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. 2021 Sep 16;16(9):e0256682. doi: 10.1371/journal.pone.0256682

Insulin management in hospitalized patients with diabetes mellitus on high-dose glucocorticoids: Management of steroid-exacerbated hyperglycemia

Yu-Chien Cheng 1,2, Yannis Guerra 1,2,*, Michael Morkos 1,2, Bettina Tahsin 1,2, Chioma Onyenwenyi 1,2, Louis Fogg 3, Leon Fogelfeld 1,2
Editor: Sun Young Lee4
PMCID: PMC8445406  PMID: 34529703

Abstract

Background

Glucocorticoid (GC)-exacerbated hyperglycemia is prevalent in hospitalized patients with diabetes mellitus (DM) but evidence-based insulin guidelines in inpatient settings are lacking.

Methods and findings

Retrospective cohort study with capillary blood glucose (CBG) readings and insulin use, dosed with 50% basal (glargine)-50% bolus (lispro) insulin, analyzed in hospitalized patients with insulin-treated DM given GC and matched controls without GC (n = 131 pairs). GC group (median daily prednisone-equivalent dose: 53.36 mg (IQR 30.00, 80.04)) had greatest CBG differences compared to controls at dinner (254±69 vs. 184±63 mg/dL, P<0.001) and bedtime (260±72 vs. 182±55 mg/dL, P<0.001). In GC group, dinner CBG was 30% higher than lunch (254±69 vs. 199±77 mg/dL, P<0.001) when similar lispro to controls given at lunch. Bedtime CBG not different from dinner when 20% more lispro given at dinner (0.12 units/kg (IQR 0.08, 0.17) vs. 0.10 units/kg (0.06, 0.14), P<0.01). Despite receiving more lispro, bedtime hypoglycemic events were lower in GC group (0.0% vs. 5.9%, P = 0.03).

Conclusions

Since equal bolus doses inadequately treat large dinner and bedtime GC-exacerbated glycemic excursions, initiating higher bolus insulin at lunch and dinner with additional enhanced GC-specific insulin supplemental scale may be needed as initial insulin doses in setting of high-dose GC.

Introduction

Hyperglycemia is associated with increased morbidity and mortality in non-critically ill hospitalized patients [1–3]. Similarly, glucocorticoid (GC)-exacerbated hyperglycemia is shown to increase morbidity, infection rates, and hospital stay [4]. Given the increasing prevalence of diabetes mellitus (DM) and widespread use of GC for various therapeutic effects in inpatient settings, establishing an appropriate protocol for treating GC-exacerbated hyperglycemia in patients with DM becomes imperative to prevent poor clinical outcomes.

Moreover, the recent results of the RECOVERY trial, that showed the effectiveness of high-dose dexamethasone in patients hospitalized with Covid-19 who required oxygen, have increased the frequency of use of this medication [5]. As an example, in our institution, the profuse use of GC for patients with Covid-19 has been causing destabilization of glucose control and the need for much higher doses of insulin for these patients. Initial data show that the percentage of patient days with average blood glucose greater than 300 mg/dl more than doubled.

GC exacerbate hyperglycemia through several mechanisms. GC stimulate hepatic glucose production and protein catabolism and impair insulin secretion and glucose uptake of the peripheral tissues. GC effects are most pronounced postprandially with skeletal muscle responsible for 80% of postprandial glucose uptake [6–8]. In small clinical studies, significant GC-exacerbated postprandial hyperglycemia was confirmed through serial blood glucose monitoring [9], continuous glucose monitoring [10, 11] and the observed higher prandial insulin requirement for normoglycemia attainment in hospitalized patients with DM on GC [12]. However, GC effects on fasting hyperglycemia are only mild [10, 13, 14].

Despite the importance for controlling GC-exacerbated hyperglycemia in hospitalized patients with DM [6], underscored by a recent call to action for clinical research on inpatient GC-exacerbated hyperglycemia management [15], there is scant high-quality evidence or consensus regarding the optimal inpatient insulin regimen [15, 16]. Current proposed evidence-based approaches include: standard basal-bolus therapy with dexamethasone use [6, 17], standard basal-bolus therapy with the addition of NPH at the initiation of GC [18, 19] or the addition of NPH at three fixed times per day with multiple daily short-acting insulin [18], the use of NPH instead of glargine as the basal therapy [20] with greater proportion of bolus insulin between midday and midnight with prednisolone use [16], and the tailoring of the type and timing of insulin used depending on the steroid prescribed [21]. Nevertheless, none of these regimens has been shown to be superior to the usual care in achieving better overall glucose control in the inpatient settings.

Not only is the optimal insulin protocol unclear but optimal dosage also remains elusive [22]. While the Endocrine Society guideline in 2012 [6] recommends insulin initiation at 0.3–0.5 units/kg/day with GC use, no specific recommendation regarding the breakdown or proportion of basal versus bolus insulin was mentioned. The 2021 American Diabetes Association Standards of Medical Care [23] also did not provide specific starting insulin dosages, although increasing prandial and supplemental insulin in addition to basal insulin in higher doses of GC was suggested. Finally, studies examining dosage requirements to achieve normoglycemia had small sample sizes, different baseline demographics and degrees of glucose control prior to hospitalizations [12, 18]; therefore, the optimal doses found in these studies are ungeneralizable.

Given the high frequency of GC use in hospitals by providers of all specialties, there is a strong need for a uniform, straightforward, efficacious insulin protocol for all types of GC, ideally based on the basal-bolus regimen most familiar to most providers. Therefore, we aimed to gain further insight into the insulin use pattern and glucose control in patients with DM treated with GC in an inpatient setting. Our inpatient hyperglycemia insulin protocol recommends a well-standardized 50% basal (glargine)-50% bolus (lispro) therapy (see S1 File). In this study, we performed a retrospective review to compare the insulin requirement and capillary blood glucose (CBG) control between hospitalized patients with DM with GC use and those without. We hypothesized that higher prandial insulin but similar basal insulin was given with GC use in the hospital.

Methods

Study design

This was a retrospective cohort study conducted at a single U.S. institution. The Institutional Review Board of the John H. Stroger, Jr. Hospital of Cook County, Chicago, Illinois, approved the study protocol.

Participants and procedures

Data was collected from two databases: 1) electronic data warehouse (Cerner PowerChart®) provided the eligible hospitalizations with demographic and clinical information including hemoglobin A1C (HbA1c) and glomerular filtration rate (eGFR) on admission, doses and types of insulin and GC with corresponding dates and times; 2) hospital glucose database collected for inpatient diabetes quality assurance provided CBG with corresponding times and dates. The collected information per hospitalization from both databases was combined for analysis.

Data was extracted from all inpatient stays to identify patients meeting the inclusion criteria of those with DM who were non-pregnant, aged ≥18 years and who received any insulin from 1/1/2015 to 12/31/2015. We used inpatient data from 2015 as a convenience sample as previous studies [13, 15, 23] have employed smaller samples.

Exclusions included hospitalizations of less than 3 days (3 days is the minimal needed for reasonable insulin titration); admittance to any intensive care unit (ICU) or eGFR<30 mL/min/1.73 m2 on admission (we have separate hyperglycemia protocols for such patients); missing weight on admission to express insulin in units/kilogram (kg); hospitalized patients not treated per protocol; those with HbA1c <6.5% (47.5 mmol/mol) to include only patients with DM.

We divided eligible patients into two groups based on whether they received GC treatment during hospitalization (GC group vs. non-GC control group). We matched those in the GC group, using one-to-one basis, to those in the control by the following variables: age (±10 years), gender, race, and HbA1c (±0.5% given the inter-individual variability) [24].

Measures

Hospitalization days

Data on CBG and insulin doses were represented by hospitalization day, with the admission day counted as hospitalization day 0, the next day as hospitalization day 1 and so on. We included CBG and insulin doses up to day 6 of the hospitalizations since 75% of our hospitalizations had a length of stay up to 7 days.

Glucocorticoids use

In the GC group, days without receiving GC treatment were eliminated. GC were converted into prednisone-equivalent doses in mg and mg/kg [25, 26], and GC dosage were totaled per hospitalization day. This was done to be able to compare patients across different therapies or to accomodate those who received different types of steroids in the same hospitalization. Due to hospitalization day being the unit of analysis, the conversion allowed us to compare the different doses of different steroids on various days.

Timing of GC administration was categorized into four times based on common time blocks for daily activities: 12:00 am to 5:59 am, 6:00 am to 11:59 am, 12:00 pm to 5:59 pm, and 6:00 pm to 11:59 pm.

Capillary blood glucose

All CBG readings obtained were used. Beyond the recommended four pre-meal and bedtime readings per day, CBG could have been obtained per primary team’s discretion or nurse-initiated hypoglycemia protocol which recommends repeated CBG checking every 15 minutes until CBG recovers to >70 mg/dL. CBG readings were categorized by hospital meal distribution timing: pre-breakfast CBG from 5:00 am to 9:30 am, pre-lunch from 9:31 am to 4:00 pm, pre-dinner from 4:01 pm to 8:00 pm, and bedtime from 8:01 pm to 4:59 am. We defined hypoglycemia as CBG <70 mg/dL. CBG <40 mg/dL and >400 mg/dL were documented in our glucose database as <40 mg/dL and >400 mg/dL respectively and were represented as 39 mg/dL and 401 mg/dL respectively in our analysis.

Insulin

Insulin doses were represented as units/kg. Daily glargine and lispro doses were totaled per patient hospitalization day. Lispro doses were provided by breakfast, lunch, and dinner. Information on whether the lispro dose given was standing or supplemental was unavailable. Our inpatient hyperglycemia insulin protocol in the non-ICU setting is total daily dose per weight (kg x 0.5 units/kg) divided into 50% basal insulin/50% bolus insulin. Bolus is divided by 3 mealtimes. Supplemental insulin is added to bolus based on pre-meal glucose algorithm.

Statistical analysis

We generated descriptive statistics for baseline demographic and clinical characteristics for each patient per hospitalization with and without GC use. GC use and dose were expressed per hospitalization day. For outcome measures, mean CBG and median insulin doses per hospitalization day were calculated. To compare baseline clinical characteristics and outcome measures between patients with and without GC, we used independent-samples t-test for normal continuous variables, Mann Whitney U test for non-normally distributed continuous variables, and χ2 test (and Fisher’s exact test if available) for categorical data. For hospitalization day measures, one-way repeated-measures ANOVA was used to analyze the differences between mean mealtime CBGs within each cohort; Friedman and Wilcoxon signed-rank tests were used to compare overall and individual median lispro doses within each cohort. Pearson’s correlation was used to examine the association between insulin and GC dose, and the association between CBG and GC dose. Analysis was performed using SPSS Version 24 (SPSS Inc., Chicago, IL, USA). All tests of significance were two tailed, with α-levels of 0.05.

Results

Eligible hospitalizations cohorts

Our initial criteria for extraction identified 8431 hospitalizations. After eliminating additional hospitalizations not meeting our inclusion criteria, 137 patients were in the GC group and 906 patients in the non-GC group (Fig 1). After matching for age (±10 years), gender, race, and HbA1c (±0.5%) [26], there were 131 patients for both GC and non-GC groups (Fig 1). Including up to day 7 of the hospitalizations, the GC group had data points for 419 hospitalization days (394 excluding days without GC treatment), and the non-GC group had 646 hospitalization days.

Fig 1. CONSORT diagram.

Fig 1

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Baseline characteristics

Cohort characteristics are shown in Table 1. There were no significant differences in age, gender, ethnicity, race, BMI, HbA1c, or length of stay between the two cohorts with 54.2% being African American and 60.3% being female.

Table 1. Demographic and clinical characteristics after matching for race, gender, age, and HbA1c.

GC (N = 131) No GC (N = 131)
Gender
    Female 60.3% 60.3%
    Male 39.7% 39.7%
Age (mean years) ± SD 58.5 ± 10.9 59.4 ± 10.7
Race
    African American 54.2% 54.2%
    White 32.8% 32.8%
    Others 13.0% 13.0%
Ethnicity
    Hispanic/Latino/Spanish Origin 29.0% 29.0%
    Non-Hispanic/Latino/Spanish Origin 71.0% 71.0%
Weight (mean kg) ± SD 90.1 ± 29.3 92.6 ± 26.2
BMI (mean kg/m2) ± SD 32.8 ± 10.0 34.0 ± 9.1
HbA1c
    % 8.5 ± 1.8 8.6 ± 1.8
    mmol/mol 69.7 ± 19.9 70.5 ± 19.3
Length of Stay (mean days) ± SD 4.9 ± 2.9 5.5 ± 3.4
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No significant differences for any variables between groups.

BMI = body mass index, GC = glucocorticoid

Glucocorticoid types, doses, and administration times

In patients with GC, the median total prednisone equivalent dose received per day was 53.36 mg (IQR 30.00–80.04) or 0.59 mg/kg (IQR 0.35–1.03). GC used by type were 51.8% prednisone, 21.5% dexamethasone, 19.8% methylprednisolone, and 6.3% hydrocortisone. Timing of GC administration was: 55.4% between 6:00 am to 11:59 am, 22.6% between 12:00 pm to 5:59 pm, 12.5% between 6:00 pm to 11:59 pm, and 9.6% between 12:00 am to 5:59 am. The median number of days for GC per hospitalization were 3 days (IQR 1–4).

Insulin doses

The median total daily glargine dose was similar in the GC vs non-GC group (0.24 units/kg (IQR 0.14–0.37) vs. 0.24 units/kg (0.17–0.34), P = 0.94). The median total daily lispro dose was 20% higher in the GC group (0.24 units/kg (IQR 0.13–0.30) vs. 0.20 units/kg (0.14–0.37), P = 0.06), albeit non-significantly. The median total daily insulin dose (glargine + lispro) was 18% non-significantly higher in the GC group (0.53 units/kg (IQR 0.32–0.79) vs. 0.45 units/kg (0.31–0.67), P = 0.21).

As shown in Fig 2, the median lispro doses at breakfast and lunch were similar in the GC vs. non-GC groups, breakfast: 0.10 units/kg (IQR 0.06–0.15) vs. 0.10 units/kg (0.06–0.13), P = 0.37; lunch: 0.10 units/kg (IQR 0.07–0.15) vs. 0.10 units/kg (0.06–0.14), P = 0.53. However, dinner lispro dose was 20% significantly higher in the GC than non-GC group (0.12 units/kg (IQR 0.08–0.17) vs. 0.10 units/kg (0.06–0.14), P <0.01).

Fig 2. Mean capillary blood glucose (CBG) readings at mealtimes and bedtime and median insulin lispro doses at mealtimes.

Fig 2

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* P<0.05 between glucocorticoid (GC) and non-GC mealtime glucoses at same mealtime. ** P<0.05 between GC and non-GC lispro dose at dinner.

In the GC group, the differences between mealtime lispro doses was significant overall (P = 0.01). Specifically, lispro doses at dinner (0.12 units/kg (IQR 0.08–0.17) were greater than breakfast (0.10 units/kg (0.06–0.15) and greater than lunch (0.10 units/kg (0.07–0.15), both P< 0.01, with no significant difference between breakfast and lunch. In the non-GC group, the differences between mealtime lispro doses were similar (P = 0.06).

Capillary blood glucose pattern

Mean average daily CBG was significantly higher in the GC group (221±58 vs. 177±43 mg/dL, P<0.001). As shown in Fig 2, mean CBG at mealtimes and bedtime were significantly greater in the GC group, especially at dinner and bedtime: breakfast (190±70 vs. 161±46 mg/dL, P<0.001), lunch (199±77 vs. 180±54 mg/dL, P = 0.03), dinner (254±69 vs. 184±63 mg/dL, P<0.001), and bedtime (260±72 vs. 182±55 mg/dL, P<0.001).

In the GC group, the CBG readings between mealtimes and bedtime were different overall (P<0.001), mainly due to dinner CBG being 30% greater than at lunch (254±69 vs. 199±77 mg/dL, P<0.001). CBG differences between breakfast and lunch (190±70 vs. 199±77 mg/dL, P = 0.20) and between dinner and bedtime (254±69 vs. 260±72 mg/dL, P = 0. 22), however, were not significant.

In the non-GC group, the CBG readings between meal times and bedtime were also different overall (P<0.001) because CBG at lunch was greater than at breakfast (180±54 vs. 161±46 mg/dL, P<0.001). CBG differences between lunch and dinner (180±54 vs. 184±63 mg/dL, P = 0.54) and between dinner and bedtime were not significant (184±63 vs. 182±55 mg/dL, P = 1.00).

The occurrence of hypoglycemic episodes per hospitalization was lower in the GC than the non-GC group, significant at dinner (0.9 vs. 11.9%, P<0.001) and bedtime (0.0 vs. 5.9%, P = 0.03) but non-significant at breakfast (7.8 vs. 14.4%, P = 0.15) and lunch (8.3 vs. 14.4%, P = 0.16).

Impact of GC dose on CBG and insulin dosing

GC dose was positively correlated with average CBG per day (R = 0.446, P<0.001). GC dose was also positively correlated total daily lispro dose/kg (R = 0.17, P<0.001) while GC dose did not correlate with total daily glargine dose/kg (R = 0.03, P = 0.58).

Discussion

The study’s intent was to evaluate the CBG pattern and insulin usage in hospitalized patients with DM with and without GC therapy. Patients with GC use exhibited significantly higher CBG at all mealtimes and bedtime, with the biggest increases being 38% higher at dinner and 43% higher at bedtime compared to non-GC group. Despite these high CBG readings, the GC group only received 20% more lispro at dinner than at lunch, which was not sufficient to control the bedtime CBG. This finding demonstrates that there is a need to increase further the prandial insulin doses beyond the 20% increase in this study.

As for the basal insulin, our data show that glargine dose/day was not different between groups treated with and without GC. Even though the fasting CBG in the GC group was significantly higher, this was likely a carryover from the higher bedtime CBG since our protocol does not recommend supplemental insulin at bedtime. Despite the higher pre-breakfast fasting CBG in the GC group, the glargine dose is still considered appropriate since the post bedtime CBG steeply declined overnight. Increasing the daily glargine dose thus may increase the risk of hypoglycemia.

Our findings of higher prandial insulin requirements with high GC use were consistent with the study led by Spanakis et al. 2014 [12], who demonstrated that double amounts of prandial insulin but similar basal glargine were required to achieve normoglycemia in 20 out of 58 hospitalized patients with DM receiving GC. However, no proportion of prandial insulin was delineated per meal. More specifically, Burt et al. 2015 [27] demonstrated that greater delivery of insulin during the afternoon and evening was needed during methylprednisolone treatment in 24 hospitalized patients with type 2 DM; despite having received higher dosages of ultra-short-acting insulin between 1200 and 1700 hours (~10% more total per day), significantly higher CBG between 1700 and 2100 hours were observed.

Limitations of our study include the retrospective nature where potential unmeasured confounders could be present despite our best attempts in matching. Not included in our study database were the types or duration of DM, severity of underlying disease(s), in-patient nutritional status (on a diet or NPO), all of which could influence insulin requirements [12]. Because of the characteristics of our database, we were not able to separate the proportion of the prandial insulin and supplemental insulin. Finally, we were unable to give exact insulin dosing recommendations for attaining euglycemia since most hospitalizations with GC use did not achieve inpatient target glycemic control of 140–180 mg/dL [23].

Our study’s strengths include well-matched cohorts, larger sample size than previous studies, insulin as the sole hyperglycemia medication, and availability of lispro doses at different meals with corresponding CBG data. This is the first study that shows that the major hyperglycemic effects of GCs begin at lunch and peaks at dinner.

Our study allowed the suggestion of an initial inpatient insulin regimen for patients with DM with GC use that is based on increasing the prandial insulin during lunch and dinner, reflecting the hyperglycemic GC pattern identified. The current protocol is 0.5 units/kg with 50% of the total dose being basal and 50% being prandial with the prandial dose divided equally for three meals. The protocol in this setting will need increased prandial doses for lunch and dinner. The particulars for protocol changes will need full corroboration in a prospective study that will test not only the achievement of targets but also their safety. An example of this could be the currently ongoing clinical trial by Cunningham et al. [28]. With the current Covid-19 pandemic increasing the use of inpatient steroids, the relevance of these adjustments take a larger footprint in our current view of inpatient hyperglycemia management.

Supporting information

S1 File. Cook county health inpatient hyperglycemia protocol.

(PDF)

Click here for additional data file. (201.3KB, pdf)

Data Availability

Data can be found on the Open Science Framework at https://osf.io/dzhu7/ (DOI: 10.17605/OSF.IO/DZHU7).

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Sun Young Lee

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

7 Apr 2021

PONE-D-21-07298

Insulin Management in Hospitalized Patients with Diabetes Mellitus on High-Dose Glucocorticoids: Management of Steroid-Exacerbated Hyperglycemia

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We look forward to receiving your revised manuscript.

Kind regards,

Sun Young Lee, MD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this paper, the authors performed a retrospective cohort study of hospitalized patients with diabetes to examine the effects of glucocorticoid use on blood glucose readings and insulin doses.

Strengths of this study include the standardized protocol where all patients are placed on a balanced basal bolus regimen and use of matching to control for age, gender, race, and hemogloblin A1c.

Limitations include its retrospective nature and reporting of data across all hospitalization days.

Specific comments:

How are insulin doses adjusted per protocol based on the blood sugar readings? I understand from the discussion that “the current protocol is 0.5 units/kg with 50% of total dose being basal (glargine) and 50% being prandial (lispro).” Is this applied to every patient on admission who has a GFR > 30, regardless of other factors (such as hemoglobin A1c, liver disease, glucocorticoid use, etc)?

From my understanding of this protocol, the starting dose of lispro would be 0.083 units/kg TID and 0.25 units/kg of glargine. The doses on hospital day 1 would be identical between the glucocorticoid exposed and unexposed groups and I suspect that differences in dosing between the groups would only start to emerge over time as the glucocorticoid exposed group’s insulin doses were increased in response to the blood sugars.

On page 7 it is reported “supplemental insulin is added to bolus based on pre-meal glucose algorithm.” Please include this algorithm in a supplemental figure. Furthermore, in the discussion there is mention that “our protocol does not recommend supplemental insulin at bedtime.” How is the glargine dose titrated per protocol? It is surprising that there was no association between the glucocorticoid dose and the glargine dose.

In the results, the median total daily glargine and lispro doses are compared between the exposed and unexposed groups. Does this include all of doses across every day of hospitalization? I would expect that the differences in the insulin doses to be larger after a few days of hospitalization where there has been titration since it sounds like both groups are started on the same weight-based dose on admission.

The authors report the median total daily lispro dose was 20% higher in the glucocorticoid exposed group compared with the unexposed group, which I suspect represents a comparison of the doses including all hospital days. It would be more meaningful to compare insulin doses after a few days of insulin titration, or on the last day of glucocorticoid use, or on the day of discharge, as the differences in insulin doses between the exposed and unexposed groups would likely be larger than on admission. The changes in insulin doses and blood sugars over time could be shown with a table of the median doses of glargine and lispro per day and median blood sugars vs. day of hospitalization stratified by exposure.

Was there any use of NPH or insulins other than lispro and glargine in this population? Were patients receiving continuous tube feeds excluded?

Reviewer #2: Comments to the editor:

Thank you for asking me to review this retrospective cohort study by Cheng and colleagues evaluating insulin doses and blood glucose values in non-critically ill, hospitalized patients with diabetes treated with glucocorticoids as compared to those not treated with glucocorticoids. This study adds to the literature regarding management strategies for steroid induced hyperglycemia in the inpatient setting, an area that has been relatively understudied and for which there is not yet an established best practice with respect to insulin dosing, particularly for rapid acting insulin. Prior to publication of their manuscript, several questions should be addressed.

1) Within the introduction, I would update the ADA Standards of Care reference to the 2021 version (of note there are no substantive changes in the recommendations but it is the most recent).

2) Within the methods section it is stated that the insulin protocol at the authors’ institution is dosed at 0.5u/kg/day and divided 50/50 basal and bolus for patients with GFR >30 ml/min and that those patients not dosed per protocol were excluded. The consort diagram suggests it is only patients who did not receive both basal and bolus insulin who were excluded and does not mention weight-based dosing. Can the authors please clarify if patients who received more or less than 0.5u/kg/day were excluded? I would assume given the insulin dosing results that there are patients included in the cohort who receive more or less insulin per this prescribed protocol.

3) The authors’ decided to convert glucocorticoids to prednisone equivalent doses and evaluate the impact on CBG and insulin dosing overall. Can they provide their rationale for this decision? It may be interesting to evaluate insulin dosing needs by type of glucocorticoid (specifically for prednisone and dexamethasone as these were the 2 most commonly used GC) as it has previously been demonstrated that prednisone and dexamethasone result in varying degrees of insulin resistance (Yasuda K et al, doi:10.1210/jcem-55-5-910).

4) Within the results section on insulin dosing, while glargine dosing was similar between groups it would be helpful for the authors to clarify which group corresponded to which doses.

5) Would specify that changes in insulin dosing and hypoglycemia were not statistically significant. I would argue that nearly 20% increase in insulin dose and nearly a doubling of hypoglycemia at breakfast are clinically significant findings. Would likely see statistical significance with a slightly larger sample size.

6) The last line of the limitations paragraph regarding requirement of further increase in bolus insulin feels out of place, would suggest that this be moved to earlier in the discussion (for example the first paragraph of discussion).

7) While the authors demonstrate higher rapid acting insulin doses at dinner and increased CBG at lunch and dinner in patients on GC, I do not believe their findings support the conclusion that a 30% increase in rapid acting insulin at lunch and 20% increase in rapid acting insulin at dinner may be recommended as this was not specifically evaluated in this study. Instead, I would argue that their data do suggest higher doses of bolus insulin are required in the mid-day and evening but that specific recommendations regarding percentage increase should be evaluated in a future prospective study. While they include a statement regarding this need for further evaluation of the proposed strategy, it should also be mentioned in the abstract conclusions and first paragraph of the discussion.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Dylan Thomas

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Sep 16;16(9):e0256682. doi: 10.1371/journal.pone.0256682.r002

Author response to Decision Letter 0

26 May 2021

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

 

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this paper, the authors performed a retrospective cohort study of hospitalized patients with diabetes to examine the effects of glucocorticoid use on blood glucose readings and insulin doses.

Strengths of this study include the standardized protocol where all patients are placed on a balanced basal bolus regimen and use of matching to control for age, gender, race, and hemogloblin A1c.

Limitations include its retrospective nature and reporting of data across all hospitalization days.

Specific comments:

How are insulin doses adjusted per protocol based on the blood sugar readings? I understand from the discussion that “the current protocol is 0.5 units/kg with 50% of total dose being basal (glargine) and 50% being prandial (lispro).” Is this applied to every patient on admission who has a GFR > 30, regardless of other factors (such as hemoglobin A1c, liver disease, glucocorticoid use, etc)?From my understanding of this protocol, the starting dose of lispro would be 0.083 units/kg TID and 0.25 units/kg of glargine. The doses on hospital day 1 would be identical between the glucocorticoid exposed and unexposed groups and I suspect that differences in dosing between the groups would only start to emerge over time as the glucocorticoid exposed group’s insulin doses were increased in response to the blood sugars.

On page 7 it is reported “supplemental insulin is added to bolus based on pre-meal glucose algorithm.” Please include this algorithm in a supplemental figure. Furthermore, in the discussion there is mention that “our protocol does not recommend supplemental insulin at bedtime.” How is the glargine dose titrated per protocol? It is surprising that there was no association between the glucocorticoid dose and the glargine dose.

We do follow the in-patient protocol which has been added as supplemental material. Our protocol does use the liver disease status to adjust the insulin dose but not the A1c or the glucocorticoid. As mentioned in the Methods, those with GFR <30 were excluded with no change in protocol for those with GFR >30.

For the supplemental insulin and the glargine dose adjustment, please see supplemental material. The finding that the glargine was not associated with glucocorticoid dose seemed to be in line with previous evidence that steroids affect mostly post-prandial glucose (Eur J Endocrinol 2010;162:729-735)

In the results, the median total daily glargine and lispro doses are compared between the exposed and unexposed groups. Does this include all of doses across every day of hospitalization? I would expect that the differences in the insulin doses to be larger after a few days of hospitalization where there has been titration since it sounds like both groups are started on the same weight-based dose on admission.

As per our inpatient protocol, there were no initial differences in dosing between the groups. Analysis was done by dose per day with every day a unit of analysis as we expected the dosing to progressively increase daily as mentioned by the reviewer.

The authors report the median total daily lispro dose was 20% higher in the glucocorticoid exposed group compared with the unexposed group, which I suspect represents a comparison of the doses including all hospital days. It would be more meaningful to compare insulin doses after a few days of insulin titration, or on the last day of glucocorticoid use, or on the day of discharge, as the differences in insulin doses between the exposed and unexposed groups would likely be larger than on admission. The changes in insulin doses and blood sugars over time could be shown with a table of the median doses of glargine and lispro per day and median blood sugars vs. day of hospitalization stratified by exposure.

We did not analyze glucose median during the entire hospitalization as we expected that those on steroids may have a longer length of stay resulting in a skewed analysis if compared day-by-day.

Was there any use of NPH or insulins other than lispro and glargine in this population? Were patients receiving continuous tube feeds excluded?

Per our inpatient protocol, NPH is primarily used on OB/GYN patients who were excluded from our study population. Insulin Regular is only used on IV drips in MICU. Continuous tube feeds in our hospital are primarily used in MICU patients who were excluded from the study.

Reviewer #2: Comments to the editor:

Thank you for asking me to review this retrospective cohort study by Cheng and colleagues evaluating insulin doses and blood glucose values in non-critically ill, hospitalized patients with diabetes treated with glucocorticoids as compared to those not treated with glucocorticoids. This study adds to the literature regarding management strategies for steroid induced hyperglycemia in the inpatient setting, an area that has been relatively understudied and for which there is not yet an established best practice with respect to insulin dosing, particularly for rapid acting insulin. Prior to publication of their manuscript, several questions should be addressed.

1) Within the introduction, I would update the ADA Standards of Care reference to the 2021 version (of note there are no substantive changes in the recommendations but it is the most recent).

The text and reference were updated.

2) Within the methods section it is stated that the insulin protocol at the authors’ institution is dosed at 0.5u/kg/day and divided 50/50 basal and bolus for patients with GFR >30 ml/min and that those patients not dosed per protocol were excluded. The consort diagram suggests it is only patients who did not receive both basal and bolus insulin who were excluded and does not mention weight-based dosing. Can the authors please clarify if patients who received more or less than 0.5u/kg/day were excluded? I would assume given the insulin dosing results that there are patients included in the cohort who receive more or less insulin per this prescribed protocol.

The assumption of the reviewer was correct. Our inpatient protocol allows to use a converted home dose of insulin. See supplemental material.

3) The authors’ decided to convert glucocorticoids to prednisone equivalent doses and evaluate the impact on CBG and insulin dosing overall. Can they provide their rationale for this decision? It may be interesting to evaluate insulin dosing needs by type of glucocorticoid (specifically for prednisone and dexamethasone as these were the 2 most commonly used GC) as it has previously been demonstrated that prednisone and dexamethasone result in varying degrees of insulin resistance (Yasuda K et al, doi:10.1210/jcem-55-5-910).

The rationale for converting steroids to prednisone equivalents was two-fold. First, it would permit us to compare patients across different therapies. Second, there are multiple patients who during the same hospitalization may have received different types of steroids. Due to our unit of analysis being day of hospitalization, the conversion allowed us to compare the different doses of different steroids on various days.

4) Within the results section on insulin dosing, while glargine dosing was similar between groups it would be helpful for the authors to clarify which group corresponded to which doses.

We clarified the groups in the beginning of Insulin Dosing in the Results section.

5) Would specify that changes in insulin dosing and hypoglycemia were not statistically significant. I would argue that nearly 20% increase in insulin dose and nearly a doubling of hypoglycemia at breakfast are clinically significant findings. Would likely see statistical significance with a slightly larger sample size.

We agree that the difference found is likely clinically significant yet within our available sample size, the current findings are as reported.

 

6) The last line of the limitations paragraph regarding requirement of further increase in bolus insulin feels out of place, would suggest that this be moved to earlier in the discussion (for example the first paragraph of discussion).

As suggested, the sentence has been moved to the first paragraph of Discussion.

7) While the authors demonstrate higher rapid acting insulin doses at dinner and increased CBG at lunch and dinner in patients on GC, I do not believe their findings support the conclusion that a 30% increase in rapid acting insulin at lunch and 20% increase in rapid acting insulin at dinner may be recommended as this was not specifically evaluated in this study. Instead, I would argue that their data do suggest higher doses of bolus insulin are required in the mid-day and evening but that specific recommendations regarding percentage increase should be evaluated in a future prospective study. While they include a statement regarding this need for further evaluation of the proposed strategy, it should also be mentioned in the abstract conclusions and first paragraph of the discussion.

We agree with the reviewers that the specific recommendations need to be studied and this was not the purpose of the study. We revised the manuscript accordingly in abstract conclusion and in the Discussion.

________________________________________

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Dylan Thomas

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: PLOS One Response to Reviewers 5-20-21.docx

Click here for additional data file. (20.6KB, docx)

Decision Letter 1

Sun Young Lee

18 Jun 2021

PONE-D-21-07298R1

Insulin management in hospitalized patients with diabetes mellitus on high-dose glucocorticoids: Management of steroid-exacerbated hyperglycemia

PLOS ONE

Dear Dr. Guerra,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please review the comments by both reviewers regarding the revision and include additional discussions as suggested by the reviewers.

Please submit your revised manuscript by Aug 02 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Sun Young Lee, MD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed my comments.

I would consider adding a reference to an ongoing randomized clinical trial to address The Management of Glucocorticoid-Induced Hyperglycemia in Hospitalized Patients: https://clinicaltrials.gov/ct2/show/NCT01810952

I would also add that there is some data to suggest that the insulin dosing pattern should be tailored to match the glucocortoid dosing and type (e.g. optimal dosing for prednisone may be different than for dexamethasone). Hence, a single protocol for all inpatients on steroids may not be optimal.

https://eje.bioscientifica.com/view/journals/eje/179/4/EJE-18-0315.xml

Reviewer #2: The authors have not yet sufficiently addressed the comment regarding the decision to convert glucocorticoid doses to prednisone equivalent within the text of the manuscript. The rationale provided in the response to reviewers should be included within the methods section.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Dylan Thomas

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Sep 16;16(9):e0256682. doi: 10.1371/journal.pone.0256682.r004

Author response to Decision Letter 1

28 Jul 2021

Reviewer #1: The authors have addressed my comments.

I would consider adding a reference to an ongoing randomized clinical trial to address The Management of Glucocorticoid-Induced Hyperglycemia in Hospitalized Patients: https://clinicaltrials.gov/ct2/show/NCT01810952

This ongoing trial is now referenced in the Discussion section.

I would also add that there is some data to suggest that the insulin dosing pattern should be tailored to match the glucocortoid dosing and type (e.g. optimal dosing for prednisone may be different than for dexamethasone). Hence, a single protocol for all inpatients on steroids may not be optimal.

https://eje.bioscientifica.com/view/journals/eje/179/4/EJE-18-0315.xml

We’ve added reference to this approach in our Introduction.

Reviewer #2: The authors have not yet sufficiently addressed the comment regarding the decision to convert glucocorticoid doses to prednisone equivalent within the text of the manuscript. The rationale provided in the response to reviewers should be included within the methods section.

The rationale provided in our prior response is now included in the Methods section.

Attachment

Submitted filename: Response to Reviewers 7-28-21.docx

Click here for additional data file. (23.3KB, docx)

Decision Letter 2

Sun Young Lee

13 Aug 2021

Insulin management in hospitalized patients with diabetes mellitus on high-dose glucocorticoids: Management of steroid-exacerbated hyperglycemia

PONE-D-21-07298R2

Dear Dr. Guerra,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Sun Young Lee, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: All of my comments have been addressed.

All of my comments have been addressed.

All of my comments have been addressed.

Reviewer #2: The authors have addressed my comments in a satisfactory fashion. My recommendation is to accept the manuscript.

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Reviewer #1: Yes: Dylan D. Thomas

Reviewer #2: No

Acceptance letter

Sun Young Lee

3 Sep 2021

PONE-D-21-07298R2

Insulin management in hospitalized patients with diabetes mellitus on high-dose glucocorticoids: Management of steroid-exacerbated hyperglycemia

Dear Dr. Guerra:

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Kind regards,

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on behalf of

Dr. Sun Young Lee

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File. Cook county health inpatient hyperglycemia protocol.

    (PDF)

    Click here for additional data file. (201.3KB, pdf)
    Attachment

    Submitted filename: PLOS One Response to Reviewers 5-20-21.docx

    Click here for additional data file. (20.6KB, docx)
    Attachment

    Submitted filename: Response to Reviewers 7-28-21.docx

    Click here for additional data file. (23.3KB, docx)

    Data Availability Statement

    Data can be found on the Open Science Framework at https://osf.io/dzhu7/ (DOI: 10.17605/OSF.IO/DZHU7).

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