Use of Neutral Protamine Hagedorn (NPH) Versus Basal Bolus Insulin for Steroid Induced Hyperglycemia
Phase: PHASE4
Conditions: Hyperglycemia Steroid-induced, Insulin Resistance, Diabetes
Sponsor: Northwestern University

PROTOCOL TITLE:  Use of NPH versus Basal Bolus Insulin for Steroid Induced Hyperglycemia 
 
PRINCIPAL INVESTIGATOR: 
Mark E. Molitch, M.D. 
Division of Endocrinology, Metabolism and Molecular Medicine 
Department of Medicine 
Northwestern University Feinberg School of Medicine 
645 N. Michigan Ave, Suite 530 
Chicago, IL 60611 
(312) 503-4130 
molitch@northwestern.edu 
 
VERSION NUMBER: 
Version Number 1 
VERSION DATE: 
2/19/2018 
 
Co-Principal Investigator 
Amisha Wallia, M.D., Division of Endocrinology, Metabolism and Molecular Medicine 
Fellow Investigator 
Smita Kumar, M.D., Division of Endocrinology, Metabolism and Molecular Medicine 
Co-Investigators: 
Kathleen Schmidt, MSN, APRN,  Glucose Management Service 
Tiffany Grant,  APRN, Glucose Management Service 
Study Site: 
Northwestern Memorial Hospital 
Study identifiers:   
STU00207079, NCT03511521 

OBJECTIVES:   
1.) To determine which insulin regimen, NPH in addition to basal/bolus insulin or just basal/bolus 
insulin, provides better glycemic control in patients on once daily dosing of steroids 
2.) Determine which dosing regimen leads to less adverse events, specifically hypoglycemia 
 
BACKGROUND: 
Glucocorticoids are known to cause an increase in insulin resistance, leading to hyperglycemia, in both 
diabetic and non-diabetic patients. In both the inpatient and outpatient setting, steroids are used for 
their anti-inflammatory property to treat a variety of conditions.  There is a paucity of information 
regarding the best way to treat steroid-induced hyperglycemia.   Generally insulin is administered in the 
hospital using a basal/bolus approach, i.e. giving a long-acting insulin such as glargine to control hepatic 
glucose production overnight and between meals and giving a short-acting insulin as a bolus before 
meals to control the postprandial rise in glucose.  Approaches that have been used to adjust for the 
additional hyperglycemia induced by high dose steroids, which are usually administered once daily in 
the morning, include the addition or substitution of NPH insulin for glargine insulin vs. adjusting the 
basal/bolus regimen. 
In 2008, Bevier et al investigated increasing doses of total daily insulin needed in Type I diabetic patients 
on an insulin pump who were administered a fixed dose of steroids for three days.  The study noted an 
increase in basal rates and insulin boluses required after six hours following the first dose of prednisone 
due to rising insulin resistance.  The study concluded that insulin doses should be increased by at least 
30% when the corticosteroid therapy is started but may need to be increased by up to 70% or more to 
normalize blood glucose levels4.  While it is known that steroids cause an increase in insulin resistance 
and an increased total daily dose of insulin requirements; the best way to administer this insulin is still 
unknown.   
While some studies have looked at using NPH versus glargine as basal insulin for steroid-induced 
hyperglycemia1,2,3, few studies have looked at the addition of NPH to a basal bolus regimen for treating 
steroid-induced hyperglycemia.   
A pilot study done at the University of Colorado looked into the use of NPH plus basal bolus insulin 
versus just basal bolus insulin doses to treat steroid induced hyperglycemia, specifically in cystic fibrosis 
related diabetes patients receiving methylprednisolone.5 Similar to Beiver et al4, they concluded that 
with the addition of steroids, there was an overall increase of total daily doses of insulin by 40%; half of 
the arm received this increase in the form of NPH in addition to glargine and lispro while half of them 
received this in the form of an increase in the glargine and lispro doses. The study showed that 
methylprednisolone raised prelunch and predinner glucose levels in patients treated with glargine/lispro 
alone; however, the addition of NPH with methylprednisolone significantly decreased the rise in 
postprandial glucose at lunch and dinner compared to the glargine/lispro group but still did not return 
the glucose levels to acceptable levels.5   
Our study aims to further study the use of NPH in addition to glargine and lispro in the setting of steroid 
use to achieve improved glycemic control in the inpatient setting.  
 
References: 

 
1. Dhital SM, SHenker Y, Meredith M, Davis DB. A retrospective study comparing neutral 
protamine Hagedorn insulin with glargine as basal therapy in prednisone-associated diabetes 
mellitus in hospitalized patients. Endocrine Pract 2012;18: 712–719. 
 
2. Ruiz de Adana MS, Colomo N, Maldonado-Araque C,et al. Randomized clinical trial of the 
efficacy and safety of insulin glargine vs. NPH insulin as basal insulin for the treatment of 
glucocorticoid induced hyperglycemia using continuous glucose monitoring in hospitalized 
patients with type 2 diabetes and respiratory disease. Diabetes Res Clin Pract. 2015;110:158–
165. 
3. Radhakutty A, Stranks JL, Mangelsdorf BL, et al. Treatment of prednisolone-induced 
hyperglycaemia in hospitalized patients: Insights from a randomized, controlled study. Diabetes, 
Obes Metab 2017;19:571-578. 
4. Bevier WC, Zisser HC, Jovanovic L et al.  Use of continuous glucose monitoring to estimate 
insulin requirements in patients with type 1 diabetes mellitus during a short course of 
prednisone. J Diab Sci Technol 2008;2: 578–583.  
5. Seggelke SA, Gibbs J, Draznin B.  Pilot study of using neutral protamine Hagedorn insulin to 
counteract the effect of methylprednisolone in hospitalized patients with diabetes. J. Hosp. 
Med., 2017;6:175–176.  
 
 
INCLUSION AND EXCLUSION CRITERIA: 
Inclusion Criteria: 
 
Patient’s receiving once daily dosing of methylprednisolone in a dose of 10 mg/day or  
greater or prednisone in a dose of  12 mg/day or greater 
 
Hyperglycemic (Glucose > 126 mg/dL) diabetic and non-diabetic patients 
 
Age Range: > age 18 
 
Expected duration of hospital stay and time on steroids > 3 days 
 
Patient or appropriate caregiver able to give Informed Consent 
 
Exclusion Criteria:   
 
Patient’s with two or more doses of methylprednisolone/prednisone per day or other 
steroids, such as hydrocortisone or dexamethasone 
 
Pregnancy 
 
eGFR < 45 ml/min/1.73m2 
 
 
 

STUDY TIMELINES: 
Once a participant is recruited for the study, participants will be followed for three days with the 
intervention on the inpatient service.  Anticipated duration of enrollment will be 2 years.   
STUDY ENDPOINTS: 
Primary endpoint:  Determine which of these regimens is superior with respect to glycemic control in 
these two groups.   
Secondary Endpoints:  A secondary outcome will be to determine which of these regimens will result in 
less hypoglycemia.   
 
PROCEDURES INVOLVED: 
Subjects 
Our study aims to recruit 25 inpatients at Northwestern Memorial Hospital to each study arm. Eligible 
patients will be those who are receiving once daily dosing of prednisone or methylprednisolone for any 
medical condition.  Examples include patients being treated with steroids for respiratory issues, stem 
cell transplant patients, and cystic fibrosis related diabetes patients.  This will be a prospective, 
randomized control study in which each patient will be randomized to one of two arms.  Consent will be 
obtained at the initial day of an Endocrine or Glucose Management Service (GMS) inpatient consult, and 
then subsequently randomized.   
Study Intervention 
One group will receive NPH in addition to their current glargine lispro basal/bolus regimen at the time of 
the prednisone administration.  Another group will continue to receive glargine and lispro; however, 
their basal and bolus regimens will be increased (see attached tables for details).    
 
DATA AND SPECIMEN BANKING: 
Data will be stored both in a locked cabinet and password protected computer and deidentified data will 
be stored on endocrine FSM research server (R Drive) where only study personnel will have access. 
Only the investigators in the study will have access to the data. 
Data will be stored until final analyses and all publications have been completed and will then be 
destroyed by erasing any stored files on the computer and any printed out data. 
There will be no specimen banking. 
 
DATA AND SPECIMEN MANAGEMENT: 
An analysis of the routine finger stick capillary blood glucose levels will be done (see below).  No extra 
fingersticks will be carried out just for the study.  Glycemic control will be assessed by measuring the 
mean of the 4 glucose levels (premeal and bedtime) for the first 3 days of treatment and comparing 
these means between the groups.    A secondary analysis will be to compare the proportions of values in 

the therapeutic targets of 80 – 140 mg/dL and 80 – 180 mg/dL.  An additional analysis will compare the 
proportion of values < 70 mg/dL, the threshold value for hypoglycemia. 
In the study by Seggelke et al (5), the 3 day means of 3 daily premeal glucose levels for the two groups 
(basal/bolus alone vs. basal/bolus + NPH) were 241 and 176 mg/dL (a difference of 65 mg/dL) with 
standard deviations of 36 and 28 mg/dL for the two groups.   If we assume that our modified basal/bolus 
regimen gives improved glycemic results comparable to theirs, we have assumed the following for our 
statistical power calculations:  a standard deviation of 30 mg/dL and assume half the difference in the 
means of about 30 mg/dL, which can be considered to be clinically significant, then a sample size of 20 
in each group would have statistical (two-tailed) power of 0.869 to demonstrate this difference between 
the groups of 30 mg/dL using an alpha=0.05.  We plan to recruit 25 in each group to allow for drop-outs, 
because some patients may not stay on methylprednisolone/prednisone for 3 days. 
 
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF PARTICIPANTS: 
There is always a risk of both hyperglycemia and hypoglycemia when managing hyperglycemic patients 
with insulin and it is not known which of our two approaches will be better with respect to reducing 
hyperglycemia and hypoglycemia.   Each patient will have a routine consultation by the Endocrinology 
Consult Service (ECS) or the Glucose Management Service (GMS) and will have blood glucose levels 
monitored at least daily by those services.  If glucose levels are outside the target range of 80 – 180 
mg/dL, insulin doses will be adjusted accordingly by those services.  Cumulative data, including the 
frequency of hypoglycemia, will be reviewed by the Principal, Co-Principal and Fellow Investigators after 
the first 3 patients are entered into each group and then after every 5 patients in each group to 
determine if the basic algorithms (see Table) need to be adjusted.   
WITHDRAWAL OF PARTICIPANTS: 
Participants with be withdrawn from the study if their steroid regimen changes or stops from once a day 
dosing of methylprednisolone or prednisone.   
RISKS TO PARTICIPANTS: 
Risks: A confidentiality breach is a risk associated with data review research.   As noted above, both 
hyperglycemia and hypoglycemia are inherent risks with inpatient glycemic management with insulin.  
Every effort will be made to reduce these by at least daily review of blood glucose levels on every 
participant with adjustments of insulin doses as needed.   
There are no dangers to an embryo/fetus from insulin but we plan to exclude women known to be 
pregnant.  Because there are no known dangers from insulin, we do not plan to do pregnancy tests, 
however. 
POTENTIAL BENEFITS TO PARTICIPANTS: 
Benefits: The participants are not likely to receive any benefit from the proposed research; however, 
society and investigators will benefit from the knowledge gained.   As with all patients seen by the ECS 
and the GMS, patients will benefit from having their glucose levels monitored closely with frequent 
insulin adjustments made as needed. 

 
VULNERABLE POPULATIONS: 
No vulnerable populations will be included in this study 
COMMUNITY-BASED PARTICIPATORY RESEARCH: 
N/A 
SHARING OF RESULTS WITH PARTICIPANTS: 
Results of the study will not be directly shared with the participants. 
 
SETTING: 
All of the research including recruitment of patients and analyzing the data will take place at 
Northwestern Memorial Hospital  
 
RESOURCES AVAILABLE: 
The PI, Co-PI, ECS and GMS have extensive experience in managing blood glucose levels in 
inpatients at NMH and have published extensively on our experience. 
 
Based on our previous experience, we anticipate that 2 –4 patients per week seen routinely by 
the ECS and GMS would be appropriate for this study and expect that at least 50% of patients 
will agree to participate.   
 
The PI and Co-PI plan to devote about 5% of our time to supervising this research and the Fellow 
Investigator plans to devote 50% of her time to carrying out this research. 
 
All patients will be seen at Northwestern Memorial Hospital.  No special facilities are needed.  
Data analysis will be carried out using the computers and software available to the PI and Co-PI. 
 
All participants will be followed individually by the Endocrinology Consult Service and Glucose 
Management Service and often will be seen by the hospital Diabetes Educator.  These will 
provide additional medical and psychological support in addition to the Investigators in this 
study. 
 
All members of the ECS and GMS will be informed about the nature of the study and instructed 
in how the study will be carried out.  The Fellow-Investigator will liason directly with them each 
day on all participants in the study.  
 
PRIOR APPROVALS: 
N/A 
 
 
 

RECRUITMENT METHODS: 
 
We will use patients primarily seen on the Endocrine Consult Service as well as the Glucose 
Management Service (GMS) who are on once daily dosing of prednisone or 
methylprednisone 
 
Consent will be obtained at the initial day of Endocrine or GMS inpatient consult, and then 
subsequently randomized.   
 
One group will receive NPH in addition to their current glargine lispro basal/bolus regimen 
with the addition of steroids.  (See Table) 
 
Another group will continue to receive glargine and lispro; however, their basal and bolus 
regimens will be increased. (see Table)   
NUMBER OF LOCAL PARTICIPANTS: 
Proposed sample size : Our study aims to recruit 25 inpatients at Northwestern Memorial Hospital to 
each study arm for a total of 50 patients in the study. 
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS: 
All glucose and demographic information will be stored on anonymized confidential files stored in 
firewalled FSM computers.  A separate file will be kept with a patient number and any identifiable 
information and stored in the firewalled FSM computers. 
Participants will be followed daily by the ECS or the GMS as well as the Fellow Investigator who will be 
able to address all questions and concerns, 
The Research Staff will create a dataset in the Enterprise Data Warehouse so as to obtain access to any 
stored data on participants. 
 
COMPENSATION FOR RESEARCH-RELATED INJURY: 
N/A 
 
ECONOMIC BURDEN TO PARTICIPANTS: 
NONE 
 
CONSENT PROCESS: 
Consent will be obtained at the initial consult while the patient in inpatient at Northwestern Memorial 
Hospital.  Consent with be obtain by the team members of the GMS or Endocrine Fellows on the ECS. 
Adults Unable to Consent/ Cognitively Impaired Adults 
Because the goal here is to improve glycemic control with less hyperglycemia and less hypoglycemia 
than standard methods, it seems reasonable to include adults who are cognitively impaired or who are 
unable to consent and who have appropriate individuals who can give appropriate assent.  Such 

appropriate individuals, in order of priority, would be those with durable power of attorney for health 
care, court appointed guardian for health care decisions, spouse, and adult child.  Such assent will be 
documented on the Consent Form. 
 
PROCESS TO DOCUMENT CONSENT IN WRITING: 
Participants will be consented at the initial day of consult.  A written document will be provided for 
signature.  (see attached) 
 
 
 
 
 
 
 
 
 

Table 1.  Continue Standard Basal/Bolus Insulin* and add NPH in units adjusted for Prednisone doses 
according to the following table: 
 
Prednisone Added 
(mg/day) 
NPH Dose (U/mg 
Prednisone/day 
Amount of total NPH 
added at top of range 
Added total NPH 
Insulin (U/kg) for 70 kg 
person 
> 80 
No additional NPH 
51 
0.73 
61 – 80 
0.3 
51 
0.73 
41-60 
0.45 
45 
0.64 
21-40 
0.6 
36 
0.51 
10-20 
1.2 
24 
0.34 
 
*Standard Basal/Bolus Insulin will be considered either a weight based dose (total daily dose of insulin 
0.5 U/kg) or patient’s home doses of insulin without adjustment 
 
 
Table 2.  Basal/Bolus Insulin adjusted for Prednisone doses according to the following table: 
 
Prednisone 
Added 
(mg/day) 
Glargine Dose 
(U/kg) 
Breakfast 
Novolog Dose 
(U/kg) 
Lunch  
Novolog Dose 
(U/kg) 
Dinner 
Novolog Dose 
(U/kg) 
>80 
0.30 
0.15 
0.35 
0.40 
61-80 
0.30 
0.15 
0.3 
0.35 
41-60 
0.30 
0.15 
0.25 
0.30 
21-40 
0.25 
0.1 
0.2 
0.25 
10-20 
0.25 
0.1 
0.15 
0.2 
0* 
0.25 
0.08 
0.08 
0.08 
*standard weight based dose of  0.5 U/kg divided 50/50 into basal (glargine) and prandial insulin divided 
into 3 premeal doses 
 
Note:  Prednisone and IV methylprednisolone will be judged to be equivalent with respect to addition of 
insulin doses according to above tables.