Stop the Madness of Glucocorticoid-Induced Hyperglycemia! A Brief Review
Steven Perzanowski, PharmD Candidate 20211
Alicia Len, PharmD Candidate 20211
Kam Capoccia, PharmD, BCPS, CDCES, Professor of Community Care1
1Western New England University College of Pharmacy and Health Sciences
Glucocorticoids have many indications for both acute and chronic disease states and are associated with increased risk for glucocorticoid-induced hyperglycemia in people with and without diabetes. It’s estimated that about 40%-50% of all inpatient consults to endocrinology service are for new or worsening diabetes caused by glucocorticoid initiation.1 In a large case control series, oral glucocorticoid therapy was associated with an odds ratio of 1.36 for developing new-onset diabetes.1 Another study found that steroid use in the elderly increases the risk of new onset diabetes with an odds ratio of 2.31 compared with not receiving steroids.1 In organ transplant patients who are on glucocorticoid therapy, the prevalence of abnormal glucose metabolism is 17% to 32% and an even greater prevalence is reported for patients with rheumatoid arthritis.2
The overall incidence of glucocorticoid-induced hyperglycemia has been reported to be 12%.3 However, the exact prevalence of hyperglycemia secondary to glucocorticoid therapy is not known, making this an unpredictable challenge for clinicians. A number of predictors of the onset of glucocorticoid-induced hyperglycemia have been identified. These include dose and duration of glucocorticoid treatment, age, weight, previous glucose intolerance, reduced sensitivity to insulin or impaired insulin secretion stimulated by glucose, a family history of diabetes, and race.3
There are several mechanisms in which glucocorticoids may affect blood glucose management, resulting in hyperglycemia (Figure 1).
- Insulin resistance
- Increase in insulin resistance in adipose and muscle tissue resulting in reduced peripheral glucose reuptake.4
- Hepatic insulin resistance is increased, which allows for hepatic glucose production through gluconeogenesis and glycogenolysis.4
- Increased glucose production
- Glucocorticoids antagonize the metabolic effects of insulin particularly in the postprandial state rather than fasting blood glucose levels.5
- The expression of nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha is necessary for glucose production induced by corticosteroids.5
- Glucocorticoids also enhance the effect of hormones such as glucagon and epinephrine, resulting in increased synthesis of glucose.5
- Effect on pancreatic beta cells
- In response to a decrease in insulin sensitivity, the pancreatic beta cell increases insulin secretion to maintain glucose homeostasis, which at times, is not sufficient to compensate for the insulin resistance, resulting in hyperglycemia.5
- Decreased glycogen synthesis
- Glucocorticoids interfere with stimulating the glucose transport 4 (GLUT4) receptors and activating the signaling cascade, which results in impaired glucose use through post receptor defects.2
- Effect on cardiovascular disease
- Observational studies of patients treated with glucocorticoids for asthma, cardiac disease, renal transplants, and rheumatoid arthritis have shown elevations of total cholesterol, triglycerides, and low-density lipoprotein with variable changes in high-density lipoprotein.2
- The longer the use of glucocorticoids, the higher the cardiovascular risk factors, however the exact duration of exposure from glucocorticoids causing these metabolic effects need further investigation.2
Understanding these mechanisms is crucial when deciding on a treatment approach. It is important to evaluate the degree of preexisting glucose intolerance, the patient’s clinical condition and the degree of hyperglycemia. The type, dose and frequency of administration of the glucocorticoid along with the mechanism of action, pharmacokinetics and pharmacodynamics of the various medications used to treat diabetes should be taken into consideration when developing the best patient-specific treatment plan.
Figure 1. Mechanisms of glucocorticoid-induced hyperglycemia6
ResearchGate. Mechanisms of glucocorticoid-induced hyperglycemia [image on the Internet]. [cited 2021 Apr 22]. Available from: https://www.researchgate.net/figure/Mechanisms-of-glucocorticoid-induced-hyperglycemia-Glucocorticoids-own-diabetogenic_fig1_323670511
Suggested treatment options for glucocorticoid-induced hyperglycemia include medications typically used in the management of type 2 diabetes. At this time, there is limited clinical trial data to support many of the potential treatment options. Insulin is the preferred treatment for glucocorticoid-induced hyperglycemia.7 While evidence is lacking, many non-insulin diabetes medications have been theorized to provide benefit in treating glucocorticoid-induced hyperglycemia. The advantages and disadvantages of treatment options should be considered on a patient-specific basis. The duration of glucocorticoid therapy, renal function, and liver function should also be considered when developing the treatment plan.
Insulin may be used to treat glucocorticoid-induced hyperglycemia in people with or without diabetes. While clinical trial evidence to choose one formulation over another is lacking, the American Diabetes Association Standards of Medical Care guidelines suggest NPH as the standard approach and suggest basal and bolus regimens as options.7 The most practical form of insulin to treat glucocorticoid-induced hyperglycemia is NPH insulin due to its pharmacokinetics. The commonly used oral glucocorticoids, prednisone and prednisolone, have a peak action between 4-8 hours and have a duration of action of 12-16 hours. Due to the similar pharmacokinetics of NPH insulin and these oral glucocorticoids, they may be administered at the same time to counteract the hyperglycemic effect of the glucocorticoid.7 One dosing recommendation recommended by Clore and Thurby-Hay is presented in Table 1.8 If a patient is already on NPH insulin or a basal/bolus regimen, the dose for treating glucocorticoid-induced hyperglycemia may be added to the usual insulin dose regimen.7 For a patient who has never used insulin before and is willing to do so, NPH insulin may be started and dosed at the same time as the glucocorticoid to match the hyperglycemic response of the glucocorticoid. For those patients who do not wish to take insulin, a non-insulin diabetes medication may be an alternative.
Metformin appears to be a safe and effective treatment for glucocorticoid-induced hyperglycemia. It may be used on its own or in combination with another oral diabetes medication or insulin. Compared to other oral diabetes medications, metformin has a mechanism of action that most closely counteracts that of a glucocorticoid. Metformin increases insulin sensitivity and decreases gluconeogenesis, whereas glucocorticoids increase insulin resistance and promote gluconeogenesis. Metformin also has a low risk of hypoglycemia. This low hypoglycemia risk makes metformin a good option for glycemic management during a glucocorticoid taper.1 As the hyperglycemic effect of the glucocorticoid wanes with decreasing doses, metformin dosing may remain stable without increasing the hypoglycemic risk. A double-blind, placebo-controlled trial by Seelig et al., found metformin to have a beneficial effect on glycemic management in patients on glucocorticoid therapy. In this study, participants received 850mg of metformin by mouth once daily for one week followed by 850mg by mouth twice daily for three weeks or placebo. Participants in the metformin group did not have a statistically significant change in glucose from baseline, whereas the placebo group had a statistically significant increase in glucose from baseline.9 Metformin should be avoided in patients with insufficient renal function. Due to the increased risk of metabolic acidosis, the risk versus benefit should be considered in patients who are being treated for conditions related to hypoxia, such as COPD.
DPP-4 Inhibitors and GLP-1 RAs
Similar to metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) carry a low risk of hypoglycemia. However, clinical evidence does not support their use in the treatment of glucocorticoid-induced hyperglycemia at this time. A study by van Genugten et al., evaluated sitagliptin in people without diabetes treated with high-dose (30mg) prednisolone. Sitagliptin did not prevent the glucose intolerance caused by the glucocorticoid.10 A retrospective study by Uchinuma et al. evaluated dulaglutide use in hospitalized patients with glucocorticoid-induced hyperglycemia. While there was no statistically significant difference in glucose, there was a statistically significant reduction in the amount of insulin and the number of injections in the dulaglutide group versus the control group.11 In addition to the lack of evidence, cost is also a barrier. More clinical evidence is needed to support the use of DDP-4 inhibitors or GLP-1 RAs in the treatment of glucocorticoid-induced hyperglycemia.
In a randomized controlled trial by Gerards et al., the sodium-glucose cotransporter 2 (SGLT-2) inhibitor, dapagliflozin, was initiated in patients being treated with at least 30mg of prednisone daily for an acute exacerbation of COPD. Dapagliflozin treatment did not demonstrate a clinical or statistical improvement in glycemic control. The mean glucose concentration in the dapagliflozin group was 10.1 mmol/L (181.8 mg/dL) compared to 10.4 mmol/L (187.2 mg/dL) for the placebo arm (P = 0.66).12 However, in theory SLGT-2 inhibitors could be beneficial in treatment due to the low risk of hypoglycemia and cardiovascular benefits. Increased genitourinary infection risk with SGLT-2 inhibitors is relevant since glucocorticoids generally increase the risk of infections. Cost is also a disadvantage and should be taken into consideration. More evidence is needed before recommending SGLT-2 inhibitors to treat glucocorticoid-induced hyperglycemia.
Sulfonylureas, Thiazolidinediones, and Meglitinides
Sulfonylureas and thiazolidinediones (TZDs) are not ideal treatment options due to the adverse effect of weight gain and fluid retention caused by TZDs. These adverse effects are less than ideal when treating glucocorticoid-included hyperglycemia because fluid retention and weight gain are common glucocorticoid adverse effects. Sulfonylureas and meglitinides also have the adverse side effect of hypoglycemia. The frequency of three times daily administration makes meglitinides a less favorable option. Overall, the adverse effects and lack of clinical evidence to support the use of sulfonylureas, TZDs, and meglitinides do not make these classes of drugs a favorable option to treat glucocorticoid-induced hyperglycemia.
At this time, insulin is the main stay for treatment of glucocorticoid-induced hyperglycemia. NPH insulin may be the best treatment choice due to its similar peak and duration of action when compared to glucocorticoids. Non-insulin diabetes medications have potential for treatment but lack robust clinical evidence to support their use. Due to its low cost, low risk of hypoglycemia, and mechanism of counteracting the insulin desensitizing effect of glucocorticoids, metformin may be an alternative oral treatment option.
- Wallace M, Metzger N. Optimizing the treatment of steroid-induced hyperglycemia. Ann Pharmacother. 2018;52(1):86-90.
- Kwon S, Hermayer KL. Glucocorticoid-induced hyperglycemia. Am J Med Sci. 2013;345(4):274-277.
- Suh S, Kyoung Park M. Glucocorticoid-induced diabetes mellitus: an important but overlooked problem. Endocrinol Metab. 2017;32:180-189.
- Morris D. Steroid-induced diabetes and hyperglycaemia. Part 1: mechanisms and risks. Diabetes & Primary Care. 2018;20(4):151-153.
- Tamez-Perez H, Quintanilla-Flores D, Rodriguez-Gutierrez R, et al. Steroid hyperglycemia: Prevalence, early detection and therapeutic recommendations: A narrative review. World J Diabetes. 2015; 6(8):1073-1081.
- Mechanisms of glucocorticoid-induced hyperglycemia [image on the Internet]. [cited 2021 Apr 22]. Available from: https://www.researchgate.net/figure/Mechanisms-of-glucocorticoid-induced-hyperglycemia-Glucocorticoids-own-diabetogenic_fig1_323670511
- American Diabetes Association. 15. Diabetes care in the hospital: standards of medical care in diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S211-S220. doi: 10.2337/dc21-S015.
- Clore J, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract. 2009;15:469-474.
- Seelig E, Meyer S, Timper K, et al. Metformin prevents metabolic side effects during systemic glucocorticoid treatment. Eur J Endocrinol. 2017;176(3):349-358.
- Van Genugten RE, van Raalte DH, Muskiet MH, et al. Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial. Eur J Endocrinol. 2014;170(3):429-439.
- Uchinuma, H., Ichijo, M., Harima, N. et al. Dulaglutide improves glucocorticoid-induced hyperglycemia in inpatient care and reduces dose and injection frequency of insulin. BMC Endocr Disord. 2020:20(58). https://doi.org/10.1186/s12902-020-0542-5.
- Gerards MC, Venema GE, Patberg KW, et al. Dapagliflozin for prednisone‐induced hyperglycaemia in acute exacerbation of chronic obstructive pulmonary disease. Diabetes Obes Metab. 2018;20(5):1306-1310.