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Glucocorticoid-Induced Hyperglycemia Including Dexamethasone-Associated Hyperglycemia in COVID-19 Infection: A Systematic Review

Objective Optimal glucocorticoid-induced hyperglycemia (GCIH) management is unclear. The COVID-19 pandemic has made this issue more prominent because dexamethasone became the standard of care in patients needing respiratory support. This systematic review aimed to describe the management of GCIH and summarize available management strategies for dexamethasone-associated hyperglycemia in patients with COVID-19. Methods A systematic review was conducted using the PubMed/MEDLINE, Cochrane Library, Embase, and Web of Science databases with results from 2011 through January 2022. Keywords included synonyms for “steroid-induced diabetes” or “steroid-induced hyperglycemia.” Randomized controlled trials (RCTs) were included for review of GCIH management. All studies focusing on dexamethasone-associated hyperglycemia in COVID-19 were included regardless of study quality. Results Initial search for non-COVID GCIH identified 1230 references. After screening and review, 33 articles were included in the non-COVID section of this systematic review. Initial search for COVID-19–related management of dexamethasone-associated hyperglycemia in COVID-19 identified 63 references, whereas 7 of these were included in the COVID-19 section. RCTs of management strategies were scarce, did not use standard definitions for hyperglycemia, evaluated a variety of treatment strategies with varying primary end points, and were generally not found to be effective except for Neutral Protamine Hagedorn insulin added to basal-bolus regimens. Conclusion Few RCTs are available evaluating GCIH management. Further studies are needed to support the formulation of clinical guidelines for GCIH especially given the widespread use of dexamethasone during the COVID-19 pandemic.


Introduction
The medical literature contains a wealth of writing about glucocorticoid (GC)-induced hyperglycemia (GCIH), which demonstrates the pronounced interest and need for practical information. Several challenges remain, including the lack of uniform terminology, standardized screening recommendations, or randomized controlled trials (RCTs) regarding management. This manuscript consists of a systematic review of literature published since 2011 on GCIH management and extends to publications regarding dexamethasone-associated hyperglycemia in patients with respiratory dysfunction from SARS-CoV-2 infection (COVID -19). For the former, higher-quality studies were included. For the latter, given the paucity of publications, relevant studies involving dexamethasone-associated hyperglycemia management in COVID-19 infection were included regardless of quality.
This review aimed to provide practical management strategies in patients who develop GCIH and summarize the available studies of dexamethasone-associated hyperglycemia management in patients with COVID-19.

Epidemiology and Impact
The incidence of GCIH varies depending on the population, GC dose, and duration, ranging from 15% to 70% in those without preexisting diabetes mellitus (DM). [1][2][3][4] The risk of developing DM in individuals with GCIH has been studied in various populations. A nested case-control study involving almost 8000 subjects demonstrated that the adjusted odds ratio for DM with !3 prescriptions for oral GC was 1.36 (95% confidence interval [CI], 1.10-1.69). 5 A cohort study of patients with rheumatoid arthritis revealed hazard ratios of 1.30 (95% CI, 1.17-1.45) and 1.61 (95% CI, 1.37-1.89) for incident DM in GC users versus nonusers, respectively, within the previous 6 months. 6 The risk of incident DM with chronic GC use is significant.

Pathophysiology
GCs are nuclear hormones that affect glucose metabolism by influencing b-cell function 7 and inducing insulin resistance at the levels of the skeletal muscle, liver, and adipose tissue through postreceptor defects in insulin signaling, including impaired phosphorylation of insulin signaling proteins. 8,9 GCs decrease insulin-stimulated insulin receptor substrate 1-associated phosphoinositide 3-kinase activity, phosphorylation of protein kinase B/ Akt and glycogen synthase kinase-3, insulin-stimulated glucose uptake, and glucose transporter type 4 translocation and inhibit insulin-stimulated glycogen synthase activation. 8,9 Glucose production is increased in the presence of GC, 8 and hyperglycemia results in predisposed individuals.

Methods
A systematic review was performed using the PubMed/MED-LINE, Cochrane Library, Embase, and Web of Science databases from 2011 to January 2022. Initial search identified 1230 studies representing 818 unique studies. Thirty-seven studies were assessed for eligibility between 2011 and 2022; 4 were excluded: 2 were duplicates; and 2 were ineligible by study design. A total of 33 studies were included in the noneCOVID-19 section with an emphasis on RCT (Fig. 1 A). For the COVID-19 section, 63 studies were identified between 2020 and 2022, 8 duplicates were removed, and 55 studies were screened. Of these, 48 references were removed based on ineligible article type or irrelevant topic. A total of 7 studies were included in the COVID-19 section (Fig. 1 B). All article types involving dexamethasone-associated hyperglycemia management, including case reports of !2 patients, were included. Additional articles were obtained via manual review of included references. We limited the search to peer-reviewed, English language articles and human studies of adults aged !18 years, all of which focused on management. Preprint articles, epidemiology studies, and quality improvement studies were excluded in both sections.
Keywords included synonyms for "steroid-induced diabetes" or "steroid-induced hyperglycemia." Our review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. 10 The details of search strategies are shown in the Supplementary Material.

Terminology
The estimates of the prevalence and incidence of GCIH vary depending on the population studied and because there are no universal definitions. "Steroidor glucocorticoid-induced hyperglycemia" is used to describe exacerbation of hyperglycemia resulting from GC use in individuals with or without pre-existing DM, whereas "steroidor glucocorticoid-associated diabetes" is used to describe hyperglycemia resulting from GC use in individuals without known DM. The term "induced" suggests that the etiology is known, whereas "associated" indicates the timing of onset after GC initiation but acknowledges that the etiology may be uncertain. GCIH is anticipated to resolve after GC are discontinued, whereas GC-associated diabetes describes hyperglycemia that persists while on chronic GC therapy or after GC discontinuation. 7 There are no standard diagnostic criteria for GCIH, with clinicians using various thresholds, such as fasting glucose levels of !126 or !140 mg/dL and random glucose levels of !180 or !200 mg/dL. The majority of studies included in this review were in an inpatient setting.

Management Strategies: GCIH
There are no standardized treatment protocols for GCIH. Although practice guidelines highlight the importance of achieving euglycemia during GC treatment, guidance on optimal therapy is limited. 11,12 Studies have incorporated different GC pharmacokinetics, treatment indications, and dosing schedules to determine adequate management strategies for GCIH. In this review, all GC types were included (Table 1).

Neutral Protamine Hagedorn Insulin With Steroid Administration Added to Basal-Bolus Insulin
Three RCTs have investigated Neutral Protamine Hagedorn (NPH) insulin added to basal-bolus insulin (BBI) in the treatment of GCIH (Table 1). Khowaja et al 13 evaluated a supplementary NPHbased regimen compared with BBI in hospitalized patients with DM (N ¼ 60) receiving steroids where the primary outcome was the mean premeal and bedtime glucose for days 1 to 5 after GC initiation. NPH was added to the home insulin regimen and administered concurrently with steroids (1-3 times daily). The mean overall, fasting, and prelunch glucose levels were lower, more glucose levels were within the target range (70-180 mg/dL), and hyperglycemia of !300 mg/dL occurred less often in the NPH group over 5 days ( Table 2). The NPH group used a higher mean insulin dose added to the usual daily regimen than BBI (46.6 vs 17.4 units/d, P <.0001). After randomization, 3 hypoglycemic episodes (<70 mg/ dL) occurred in the NPH group, whereas none occurred in the control group. 13 Grommesh et al 14 compared BBI versus NPH added to BBI in hospitalized patients with and without DM (N ¼ 61) who received GC within 1 day prior to randomization with hyperglycemia of >180 mg/dL ( Table 1). The primary outcome was the mean glucose level. NPH dosing (5-20 units) was determined using DM history and steroid dose; it was administered at the same time as the steroid except for methylprednisolone or hydrocortisone (every 4-6 hours) or dexamethasone where it was dosed 3 times daily. The glycemic control and rates of hypoglycemia were similar between the groups over the study period's 5 days, with day 3 time in range (70-180 mg/dL) trending toward significance in the NPH group (Table 2). 14 Seggelke et al 15 reported significantly lower premeal glucose levels over 3 days in posttransplant patients with cystic fibrosis-related diabetes (N ¼ 20) receiving BBI with NPH given once daily with methylprednisolone than those in patients receiving BBI ( Table 2). The latter 2 studies demonstrated a trend toward improved glycemic control with the addition of NPH to BBI despite similar total daily insulin doses (TDDs) between the control and experimental groups.

NPH Insulin 3 Times Daily With Bolus Insulin
Ruiz de Adana et al 16 investigated NPH compared with glargine in hospitalized patients with type 2 DM (N ¼ 53) receiving GC for pulmonary disease (Table 1). Continuous glucose monitoring (CGM) was used, and the primary end point was the mean blood glucose level. Glargine was dosed once each morning, whereas NPH was given in 3 doses with meals. Insulin doses were calculated in the same way for each group. The mean TDD, blood glucose level, time in range (80-180 mg/dL), and glycemic variability were similar over 6 days ( Table 2). Three severe hypoglycemic episodes (<40 mg/dL) occurred in the NPH group, whereas none occurred in the glargine group. 16

NPH Insulin Once Daily With Bolus Insulin
Radhakutty et al 17 compared an NPH-based regimen with BBI in hospitalized patients with and without DM receiving prednisolone (N ¼ 50) with 2 finger-stick glucose (FSG) levels of >180 mg/dL or 1 FSG level of >270 mg/dL in the 24 hours prior to randomization (Table 1). CGM was used, and the primary outcome was the mean glucose on day 1 after steroid initiation. The starting doses of insulin were the same in each group, and both received premeal insulin aspart; however, the NPH group received a higher proportion of aspart with lunch and dinner ( Table 2). The glycemic control by CGM, mean glucose, and rates of hypoglycemia were similar between the groups on day 1 after steroid initiation. Day 1 prednisolone doses and TDD were similar. Despite receiving 130% of TDD, patients with prior insulin use experienced more time outside the target range (72-180 mg/dL) and higher mean glucose levels, suggesting the need for higher starting doses (Table 3). 17 Correctional Insulin According to GC Type Lakhani et al 18 evaluated BBI compared with BBI combined with a correctional insulin whose pharmacokinetics matched the GC's glycemic profile in hospitalized patients with and without DM (N ¼ 92) who received GC within 24 hours prior to randomization with 2-hour postprandial hyperglycemia of !200 mg/dL (Tables 2 and 3). The primary outcome was the mean blood glucose level. BBI was added to correctional insulin for patients with DM history. Patients receiving GC-matched correctional insulin experienced improved glycemic control and had a significantly lower overall mean blood glucose level than patients on BBI, without increasing hypoglycemia ( Table 2). Hyperglycemia of >300 mg/dL was also less frequent with correctional insulin. 18 Add-on Short-Acting Versus Intermediate-Acting Insulin Gerards et al 19 compared supplemental short-acting versus intermediate-acting insulin (IMI) combined with standard regimens in patients treated with GC-based chemotherapy (N ¼ 26) in a randomized cross-over study of patients with type 2 DM or prior  hyperglycemia of >216 mg/dL (Table 1). Only 4 patients in the study were hospitalized, and the insulin types were not specified. The supplemental short-acting protocol dosed insulin according to the glucose level, whereas the IMI regimen was administered according to the steroid dose and body weight. The IMI protocol involved higher TDD and resulted in a higher proportion of time in range (70-180 mg/dL) ( Table 2). CGM-detected asymptomatic hypoglycemia was similar between groups. The mean glucose level was lower with IMI, but glycemic control was not achieved (223.2 ± 52.2 vs 243 ± 50.4 mg/dL, P <.05). 19 Basal-Bolus Insulin A prospective nonrandomized study by Agudo-Tabuenca et al 20 evaluated a BBI protocol in hospitalized patients with type 2 DM treated with methylprednisolone for pulmonary disease (Table 1). Both groups were treated with BBI, but the intervention group received higher starting doses. For the experimental group, half of the TDD was given as basal insulin twice daily (glargine or detemir), whereas the remaining insulin was divided prandially (aspart). The overall mean glucose level was lower in the intervention group, which had a higher mean TDD. There was no difference in hypoglycemia (Table 2). Euglycemia was achieved in half the time in the experimental group compared with that in the control (5 vs 10 days). 20

Noninsulin Antihyperglycemic Therapy and Decision Support Tools
Acarbose and nateglinide may reduce postprandial hyperglycemia in patients treated with prednisolone for connective tissue disorders. 21 In an RCT of patients with type 2 DM with chronic obstructive pulmonary disease exacerbations treated with prednisone, dapagliflozin did not lead to improved glycemic control or reduction in insulin requirements. 22 The EmpAgliflozin compared with NPH Insulin for sTeroId diAbeTEs study is an ongoing noninferiority trial evaluating the use of empagliflozin versus NPH in the treatment of GCIH. 23 Metformin has been shown to reduce 2-hour postprandial hyperglycemia in oncology patients without DM receiving prednisone. 24 Metformin significantly reduces postprandial hyperglycemia after 2 weeks of prednisone 24 and has additionally been shown to prevent impaired glucose tolerance and improve insulin resistance in patients without DM receiving supraphysiologic GC. 25 Similar findings have been described with exenatide. 26 Sitagliptin improves pancreatic islet cell function, but not GCinduced glucose intolerance, in men with metabolic syndrome without DM receiving prednisolone. 27 A study of 5 patients without DM treated with prednisolone for rheumatologic disorders demonstrated that linagliptin did not prevent GCIH; however, it may have reduced the need for insulin. Fasting hypoglycemia occurred during the first 2 weeks of GC administration, which may have been exacerbated by the concomitant use of insulin secretagogues. 28 Automated decision support tools, such as GlucoTab, a software that recommends BBI dosing (ie, 50% basal and 50% bolus), show promise in GCIH management. Aberer et al 29 demonstrated that GlucoTab use led to a higher mean TDD (38 vs 11 units, P <.001) with lower median, fasting, and bedtime glucose levels and higher time in range (70-180 mg/dL; 67.2% vs 60.2%, P <.001).

COVID-19 and Diabetes
The COVID-19 pandemic presented a new and challenging entity for clinicians beginning in 2020. DM was soon identified as a notable risk factor for severe disease and mortality. [30][31][32] The bidirectional relationship of COVID-19 and DM has been described; hyperglycemia can occur in patients with and without pre-existing  Table 3 shows the details of the study protocol.   For both groups: 50% TDD, basal; 50% TDD, premeal bolus divided equally. Glargine was given daily at 9AM. NPH was divided equally to be given before each meal.
Patients received TDD 0.5 units/kg or 130% of current TDD where the higher dose was chosen.
Correctional aspart was given in both groups according to a hospital protocol. DM and is an independent risk factor for worse outcomes in COVID-19. 30,33,34 Potential mechanisms of COVID-19-induced hyperglycemia include stress hyperglycemia from marked inflammation and beta-cell dysfunction. [35][36][37][38][39][40][41] Cases of newly diagnosed DM have been reported with COVID-19 and may reflect varying mechanisms, including stress hyperglycemia, previously unrecognized type 2 DM, or COVID-induced DM. 37,42 Remission has been noted for 40.6% of new DM cases. 43 Worse outcomes have been reported for new versus pre-existing DM with COVID-19. 34 SARS-CoV-2 has been associated with an increased occurrence of diabetic ketoacidosis (DKA) primarily in patients with type 2 DM. 44 Although higher rates of pediatric type 1 DM diagnoses have been reported, a definite causal relationship between COVID-19 and type 1 DM has not been established. 45,46 Early in the pandemic, optimal treatment was uncertain. This changed with the Randomized Evaluation of COVID-19 Therapy trial, which demonstrated that dexamethasone 6 mg daily for 10 days significantly reduced 28-day mortality in patients requiring oxygen or mechanical ventilation. 47 Dexamethasone became standard of care, and GCIH became more common with a need for evidence and expertise in GCIH management. Although studies report the high prevalence of DM and hyperglycemia in COVID-19, accurate data on the frequency of dexamethasone-induced hyperglycemia are not available. Hyperglycemia of COVID-19 coupled with dexamethasone therapy has been termed a "triple insult" with COVID-19-induced insulin resistance, COVID-19 effects on pancreatic islets to cause impairment of insulin production, and GC-induced metabolic derangements. 39

Management Strategies: Dexamethasone-Induced Hyperglycemia in COVID-19
Management of severe hyperglycemia is important in COVID-19. 41,48 Few studies have assessed the management of dexamethasone-induced hyperglycemia in COVID-19 although several guidance documents have been published. 39,[49][50][51][52][53][54] The lack of personal protective equipment at the beginning of the pandemic led to a need to minimize direct patient contact while maintaining adequate glycemic control. Recommendations were made to reduce glucose monitoring when feasible and manage insulin infusion pumps from outside the patient's room. Verifying appropriate GC prescribing to minimize hyperglycemia, measuring the hemoglobin A1c level, and point-of-care testing for glucose measurement for patients on dexamethasone were recommended although a reduced frequency of testing in patients without preexisting DM may be adequate. [55][56][57][58] 24 Patients were randomized 1:1 to the control group (standard of care) or intervention group (standard of care with metformin 850 mg daily Â 2 wk, followed by 850 mg BID Â 2 wk).

Presence of GC-induced hyperglycemia
Mean 2-hour postprandial BG were significantly lower in the metformin group at weeks 2-4. There was no difference in fasting BG.

Small sample size
Gerards (2016) 19 Patients were randomized to either SSI or IMI first as add-on treatment to routine DM medications.
SSI was dosed according to the blood glucose level based on a scale.
IMI was dosed based on: 0.01 IU/mg prednisone-equivalent GC per kg body weight (capped at 0.5 IU per kg). IMI doses were adjusted by 10% daily if above target.
Study team managed insulin.
% time in target range and hypoglycemic events % time in target range: 34.4% for IMI vs 20.9% for SSI (P <.001).
The median TDD was higher for IMI cycle than for SSI (40.3 vs 26.0 IU, P <.01).
Two participants in each cycle had asymptomatic hypoglycemia, all of which occurred during days 3-5.
Specific insulin types used were not described.

Mean BG level
The mean TDD was lower in the control group than in the intervention group (29.4 ± 21 vs 57.4 ± 24 units, P <.0001). The Food and Drug Administration lifted its restriction on the inpatient use of CGM in April 2020, and CGM has been shown to be feasible in small numbers of patients. 53,[59][60][61] An RCT in Denmark has been initiated to assess glycemic outcomes with CGM compared with point-of-care testing for glucose measurement in patients with COVID-19. 48 Factors such as hypoxia, use of pressors, fluid shifts, edema, and high-dose acetaminophen use can limit the accuracy of CGM in severely ill patients with COVID-19.
Published guidance documents align regarding insulin therapy as the standard of care for GCIH; intravenous insulin infusion is preferred in the intensive care unit, and BBI is recommended for those who are not critically ill. Varying preference exists for the use of NPH twice daily 39 or once daily basal insulins, such as glargine or detemir. 49,50 Although most noninsulin agents should be discontinued, Pasquel et al 50 considered the use of dipeptidyl peptidase-4 inhibitors as an adjunct to insulin to help reduce the frequency of injections. Gianchandani et al 51 suggested trending COVID-19 inflammatory markers, such as procalcitonin, to gauge the need to adjust insulin doses because a correlation was noted.
Asiri et al 62 published the first study to examine the effectiveness of an insulin protocol for the management of dexamethasone-induced hyperglycemia in COVID-19 (Table 3). This study retrospectively assessed noneintensive care unit patients with COVID-19 (N ¼ 163) at a tertiary center in Saudi Arabia managed with an insulin protocol compared with routine treatment. The insulin starting dose included glargine 0.1 units/kg/day (or home basal insulin dose) and rapid-acting insulin 0.1 units/kg/ meal. The protocol group had a higher proportion of patients with glucose levels in the target range (70-180 mg/dL) as well as reduced in-hospital mortality ( Table 3). The authors comment that their starting dose of glargine may have been too low out of concern for reduced patient contact and to consider using 0.2 units/kg/day. 62 In our experience, weight-based insulin requirements for dexamethasone hyperglycemia in COVID-19 can be considerably higher than traditional dosing formulas and may be positively correlated with hemoglobin A1c. 63 A retrospective study performed in the first pandemic wave found that patients with type 2 DM with DKA and COVID-19 required a significantly larger cumulative insulin dose, longer time, and higher weightbased insulin infusion dose to achieve DKA resolution than patients without COVID-19. 64 CRITICal, an RCT examining whether NPH combined with BBI compared with BBI alone improves the mean daily glucose levels for dexamethasone-induced hyperglycemia in patients with DM with COVID-19, is in progress in Australia (Table 3). 65 At this time, there are no completed RCT to assess the insulin management of GCIH in COVID-19.
The Dapagliflozin in Respiratory Failure in Patients With COVID-19 trial, a multicenter RCT of nonecritically ill patients hospitalized with COVID-19 and at least 1 cardiometabolic risk factor examined the effect of dapagliflozin 10 mg daily versus placebo (N ¼ 1250) on the prevention of severe disease or death ( Table 3). The study population included 50.9% of participants with type 2 DM, and 21.5% received dexamethasone. The primary end point was not met; however, dapagliflozin was well tolerated, and only 2 nonsevere cases of DKA were reported in the treatment group. 66 It is important to note that while potentially beneficial in GCIH, sodium-glucose cotransporter inhibitors can be associated with euglycemic DKA, an increased risk of genitourinary infections, and volume depletion. 67 Observational studies support a correlation between metformin use and reduced mortality from COVID-19; however, inpatient use is not recommended. 68,69 Further studies regarding the potential role of other noninsulin agents in COVID-19 treatment are needed. Research in the area of dexamethasone-induced hyperglycemia in Table 3 Studies

Discussion
GCIH management studies have assessed varying combinations of insulin formulations. Few RCTs have been completed, and in the limited group of studies available, the treatment protocols are vastly different. Furthermore, terminology used to define GCassociated hyperglycemia is inconsistent and confusing. Evidencebased guidelines do not exist for GCIH management, and clinical practice varies widely. 11,12 The insulin regimen with the greatest likelihood of effectiveness was demonstrated in studies using BBI with NPH. [13][14][15]18 The late peak and prolonged duration of action of NPH more closely matches the insulin resistance and hyperglycemia observed with GC use. However, adequate NPH dosing has not been identified because the insulin regimens assessed thus far have been suboptimal in achieving glycemic control. All of the studies involve small sample sizes, short study duration, and patients with either well-controlled or moderately controlled DM, factors which limit generalizability.
The studies assessed in this review demonstrate a need for higher initial doses of insulin in GCIH management. However, the more physiologic approach using multiple doses of NPH may limit broad applicability due to dosing complexity and administration of multiple insulins. Figure 2 summarizes the treatment protocols assessed in this review. Figure 3 shows 3 practical approaches favored by the authors. We recommend initiating BBI at 0.5 units/ kg; NPH can be added using either 0.5 units/mg of prednisone equivalent or 0.1 units/kg per prednisone 10-mg dose increments. NPH may be helpful to use concomitantly with prednisone given their similar pharmacokinetic profiles. 70 An alternative approach without NPH involves starting BBI at 0.5 to 0.6 units/kg with 30% to 40% of TDD as basal insulin and 60% to 70% of TDD as prandial insulin. The authors acknowledge the heterogeneity in GC studied in this review and summarized our preferred approaches for patients receiving supraphysiologic steroids.
Noninsulin agents offer a simpler treatment option for GCIH, particularly for patients without pre-existing DM who require extended GC courses. Unsurprisingly, agents such as dipeptidyl  peptidase-4 inhibitors are not sufficient to manage GCIH in patients with DM 22 ; however, metformin and exenatide may have a role in ameliorating hyperglycemia in patients without DM receiving GC. [24][25][26] Additional research is needed to determine whether noninsulin agents can be used in GCIH prevention or treatment. The COVID-19 pandemic has dramatically increased the number of patients requiring hyperglycemia treatment, particularly in the setting of dexamethasone use for patients requiring supplemental oxygen or mechanical ventilation. 47 Insulin is the standard of care for dexamethasone-associated hyperglycemia in COVID-19. As with GCIH not associated with COVID-19, practice varies widely with regard to insulin regimens; however, it is clear that insulin requirements exceed standard dosing.
The limitations of this review include variable study designs with multiple GC types for diverse indications, small sample sizes, varying clinical end points, and lack of outpatient data.

Conclusion
With variable study designs, small sample sizes, and differing treatment protocols in GCIH studies, it is not surprising that management guidelines are not well established. Larger studies, pragmatic trials, and real-world data are needed to inform the development of guidelines for effective GCIH treatment because GCs continue to be used extensively, the risk of GCIH is increasing as the prevalence of prediabetes and DM increase steeply, and the prevalence of GCIH increases during the COVID-19 pandemic.

Disclosure
The authors have no multiplicity of interest to disclose.