1 PL Detail-Document # This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER October 2011 Hyperglycemia Associated with Non-oral and Locally Injected Corticosteroids Introduction Corticosteroids are used for a wide array of indications and are given by many different routes (oral, topical, intra-articular, inhaled, epidural, etc). Hyperglycemia is a well known complication of systemic (oral, intramuscular, intravenous) corticosteroid therapy, but less well recognized with other routes of administration. This document reviews hyperglycemia associated with corticosteroids given by topical, intraarticular, inhaled, and epidural routes of administration. Hyperglycemia and Corticosteroids Hyperglycemia is a well-known adverse effect of corticosteroid therapy. Orally administered corticosteroids have been shown to worsen glucose control in patients who already have diabetes and to cause hyperglycemia in patients without preexisting diabetes. 1 The incidence of corticosteroid-induced hyperglycemia is difficult to quantify because it is dependent on many patient-specific (type of diabetes, body mass index, age, family history) and treatment-specific (drug, dose, route of administration, duration) factors. 1 There are a number of mechanisms by which hyperglycemia occurs. Corticosteroids reduce glucose utilization, increase glucose production, inhibit the effects of insulin on myocytes and adipocytes, and increase hepatic glucose release. 2 The effects can be seen as early as 12 hours after beginning therapy. 3 In patients taking oral prednisone, the most pronounced hyperglycemic effect occurs one to two hours after a meal. 3 Certain corticosteroids have a more pronounced effect on blood glucose than others. For example, the synthetic corticosteroids prednisone and dexamethasone are four and 30 times more potent, respectively, than natural corticosteroids such as hydrocortisone at reducing carbohydrate metabolism. 3 There appears to be an association between the cumulative oral corticosteroid dose and the development of diabetes. In a case-control study, the risk of developing hyperglycemia requiring treatment was 1.77 (compared with controls) for patients receiving 1 mg to 10 mg a day of prednisone or the equivalent, 3.02 for 10 mg to 20 mg of daily prednisone, 5.82 for those taking 20 mg to 30 mg daily, and for those who received more than 30 mg of prednisone a day. 4 Similar results were seen by Ariza-Andraca and colleagues who found that the cumulative prednisone dose was significantly higher in those who developed diabetes compared with those who did not (26.6 g +/- 28 g vs 11.6 g +/- 11 g, p<0.02, odds ratio, 6.35). 5 In two other studies of patients without a history of diabetes with neurologic disease and those with respiratory disease, older age was also identified as a risk factor. 6,7 Of note, in the study of patients with respiratory disease, corticosteroid-induced diabetes occurred after a median of 193 days of therapy. 6 Upon discontinuation of the corticosteroid, the hyperglycemic effects of corticosteroids typically dissipate and blood glucose concentrations return to normal. 3 Intra-articular Corticosteroids Intra-articular injection of corticosteroids into a painful joint is common. Commonly injected joints include knee, shoulder, wrist, temporomandibular joint, ankle, and elbow. Intra-articular administration is touted as being effective while minimizing the systemic adverse effects commonly seen with systemic corticosteroid therapy. Despite widespread use, data regarding the effects on glucose are sparse and contradictory. 8 One of the first reports involved an elderly patient who developed a blood glucose concentration of greater than 1000 mg/dl

2 (55.6 mmol/l) within two hours after injection into the knee. 9 Since then, there have been a variety of conflicting reports regarding the effects of intraarticular injection on blood glucose. In a study of 18 patients with diabetes, no clinically significant effect was noted on blood glucose following 35 mg of methylprednisolone at the shoulder joint. 10 Conversely, two studies of corticosteroid injections in the knee showed increases in blood glucose. Following methylprednisolone 50 mg in nine patients with well-controlled diabetes, peak blood glucoses levels of approximately 300 mg/dl (16.7 mmol/l) were noted between five and 84 hours after injection and typically remained elevated for two to three days (but as long as five days). 11 However, one patient experienced a peak blood glucose level of 500 mg/dl (27.8 mmol/l) 48 hours after injection. 11 Following injection of 1 ml of Celestone Chronodose (a betamethasone depot product composed of 3 mg of betamethasone acetate and 3 mg of betamethasone sodium phosphate), six patients experienced significant preprandial and postprandial elevations of blood glucose for 18 to 46 hours after injection. 12 Increases in blood glucose were noted in patients with diabetes who received 10 mg methylprednisolone injections for trigger finger for five days. 13 In general, hyperglycemia following intraarticular injections of corticosteroids can be seen two to five days after injection [Evidence level B; nonrandomized study] ,14 In most patients, the clinical significance is minimal. However, in brittle patients with type 1 diabetes or in poorly controlled patients with type 2 diabetes, more frequent monitoring of blood glucose concentrations and diabetes medication dosage adjustments may be warranted. 14 Topical Corticosteroids Systemic effects of topical corticosteroids (applied to the skin) are determined by the bioavailability after topical administration. Topical corticosteroids such as mometasone furoate and fluticasone propionate have a small bioavailability with less than 1% systemically absorbed. Conversely, betamethasone dipropionate has a bioavailability of approximately of 44%. 3 (PL Detail-Document #271011: Page 2 of 5) In a nested case-control retrospective study of a drug database in the Netherlands, the association of topical corticosteroid use and diabetes was investigated. Corticosteroid use was defined as filling two or more prescriptions for topical corticosteroids and the onset of diabetes was defined as the first occurrence of filling a prescription for a diabetes medication. Control subjects were patients who filled two or more prescriptions for topical corticosteroids who did not subsequently fill a prescription for a diabetes medication. 15 The authors found that of the 192,893 topical corticosteroid users, 2212 developed diabetes. Current use of topical corticosteroids was associated with a 1.24-fold increased risk of diabetes (odds ratio 1.24, 95% confidence interval 1.11 to 1.40). When topical corticosteroids were used for more than 180 days, there was a fold risk in the development of diabetes (odds ratio 1.32, 95% confidence interval 1.14 to 1.54). Cumulative topical dose also appeared to be associated with the development of diabetes. 15 Based on the literature, it appears that topical corticosteroids can cause hyperglycemia [Evidence level B; case-control study]. 15 In patients using topical corticosteroids, especially for prolonged periods of time, or at a high steroid load (a combination of dose and potency), monitoring of blood glucose concentrations may be warranted. This is especially true for patients with an increased risk of absorption through the skin such as those with excoriated skin (psoriasis) or those who use topical steroids over large areas. Inhaled Corticosteroids Despite the widespread use of inhaled corticosteroids in the treatment of asthma and chronic obstructive pulmonary disease, there is limited information concerning their effects on blood sugar. One of the earliest reports of loss of glycemic control in a patient with diabetes receiving inhaled corticosteroids was reported in In this report, a 67-year old patient with well-controlled type 2 diabetes and asthma was started on fluticasone 2000 mcg daily. Although asthma symptoms improved, A1C increased from a baseline of 7 to 7.3% to 8.2%. After a fluticasone dose reduction to 1000 mcg daily, the A1C declined to 7.8%. In addition, glycosuria occurred when the patient was taking 2000 mcg daily, but

3 resolved when the dose was reduced to 500 mcg daily. 16 In a retrospective, population-based cohort trial patients who received three or more prescriptions for respiratory medications over a one-year period were studied. Only those without a diagnosis of diabetes and who had not received treatment for diabetes were included, so only patients with new-onset diabetes would be identified. Of 388,584 patients, 30,167 were identified as having new-onset diabetes during the 5.5 year follow-up period. Current use of inhaled corticosteroids was associated with a 1.34-fold increased in diabetes (odds ratio 1.34, 95% confidence interval 1.29 to 1.39). The greatest increase in risk occurred in those treated with the highest doses of inhaled corticosteroids (equivalent to fluticasone 1000 mcg daily or more, relative risk 1.64, 95% confidence interval 1.52 to 1.76). 17 The first small prospective randomized, double-blind, placebo-controlled study to evaluate the effects of inhaled corticosteroids in patients with type 2 diabetes was reported in In this study, 12 patients were randomized to either fluticasone 440 mcg twice daily and oral placebo or placebo inhaler and oral montelukast. After six weeks, patients were switched to the opposite treatment. A1C concentrations were measured during each phase of therapy. 18 Of the ten patients who completed the study, the changes in A1C were small but statistically significant. The mean change in A1C was 0.11% compared with baseline when using fluticasone. Conversely, during the montelukast phase, the A1C change from baseline was -0.14%. During inhaled fluticasone phase, seven patients had an increase in A1C over baseline, one was unchanged, and two had a reduction. During the montelukast phase, six patients experienced a reduction in A1C compared with baseline, two had an increase, and one remained unchanged. 18 Although there are no trials of intranasal corticosteroids and their effect on glucose concentrations, it is likely that this route of administration can also lead to hyperglycemia. Based on limited information, it appears to be prudent to monitor blood sugar values in patients using inhaled corticosteroids, especially in those receiving higher doses (e.g., fluticasone 1000 mcg/day or higher or the equivalent) (PL Detail-Document #271011: Page 3 of 5) [Evidence level B; lower quality RCT and case control studies]. 17,18 In patients who develop hyperglycemia, consider lowering the inhaled steroid dose and adding other therapies such as montelukast (Singulair), tiotropium (Spiriva), or a long-acting beta-agonist (Serevent, etc), depending on the condition being treated. Epidural Corticosteroids As with other non-oral routes of administration, epidural corticosteroids can increase glucose concentrations. Glucose elevations can persist for up to two weeks after an epidural injection. 20 In a report of 18 patients (four with diabetes and 14 without diabetes) who received epidural injections, investigators found that epidural injections caused increased postprandial glucose concentrations in all patients. They also noted that these increases were more pronounced and lasted longer in patients with diabetes compared to those without diabetes. 21 However, the statistical analysis of the data included data from an additional 11 patients who received intraarticular injections into the shoulder. Therefore, it is impossible to tease out those who received only epidural corticosteroids. 21 Based on this study, it appears that epidural injections can cause hyperglycemia and that blood glucose monitoring for up to two weeks may be warranted in patients, especially in those with preexisting diabetes [Evidence level B; nonrandomized study]. 21 Conclusion There is no consensus on the optimal monitoring and treatment of corticosteroidinduced hyperglycemia. In general, for most patients with normal pancreatic function and no insulin resistance, inhaled or topical corticosteroids are not likely to cause significant hyperglycemia. Additionally, in patients in whom corticosteroid therapy is for a limited time (e.g., a single intra-articular injection), no treatment may be necessary. 19 In patients with risk factors for diabetes such as metabolic syndrome or a history of impaired fasting glucoses, or in those with pre-existing diabetes, monitoring of blood glucose is warranted. The optimal timing and frequency of glucose monitoring is unknown.

4 Hyperglycemia has been reported with topical, intra-articular, inhaled, and epidural corticosteroids. Topical steroids can cause hyperglycemia with high doses or prolonged use, especially in at-risk patients with diffuse skin conditions such as psoriasis. Patients using higher dose or potency topical steroids for longer than six months should be monitored. Inhaled steroids can increase the risk of hyperglycemia when used in high doses, such as fluticasone 1000 mcg/day or more. Patients, especially those with diabetes or at risk for diabetes, should be monitored. Steroid injections into joints can cause hyperglycemia for about two to five days in patients, and potentially longer for long-acting, depot corticosteroid formulations. Finally, epidural injections of corticosteroids can increase blood glucose concentrations for up to two weeks after injection, and this effect appears more pronounced in patients with pre-existing diabetes. If significant hyperglycemia occurs, a trial of a lower steroid dose or non-steroid treatment should be considered, if possible. Optimal treatment for corticosteroid-induced hyperglycemia in patients who require long-term corticosteroids is not known. It appears rational for a patient who has not had hyperglycemia in the past to modify their diet and exercise to lower blood glucose. In patients taking oral antidiabetes medications, increasing the dose of these agents can be tried. Finally, in patients already taking insulin, increasing the dose of insulin appears logical. Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Project Leader in preparation of this PL Detail- Document: Neeta Bahal O Mara, Pharm.D., BCPS, Drug Information Consultant References 1. Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract 2009;15: Keenan GF. Management of complications of glucocorticoid therapy. Clin Chest Med 1997;18: Poetker DM, Reh DD. A comprehensive review of the adverse effects of systemic corticosteroids. Otolaryngol Clin North Am 2010;43: (PL Detail-Document #271011: Page 4 of 5) 4. Gurwitz JH, Bohn RL, Glynn RJ, et al. Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch Intern Med 1994;154: Ariza-Andraca RC, Barile-Fabris LA, Frati-Munari AC, Baltazar-Montufar P. Risk factors for steroid diabetes in rheumatic patients. Arch Med Res 1998;29: Kim SY, Yoo CG, Lee CT, et al. Incidence and risk factors of steroid-induced diabetes in patients with respiratory disease. J Korean Med Sci 2011;26: Iwamoto T, Kagawa W, Naito Y, et al. Steroidinduced diabetes and related risk factors in patients with neurologic diseases. Pharmacotherapy 2004;24: Habib GS. Systemic effects of intra-articular corticosteroids. Clin Rheumatol 2009;28: Black DM, Filak AT. Hyperglycemia with noninsulin-dependent diabetes following intraarticular steroid injection. J Fam Pract 1989;28: Habib GS, Abu-Ahmad R. Lack of effect of corticosteroid injections at the shoulder joint on blood glucose levels in diabetic patients. Clin Rheumatol 2007;26: Habib GS, Bashir M, Jabbour A. Increased blood glucose levels following intra-articular injection of methylprednisolone acetate in patients with controlled diabetes and symptomatic osteoarthritis of the knee. Ann Rheum Dis 2008;67: Habib G, Safia A. The effect of intra-articular injection of betamethasone acetate/betamethasone sodium phosphate on blood glucose levels in controlled diabetic patients with symptomatic osteoarthritis of the knee. Clin Rheumatol 2009;28: Wang AA, Hutchinson DT. The effect of corticosteroid injection for trigger finger on blood glucose level in diabetic patients. J Hand Surg Am 2006;31: MacMahon PJ, Eustace SJ, Kavanagh EC. Injectable corticosteroid and local anesthetic preparations: a review for radiologists. Radiology 2009;252: Van der Linden MW, Penning-van Beest FJ, Nijsten T, Herings RM. Topical corticosteroids and the risk of diabetes mellitus. A nested case-control study in the Netherlands. Drug Saf 2009;32: Faul JL, Tormey W, Tormey V, Burke C. High dose inhaled corticosteroids and dose dependent loss of diabetic control. BMJ 1998;317: Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risk of diabetes onset and progression. Am J Med 2010;123: Faul JL, Wilson SR, Chu JW, et al. The effect of an inhaled corticosteroid on glucose control in type 2 diabetes. Clin Med Res 2009;7: Fardet L, Kassar A, Cabane J, Flahault A. Corticosteroid-induced adverse events in adults. Frequency, screening and prevention. Drug Saf 2007;30:

5 (PL Detail-Document #271011: Page 5 of 5) 20. Spaccarelli KC. Lumbar and caudal epidural corticosteroid injections. Mayo Clin Proc 1996;71: Younes M, Neffati F, Touzi M, et al. Systemic effects of epidural and intra-articular glucocorticoid injections in diabetic and non-diabetic patients. Joint Bone Spine 2007;74: Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65: Cite this document as follows: PL Detail-Document, Hyperglycemia Associated with Non-oral and Locally Injected Corticosteroids. Pharmacist s Letter/Prescriber s Letter. October Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA ~ TEL (209) ~ FAX (209) Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to or