Evaluation of Glycemic Control Obtained from
NPH Insulin in Patients Experiencing
Megan N Hodges1, Katie B Tellor2* and Anastasia L Armbruster2
1Clinical Pharmacist, Virginia Mason Memorial Hospital, USA
2Department of Pharmacy Practice, St. Louis College of Pharmacy, USA
Submission: October 28, 2017; Published: November 28, 2017
*Corresponding author: Katie B Tellor, Associate Professor of Pharmacy Practice, Department of Pharmacy Practice, St. Louis College of Pharmacy, USA, Tel: 314-996-5043; Fax: 314-996-5309; Email: [email protected]
How to cite this article: Hodges MN, Tellor KB, Armbruster AL. Evaluation of Glycemic Control Obtained from NPH Insulin in Patients Experiencing
002 Corticosteroid-Induced Hyperglycemia. Curre Res Diabetes & Obes J. 2017; 5(2): 555656. DOI: 10.19080/CRDOJ.2017.05.555656.
Objective:To compare the safety and efficacy of neutral protamine Hagedorn (NPH) insulin to other antidiabetic regimens in the treatment of corticosteroid-induced hyperglycemia in non-critically ill; hospitalized patients.
Methods:This retrospective cohort included patients treated with methylprednisolone or prednisone concomitantly with NPH or other antidiabetic medications for at least two days. Patients were screened for inclusion in reverse chronological order and matched based on gender; age; body mass index; steroid dose; and history of diabetes. The primary objective was mean daily blood glucose (BG). Secondary outcomes included percentage of readings between 70mg/dL-180mg/dL; median daily BG; number of hypoglycemic events; daily steroid to NPH ratios; and mean weight-based dose of NPH for each 10mg increment of prednisone when BG readings were within goal.
Results:A total of 72 patients were included in each arm. The primary efficacy endpoint of mean daily BG ranged from 111-217mg/dL in the control group and 163-228mg/dL in the NPH arm; however; there were no statistically significant differences (p>0.05). Overall rates of hypoglycemia were slightly lower in the NPH group but with no statistically significant differences (0.61% vs. 1.12%; p = 0.51).
Conclusions:NPH; compared to other regimens; may not have an impact on achieving glycemic controlin corticosteroid-induced hyperglycemia.
Systemic corticosteroids are commonly used for a wide variety of medical conditions on both an inpatient and outpatient basis for the treatment of inflammation and immune suppression. Acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations, rheumatoid arthritis, and organ transplant comprise just a few of the many indications. Although corticosteroids are highly efficacious, its use is limited by many serious adverse effects during acute and chronic treatment [1-6]. During short-course therapy, patients commonly develop hyperglycemia. Several studies have reported odds ratios from 1.5 to 2.5 for the development of new-onset diabetes relating specifically to steroid utilization [2-5]. Corticosteroids also have the potential to significantly worsen hyperglycemia in patients with a history of diabetes mellitus [1,7] . This
represents a substantial health risk to patients since studies have found a correlation between hyperglycemia and decreased wound healing, increased length of stay (LOS) and mortality in hospitalized patients .
Several studies have been undertaken to better understand the exact mechanism of steroid-induced hyperglycemia. In patients receiving short-term therapy, skeletal muscle and hepatic cells develop reduced insulin sensitivity leading to decreased glucose uptake. During the post-prandial phase in particular, blood glucose (BG) levels are further elevated by impaired suppression of glucose production secondary to hepatic insulin resistance .
Insulin acts on liver, adipose tissue, and skeletal muscle to regulate metabolism of carbohydrates, fat, and protein. A cross- sectional review of 66 patients suggested that patients receiving
≥10mg per day of prednisolone compared to those not receiving
corticosteroids experience afternoon and evening hyperglycemia
despite receiving basal-bolus insulin regimens . Neutral
protamine Hagedorn (NPH) is a crystalline suspension of human
insulin with protamine and zinc, which makes it intermediate
acting insulin. Neutral protamine Hagedorn insulin produces a
peak effect four to eight hours after administration with a total
duration of sixteen to eighteen hours. These kinetic properties
closely mirror the action of prednisone. Methylprednisolone
also has a similar duration of action with a shorter onset of one to
two hours [10-12]. In theory, the pharmacokinetic principles of
subcutaneous NPH make it a prime candidate for the treatment
of glucocorticoid induced hyperglycemia. The objective of this
study is to compare NPH to other antidiabetic agents in the
treatment of steroid-induced hyperglycemia.
This single-center retrospective cohort study evaluated
patients at a 450-bed community hospital. The trial was
approved by the hospital Institutional Review Board before data
collection began. Due to the retrospective nature of the study,
informed consent was not necessary. All data was obtained
through electronic medical records.
Eligibility requirements included age ≥18 years, concurrent
treatment with methylprednisolone or prednisone with NPH
insulin or other antidiabetic medications for at least two days,
and steroid doses ≥10mg prednisone equivalent on day one.
Patients receiving NPH for the treatment of steroid-induced
hyperglycemia were included in the treatment arm and patients
being treated with any other combination of antidiabetic
medications were evaluated in the control arm. Patients in
the NPH arm with glargine insulin as a home medication were
included in the study if the glargine titration was limited
to± 20% during the hospitalization since a 20% reduction is
recommended at admission to decrease risk of hypoglycemia
and to limit confounding adjustments to the glargine during
steroid titration . Patients were not eligible for inclusion in
the NPH treatment arm if they received any other antidiabetic
medications in addition to NPH, rapid acting insulin, or glargine
as described above. Oral antidiabetic agents were allowed in the
control arm; however, per institutional protocols and American
Diabetes Association (ADA) recommendations these agents are
routinely discontinued upon admission to the hospital .
Patients admitted with a BG>400mg/dL, those in the intensive
care unit, patients on insulin pumps, and pregnant patients were
excluded. Patients were also excluded if they had less than two
BG readings per day or no recorded weight.
Patient characteristics were identified through queries
of the hospital electronic medical record. Starting October
2014 through October 2012, all patients receiving ≥10mg of
prednisone equivalent of methylprednisolone or prednisone
for at least one day were consecutively screened for inclusion
in reverse chronological order. After patients were identified for
analysis in the NPH arm, controls were then matched by manual
chart review to the NPH patients based on age, gender, body
mass index (BMI) classification, steroid dose on day one, and
history of diabetes.
The primary outcome was the mean daily BG. Secondary
outcomes included the percent of BG readings within a
preset goal of 70mg/dL to 180mg/dL. All BG readings were
incorporated in the analysis regardless of the patients’ fasting
state, thus a higher goal of <80mg/dL was established based
on the ADA random BG recommendations for non-critically ill,
hospitalized patients. The low end of this range was based on
the ADA definition of hypoglycemia, which is BG<70mg/dL .
Other secondary objectives included median daily BG, number of
hypoglycemic and severe hypoglycemic events with and without
intervention. Intervention was defined as intake of juice, oral
glucose tablets or administration of glucagon or dextrose 50%
water. As defined by the ADA, BG<40mg/dL is considered severe
hypoglycemia.  Daily steroid to NPH ratios and steroid
to NPH ratios on the index day were also collected. The index
day was defined as the last day of steroid therapy or the day
of discharge if the patient continued steroids as an outpatient.
Mean weight-based dose of NPH for each 10mg increment of
prednisone equivalent (8mg methylprednisolone) was collected
for days on which all BG readings were within the goal range
with the intention of formulating a standardized NPH protocol.
Two subgroup analyses were performed on mean blood glucose
to compare NPH to sliding scale insulin alone and to compare
NPH to other antidiabetic regimens in patients admitted with a
documented history of diabetes.
The outcomes data was analyzed to determine the glycemic
control achieved with each regimen by looking at all available
BG readings throughout the patients’ hospitalizations excluding
repeat readings within 10 minutes. Baseline characteristics and
outcomes were reported using means, medians, and standard
deviations for interval level data and percentages for nominal
and ordinal level data. Baseline demographics and study
outcomes were compared between groups using Student’s
t-test for continuous data and Fisher’s exact or chi-square test
for categorical data. A p value of <0.05 indicated statistical
significance. All analyses were performed with IBM SPSS
Statistics for Windows.
To the authors’ knowledge, the only other published trials
addressing this treatment regimen included a maximum of 66
patients in each arm and did not find a statistically significant
difference; therefore, power was not calculated [15-17]. Based
on available information, 72 patients were included in each arm.
A total of 241 patients were identified through the pharmacy
informatics system for potential inclusion in the NPH arm.
Of these patients, 72 were eligible based on the inclusion and
exclusion criteria. Patients were well matched in regards to
baseline demographics (Table 1). The only significant difference
between groups was total LOS, which was significantly higher
in the NPH group (6.98days vs. 4.88days, p =0.003). However,
no differences existed among indication for steroid utilization.
Baseline glycemic control was similar between groups: mean
BG of 186mg/dL in the NPH group and 177mg/dL in the control
group at admission (p=0.492).
*There were no significant differences between the two groups except
for LOS (p=0.003)
The primary efficacy endpoint of mean daily BG ranged from
111-217mg/dL in the control group and 164-228mg/dL in the
NPH arm; however, no statistically significant differences were
detected for any day (Figure 1) & (Table 2). The results on the
index day (Table 3) showed numerically though not statistically
improved glycemic control for the control group compared with
the NPH arm with a mean BG of 195mg/dL for the NPH group
and 179mg/dL for the control group (p =0.135).
In regards to efficacy, the only statistically significant
difference found was in the percent of BG readings between 70-
180mg/dL for day 1 in favor of the control arm (41.9%vs.28.1%,
p=0.01) (Table 4). No trends were observed for the steroid:
NPH ratios or weight-based NPH doses. Consistent glycemic
control was achieved faster in the control arm; mean daily BG
readings were <180mg/dL starting on day 5 compared to day
10 in the NPH arm (Figure 1). In contrast to a previous study,
the NPH arm received a significantly higher total daily insulin
dose on the index day compared to the control arm (0.37unit/kg
vs. 0.21unit/kg, p=0.002). However, these differing results are
likely accounted for by the inclusion of glargine insulin in the
NPH arm .
aData presented as mean ± standard deviation.
Glycemic control was similar in both subgroup analyses
(patients with a history of diabetes and those receiving only
slide scale insulin compared to NPH) (data not shown). In
patients with a documented history of diabetes, the mean BG
on the index day was 197mg/dL in the NPH arm compared to
185mg/dL in the control arm (p=0.313). When comparing NPH
and sliding scale insulin versus sliding scale insulin alone, BG on
the index day was 187mg/dL in the NPH group and 174mg/dL in
the sliding scale insulin group (p=0.246).
Overall, the incidence of hypoglycemia was low in both arms,
with more events occurring in the control arm (Figure 2). A total
of 9(0.61%) hypoglycemic episodes occurred in the NPH arm
and 15(1.12%) in the control arm (p=0.51). Only one episode of
severe hypoglycemia was noted in the control arm.
When interpreting these results, it is important to note that
the number of patients evaluated dropped considerably each
consecutive day. By day eleven, only two patients remained in the
NPH arm compared to one patient in the control arm. Although
daily trends are important to consider, the results on the index
day may provide the most insight on glycemic control.
Several limitations exist within this study. Due to the
retrospective design, there is also potential for data extraction
errors and chart documentation errors. Another limitation is the
lack of standardized NPH dosing at this institution. The doses
prescribed varied greatly between patients, and the majority of
weight-based NPH doses were much lower than other institution
protocol recommendations [1,8-15]. Overall glycemic control
was also relatively poor in both groups compared to previous
studies. This could be partly due to higher daily steroid doses
and lack of Diabetes Management Services . Lastly, patients
in the NPH group had a significantly longer LOS compared to the
control group, which could have resulted in worse overall BG
control with increased time of steroid exposure. However, there
were no measurements to determine severity of illness to help
explain the extended LOS. Although this study was conducted at
a single community hospital with a limited sample size, it is the
largest study to evaluate this topic.
Despite a lack of evidence, several institutions have
implemented protocols for the use of weight-based NPH dosing
for hyperglycemic patients treated with steroids. The doses
usually range from 0.1units/kg to 0.5units/kg depending on
steroid doses [1,8-15]. One retrospective cohort of 120 patients
found no difference between NPH versus glargine to control
steroid-induced hyperglycemia in patients with type 2 diabetes
. A randomized control trial of 50 patients evaluated whether
an NPH-based insulin regimen is safer and more effective
than a glargine-based regimen in hospitalized adults with
prednisolone-induced hyperglycemia. The initial daily insulin
dose was 0.5units/kg or 130% of the current daily insulin dose.
No differences in either outcome was observed . Another
randomized control trial of 53 patients examining glargine
versus NPH in type II diabetics with respiratory disease and
glucocorticoid induced hyperglycemia yielded similar results
. This current trial included patients regardless of their
diabetes history or steroid indication. Despite the similarity
in pharmacokinetic profiles between corticosteroids and NPH,
this approach may not offer better glycemic coverage in steroidinduced
hyperglycemia over other regimens as shown in this trial
and in the studies by Dhital et al. , Ruiz de Adana et al. , & Radhakutty et al. . Additional large, randomized-controlled
trials are warranted to further help direct future evidence-based
treatment strategies for steroid-induced hyperglycemia.
Based on the results of this study, no conclusions can be
determined about the efficacy of NPH insulin for corticosteroidinduced
hyperglycemia. Patients receiving standard care
(control group) appeared to have better glycemic control over
patients in the NPH arm; however, the resulting differences were
not statistically significant and hampered by small sample size.