ORIGINAL
E n d o c r i n e
ARTICLE
C a r e
Comparison of Inpatient Insulin Regimens with
Detemir plus Aspart Versus Neutral Protamine
Hagedorn plus Regular in Medical Patients with Type
2 Diabetes
Guillermo E. Umpierrez, Tiffany Hor, Dawn Smiley, Angel Temponi, Denise Umpierrez,
Miguel Ceron, Christina Munoz, Christopher Newton, Limin Peng, and David Baldwin
Department of Medicine (G.E.U., D.S., A.T., D.U., M.C., C.N.) and Rollins School of Public Health (L.P.), Emory
University, Atlanta, Georgia 30303; and Rush University Medical Center (T.H., C.M., D.B.), Chicago, Illinois 60612
Background: Studies comparing the use of basal bolus with insulin analogs vs. split-mixed regimens
with human insulins in hospitalized patients with type 2 diabetes are lacking.
Research Design and Methods: In a controlled multicenter trial, we randomized 130 nonsurgical
patients with blood glucose (BG) between 140 and 400 mg/dl to receive detemir once daily and
aspart before meals (n ⫽ 67) or neutral protamine Hagedorn (NPH) and regular insulin twice daily
(n ⫽ 63). Insulin dose was started at 0.4 U/kg 䡠 d for BG between 140 and 200 mg/dl or 0.5 U/kg 䡠 d
for BG 201-400 mg/dl. Major study outcomes included differences in mean daily BG levels and
frequency of hypoglycemic events between treatment groups.
Results: Glycemic control improved similarly in both groups from a mean daily BG of 228 ⫾ 54 and
223 ⫾ 58 mg/dl (P ⫽ 0.61) to a mean daily BG level after the first day of 160 ⫾ 38 and 158 ⫾ 51 mg/dl
in the detemir/aspart and NPH/regular insulin groups, respectively (P ⫽ 0.80). A BG target below
140 mg/dl before meals was achieved in 45% of patients in the detemir/aspart group and 48% in
the NPH/regular group (P ⫽ 0.86). During treatment, 22 patients (32.8%) in the detemir/aspart
group and 16 patients (25.4%) in the NPH/regular group had at least one episode of hypoglycemia
(BG ⬍60 mg/dl) during the hospital stay (P ⫽ 0.34).
Conclusions: Treatment with basal/bolus regimen with detemir once daily and aspart before meals
results in equivalent glycemic control and no differences in the frequency of hypoglycemia compared to a split-mixed regimen of NPH and regular insulin in patients with type 2 diabetes. (J Clin
Endocrinol Metab 94: 564 –569, 2009)
ncreasing evidence from observational studies (1–4) and a recent
meta-analysis (5) indicate that hyperglycemia is associated with an
increased risk of complications and mortality in hospitalized patients.
Amongcriticallyillpatients,prospectiverandomizedtrialshaveshown
that improved glycemic control reduces short- and long-term mortality, rates of multiorgan failure and systemic infections, and length of
hospitalization (6–8). Similarly, observational studies in diabetic subjects admitted to general medical and surgical areas have also shown
that poor glycemic control is a predictor of poor clinical outcome. In
such patients, the presence of hyperglycemia is associated with pro-
I
longed hospital stay, infection, disability after hospital discharge, and
death (1, 4, 9).
Hyperglycemia is commonly not well addressed in patients
with diabetes admitted to general medicine wards (1, 10 –12). In
the presence of altered nutrition and associated medical illness,
physicians frequently discontinue their patient’s previous outpatient antidiabetic regimen and initiate sliding-scale insulin
coverage with short-acting insulins, a practice associated with
limited therapeutic success mainly because of the lack of basal
insulin coverage (13–15). The use of a split-mixed insulin regi-
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2009 by The Endocrine Society
doi: 10.1210/jc.2008-1441 Received July 7, 2008. Accepted November 10, 2008.
First Published Online November 18, 2008
Abbreviations: BG, Blood glucose; ICU, intensive care unit; NPH, neutral protamine Hagedorn; NS, not significant; TDD, total daily dose.
564
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J Clin Endocrinol Metab. February 2009, 94(2):564 –569
J Clin Endocrinol Metab, February 2009, 94(2):564 –569
men of intermediate neutral protamine Hagedorn (NPH) and
regular insulin is usually delayed due to fear of hypoglycemia (16,
17). The inadequate duration of action of NPH insulin and an
undesirable peak activity at 4 – 6 h after injection (16), as well as
the high day-to-day variability in absorption (17), have been proposed as barriers to achieving appropriate targets of blood glucose
(BG) control in patients with diabetes. In recent years, the basal
insulin analogs glargine and detemir have been developed to overcome some of the barriers to insulin initiation, including concerns
over hypoglycemia. The combination of a long-acting basal and a
rapid-acting prandial insulin has been recommended as a more
physiological approach to glucose control in the hospital (9, 18). We
recently reported that a basal/bolus insulin algorithm is a simple and
more effective intervention than a sliding-scale regular insulin for
glucose control in hospitalized patients with type 2 diabetes (19).
The use of a basal/bolus regimen, however, has not been compared
with an NPH/regular insulin regimen in the inpatient setting. Accordingly, we compared the efficacy and safety of a basal/bolus
regimen of detemir once daily plus aspart insulin before meals to an
NPH and regular insulin twice daily regimen in patients with type
2 diabetes mellitus in general medicine services.
Patients and Methods
In this multicenter, prospective, open-label randomized study, we enrolled 130 nonsurgical patients 18 – 80 yr old that were admitted to
general medicine wards with BG levels between 140 and 400 mg/dl.
Further inclusion criteria included a known history of type 2 diabetes for
longer than 3 months, treatment with diet alone, any combination of oral
antidiabetic agents and/or insulin before admission, and the absence of
diabetic ketoacidosis (20). Exclusion criteria included subjects with hyperglycemia without a known history of diabetes, intensive care unit
(ICU) patients, subjects expected to undergo surgery during the hospitalization course, patients with clinically relevant hepatic disease or impaired renal function (serum creatinine ⱖ3.0 mg/dl), pregnancy, and any
mental condition rendering the subject unable to give informed consent.
This study was conducted at Grady Memorial Hospital in Atlanta,
Georgia, and at Rush University Medical Center in Chicago, Illinois. The
institutional review boards at Emory University and Rush University
approved the study protocol. Informed consent was obtained from all
subjects after explanation and understanding of the nature, purpose, and
potential risks of the study. Insulin management was directed by the
specific assigned protocol and was carried out daily by members of the
internal medicine residency program, a research fellow, or a research
nurse practitioner. The primary care teams decided on the treatment for
all other medical problem(s) for which patients were admitted. No follow-up visit after discharge is included in this study. Patients were randomly assigned to receive either a basal/bolus regimen with detemir and
aspart or a split-mixed regimen with NPH and regular insulin. All oral
antidiabetic drugs were discontinued on admission. Subjects receiving
insulin therapy before admission initially received the same total daily
dose (TDD) unit for unit as their outpatient regimen. Subjects not treated
with insulin before admission were started at a TDD of 0.4 U/kg 䡠 d for
a BG between 140 and 200 mg/dl or 0.5 U/kg 䡠 d for a BG between 201
and 400 mg/dl based on the first BG obtained on the general medical floor
after consent.
Patients treated with detemir/aspart received 50% of TDD as detemir
and 50% as aspart insulin. Detemir was given (using the Flex-Pen) once
daily at the same time of the day. Aspart was given (using the Flex-Pen)
in three equally divided doses with each meal. To prevent hypoglycemia,
if a subject was not able to eat a given meal, the dose of aspart was held.
Insulin dosage was adjusted daily according to BG values. If the fasting
jcem.endojournals.org
565
and predinner BG were between 140 and 180 mg/dl in the absence of
hypoglycemia, the dose of insulin detemir was increased by 10% every
day. If the fasting and predinner BG were above 180 mg/dl in the absence
of hypoglycemia, the insulin detemir dose was increased by 20% every
day. If a patient developed hypoglycemia (BG ⬍60 mg/dl), the dose of
insulin detemir was decreased by 20%. Scheduled mealtime insulin aspart was supplemented for BG greater than 140 mg/dl using the supplemental insulin protocol (Table 1).
Patients treated with NPH/regular insulin received two thirds of TDD
before breakfast and one third of TDD before dinner. The insulin dose
was given as two thirds NPH and one third regular insulin (using vials
and syringes) in the morning with breakfast, and two thirds NPH and one
third regular insulin in the evening with dinner. To prevent hypoglycemia, if a subject was not able to eat a given meal, the dose of regular
insulin was held. If a patient received nothing by mouth all day, the
morning dose of NPH was reduced by 50%. Insulin dosage was adjusted
daily according to BG values. If the fasting and predinner BG were between 140 and 180 mg/dl in the absence of hypoglycemia, the dose of
NPH insulin was increased by 10% every day. If the fasting and predinner BG were above 180 mg/dl in the absence of hypoglycemia, the dose
of NPH insulin was increased by 20% every day. If a patient developed
hypoglycemia (BG ⬍60 mg/dl), NPH dose was decreased by 20%. Supplemental regular insulin was given in addition to scheduled regular
insulin for BG above 140 mg/dl using a supplemental insulin protocol
(Table 1).
BG was measured before each meal and at bedtime (or every 6 h if a
patient was not eating) using a point of care glucose meter. In addition,
BG was measured at any time if a patient experienced symptoms of
hypoglycemia or if requested by the treating physician. Hemoglobin A1C
was measured on the first day of hospitalization. The results of BG values
are presented as premeal glucose, bedtime glucose, and mean daily BG
during the hospital stay after d 1.
The goal of insulin therapy was to maintain premeal and bedtime BG
levels lower than 140 mg/dl while avoiding hypoglycemia. The primary
outcome of the study was to determine differences in glycemic control
between treatment groups as measured by mean daily BG concentration
during the hospital stay. Secondary outcomes include differences between treatment groups in premeal and bedtime glucose levels, number
of hypoglycemic events, length of hospital stay, and mortality rate. Hypoglycemic episodes were classified as major (BG ⬍40 mg/dl or associated with impaired mental status or loss of consciousness), or minor (BG
between 40 and 59 mg/dl) events.
Statistical analysis
Power calculation was conducted based on the data from our previous Rabbit-2 study (19), from which we hypothesized a mean daily BG
difference greater than 30 mg/dl between basal bolus with insulin analogs
vs. split-mixed regimens with human insulins in hospitalized patients
with type 2 diabetes. Assuming a within-group SD of 40 mg/dl and ␣ error
rate of 5%, we estimated that 65 subjects per group (130 total) will be
needed to achieve 80% power.
Statistical analysis was performed using the SPSS software package (SPSS
Inc., Chicago, IL). Cross-sectional comparisons between groups were carried
out using two-sample t-tests. Multiple comparisons across different days on
therapy were adjusted conservatively by using Tukey’s adjustment.
A P value ⬍0.05 was considered significant.
Results
A total of 130 subjects with type 2 diabetes were recruited. After
randomization, 67 patients received insulin detemir once daily
and insulin aspart before meals, and 63 patients received splitmixed regimen with NPH and regular insulin twice daily. The
clinical and demographic characteristics of the treatment groups
were similar at randomization (Table 2). The most common ad-
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Umpierrez et al.
Detemir/Aspart vs. NPH/Regular in Type 2 Diabetes
J Clin Endocrinol Metab, February 2009, 94(2):564 –569
TABLE 1. Insulin treatment protocols
1. Detemir plus aspart insulin treatment orders
A. Insulin-treated patients
Give total outpatient insulin daily dose, one half as detemir and one half as aspart insulin.
Detemir is given once daily, at the same time of the day.
Aspart is given in three equally divided doses before each meal.
To prevent hypoglycemia, if a subject is not able to eat, hold dose of aspart insulin.
B. No insulin-treated patients (diet or oral agents)
Hold oral antidiabetic drugs on admission.
Starting total daily insulin dose:
BG between 140 and 200 mg/dl: 0.4 U/kg 䡠 d
BG between 201 and 400 mg/dl: 0.5 U/kg 䡠 d
Give half of total insulin dose as detemir and half as aspart insulin.
Detemir is given once daily, at the same time of the day.
Aspart is given in three equally divided doses before each meal.
To prevent hypoglycemia, if a subject is not able to eat, hold dose of aspart insulin.
C. Insulin adjustment
If premeal BG ⬍140 mg/dl in the absence of hypoglycemia: no change.
If premeal BG between 140 and 180 mg/dl: increase detemir insulin dose by 10%.
If premeal BG ⬎180 mg/dl: increase detemir insulin dose by 20%.
If BG ⬍60 mg/dl, decrease insulin detemir daily dose by 20%.
D. Supplemental insulin
Give aspart insulin after the supplemental insulin scale before each meal and at bedtime if able to eat, or every 6 h if not able to eat.
2. NPH plus regular insulin treatment orders
A. Insulin-treated patients
Total outpatient insulin daily dose to be given two thirds in the morning and one third in the evening.
Give morning and evening dose as two thirds NPH and one third regular insulin.
To prevent hypoglycemia, if a subject is not able to eat, hold dose of regular insulin.
B. No insulin-treated patients (diet or oral agents)
Hold oral antidiabetic drugs on admission.
Starting total daily insulin dose:
BG between 140 and 200 mg/dl: 0.4 U/kg 䡠 d
BG between 201 and 400 mg/dl: 0.5 U/kg 䡠 d
Give two thirds of total insulin dose in the morning and one third in the evening.
Give morning and evening dose as two thirds NPH and one third regular insulin.
To prevent hypoglycemia, if a subject is not able to eat, hold dose of regular insulin.
C. Insulin adjustment
If premeal BG ⬍140 mg/dl in the absence of hypoglycemia: no change.
If premeal BG between 140 and 180 mg/dl: increase NPH insulin dose by 10%.
If premeal BG ⬎180 mg/dl: increase daily NPH insulin dose by 20%.
If BG ⬍60 mg/dl: decrease NPH insulin dose by 20%.
D. Supplemental insulin
Give short-acting insulin after the supplemental insulin scale before each meal and at bedtime if able to eat, or every 6 h if not able to eat.
3. Supplemental insulin protocol
Before meal: supplemental scale insulin (no. of units)—add to scheduled insulin dose.
Bedtime: give half of supplemental insulin dose.
BG (mg/dl)
Insulin sensitive
Usual
Insulin resistant
ⱖ141–180
181–220
221–260
261–300
301–350
351– 400
⬎400
2
4
6
8
10
12
14
4
6
8
10
12
14
16
6
8
10
12
14
16
18
mitting illnesses included a variety of cardiovascular (35%), infectious (15%), pulmonary (12%), and gastrointestinal (14%)
conditions. The mean hospital length of stay was 6.5 ⫾ 7 d in
patients treated with detemir plus aspart and 7.1 ⫾ 7 d in the
NPH plus regular group 关P ⫽ not significant (NS)兴. There was no
mortality reported in this trial.
The mean admission, pretreatment, and mean daily BG levels
were similar between treatment groups. The mean admission
glucose levels in the detemir/aspart and NPH/regular insulin
treatment groups were 230 ⫾ 102 and 231 ⫾ 145 mg/dl, respectively (P ⫽ NS). BG was 228 ⫾ 54 mg/dl before starting insulin
therapy in the detemir/aspart group and 223 ⫾ 58 mg/dl in the
NPH/regular group (P ⫽ NS). The mean BG level after the first
day of therapy was 160 ⫾ 38 mg/dl in the detemir/aspart group
and 158 ⫾ 51 mg/dl in the NPH/regular group (P ⫽ NS). The
mean daily BG levels are shown for both groups in Fig. 1. The BG
target of less than 140 mg/dl before meals was achieved in 45%
of the detemir/aspart group and in 48% of the NPH/regular
insulin group (P ⫽ NS). BG levels were similar at prebreakfast,
predinner, and bedtime times but were higher before lunch in
both treatment groups (Fig. 2). Differences in mean BG from
morning to evening values in the detemir/aspart group (31 ⫾ 80
mg/dl) were higher but not significantly different than in the
NPH/regular group (15 ⫾ 74 mg/dl) group (P ⫽ NS).
J Clin Endocrinol Metab, February 2009, 94(2):564 –569
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567
TABLE 2. Characteristics of study subjects
No. of patients
Age (yr)
Gender (males/females) (n)
Race (B/W/H)
Body weight (kg)
Body mass index (kg/m2)
Diabetes treatment prior to
admission, n (%)
Insulin
Insulin plus oral agents
Oral agent monotherapy
Multiple oral agents
No pharmacological
agents
BG on admission (mg/dl)
BG prior treatment (mg/dl)
Hemoglobin A1C (%)
Creatinine (mg/dl)
NPH/regular
Detemir/aspart
63
58 ⫾ 10
30/33
39/12/12
99 ⫾ 29
34 ⫾ 13
67
59 ⫾ 10
30/37
44/14/9
91 ⫾ 25
33 ⫾ 8
24 (38)
10 (16)
14 (22)
8 (13)
7 (11)
33 (49)
6 (9)
13 (19)
10 (15)
5 (8)
231 ⫾ 145
223 ⫾ 58
8.1 ⫾ 2
1.1 ⫾ 0.3
230 ⫾ 102
228 ⫾ 54
8.5 ⫾ 2
1.2 ⫾ 0.3
Data are means ⫾ SD. To convert the values for BG from mg/dl to millimoles/liter,
multiply by 0.05551. B, Black; W, White; H, Hispanic.
The mean total daily insulin dose was not significantly higher
in the detemir/aspart group (57 ⫾ 45 U) compared with the
NPH/regular insulin group (45 ⫾ 32 U) (P ⫽ 0.08). The mean
daily dose of detemir insulin given once daily (30 ⫾ 28 U) was
similar to the TDD of NPH insulin (27 ⫾ 20 U) given twice daily.
The TDD of aspart (27 ⫾ 20 U) insulin given before meals was
higher than the dose of regular insulin (18 ⫾ 14 U) that was given
twice daily (P ⬍ 0.05).
Nineteen patients (28.4%) in the detemir/aspart group had a
BG between 40 and 59 mg/dl, and three patients (4.5%) had a BG
below 40 mg/dl. Fifteen patients in the NPH/regular group
(23.8%) had a BG of 40 –59 mg/dl, and one patient (1.6%) had
a BG below 40 mg/dl (P ⫽ 0.20 vs. detemir/aspart group). A total
of 1090 glucose readings were performed in the detemir/aspart
group; of them, 23 readings (2.1%) were 40 –59 mg/dl, and only
three readings (0.3%) were below 40 mg/dl. Of the 1021 BG
FIG. 1. Changes in mean daily BG concentration in patients treated with a basal/
bolus regimen with detemir once daily and aspart before meals (open bars) and
with split-mixed regimen with NPH and regular insulin twice daily (closed bars).
Day 0, Randomization day. Depending on the time of admission, during the
randomization day a patient could have received one or two doses of
NPH/regular insulin or one dose of detemir and one to three doses of aspart
insulin per day. Data are means ⫾ SD.
FIG. 2. Mean BG concentration before breakfast, lunch, dinner, and bedtime in
detemir/aspart group (open circles) and NPH/regular insulin (closed circles).
Differences between treatment groups were not statistically significant. Data are
means ⫾ SE.
readings in the NPH/regular insulin group, 19 (1.9%) were
40 –59 mg/dl, and only two readings (0.2%) were below 40
mg/dl (P ⫽ 0.86 vs. detemir/aspart group). The frequency of
hypoglycemic events in patients treated with insulin or with insulin plus oral agents was higher than in patients not treated with
insulin before admission. Twenty-five of 73 patients (37.3%)
treated with insulin before admission had at least one episode of
BG below 60 mg/dl compared with 14 (24.6%) subjects treated
without insulin (P ⫽ 0.32). There was no significant difference
in the time of day of hypoglycemic events between groups. None
of the episodes of hypoglycemia in either group were associated
with loss of consciousness or seizure.
Discussion
This is the first prospective randomized multicenter trial that
compared the efficacy and safety of a basal/bolus insulin regimen
with detemir once daily and aspart before meals to a standard
split-mixed regimen of NPH and regular insulin in non-critically
ill patients with type 2 diabetes. Both treatment regimens resulted in a rapid and significant improvement in glycemic control
throughout the hospital stay. Starting at a similar BG concentration of approximately 225 mg/dl, the mean BG level after the
first day of hospital stay was 160 ⫾ 38 mg/dl in the detemir/
aspart group and 158 ⫾ 51 mg/dl in NPH/regular insulin group.
However, a BG target below 140 mg/dl before meals was
achieved in less than half of patients in both treatment regimens,
and approximately 30% of patients experienced one or more
episodes of hypoglycemia during the hospital stay. These results
indicate that the basal/bolus regimen with detemir once daily and
aspart before meals results in equivalent glycemic control with
no significant differences in the frequency of hypoglycemia compared with a twice daily split-mixed human insulin regimen with
NPH and regular insulin in patients with type 2 diabetes.
Hyperglycemia in hospitalized patients is a common, serious,
and costly health care problem. Evidence from observational and
interventional studies indicates that hyperglycemia in critical
and noncritical illness is associated with an increased risk of
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Umpierrez et al.
Detemir/Aspart vs. NPH/Regular in Type 2 Diabetes
complications and mortality (1, 9, 21–26). Despite the evidence
that inpatient glycemic control is important and despite guidelines recommending tighter inpatient glycemic control, clinical
practice has been slow to change (27). The University Health
System Consortium (UHC) benchmarking project (28), an alliance of 90 academic health centers across the United States,
showed widespread gaps in processes and outcomes regarding
diabetes care. In the non-ICU setting, sc insulin therapy was
prescribed in 45% of patients, with a range of 12 to 77% across
measured hospitals. In such patients, only 26% of patients had
all BG measurements no greater than 180 mg/dl on the second
measurement day, with a range of 7 to 48%. Other studies have
also provided insight into gaps in diabetes care. Schnipper et al.
(11) examined practices on the general medicine service of an
academic medical center in Boston in 2004. Among patients with
a known diagnosis of diabetes or at least one glucose reading
above 200 mg/dl, they found that scheduled long-acting insulin
was prescribed in only 43% of patients, and 90% of patients
remained on the same sliding-scale insulin regimen despite
widely varying insulin requirements. A study by Cook et al. (29)
reported that among non-ICU patients, 20% of patients had
persistent hyperglycemia (defined as a mean BG ⬎200 mg/dl),
and 46% of such patients did not have their insulin regimen
intensified, a concept that they termed “negative therapeutic momentum.” Concern about hypoglycemia due to altered nutrition
and the presence of associated medical illness is reported as the
leading limiting factor in improving glycemic control in patients
with diabetes (9, 30). In a 3-month prospective review of consecutive medical records in 2174 hospitalized patients receiving
antidiabetic agents, 206 (9.5%) experienced a total of 484 hypoglycemic episodes (31). In a noncritical care setting, factors
that increase the risk of hypoglycemia include treatment with
insulin and sulfonylureas, interruption of carbohydrate intake,
lack of coordination between feeding and medication administration, insufficient frequency in BG monitoring, and failure to recognize changes in insulin requirements due to advanced age, renal
failure, and liver disease. Minimizing the rate of hypoglycemia
events is of major importance in hospitalized patients because it has
been shown to be an independent risk factor of poor clinical outcome (32, 33). In the present study, one fourth of the patients in both
treatment groups had a BG between 40 and 59 mg/dl and 3% had
a BG below 40 mg/dl during the hospital stay. The American Diabetes Association recently recommended a level below 70 mg/dl to
define hypoglycemia (34). Using this definition, we observed that 24
patients (38%) in the NPH/regular insulin group and 29 patients
(43%) in the detemir/aspart group had at least one episode of hypoglycemia (P ⫽ 0.67) during the hospital stay.
We recently reported the results of the Rabbit-2 trial, a prospective, randomized multicenter study comparing the efficacy and
safety of a basal/bolus insulin regimen with glargine once daily and
glulisine before meals and a sliding-scale regular insulin four times
daily in patients with type 2 diabetes in general medicine services
(19). We reported that among 130 insulin-naive patients with a
mean admission BG of 229 ⫾ 6 mg/dl and hemoglobin A1C of
8.8 ⫾ 2%, the use of basal/bolus insulin was superior in improving
BG control to a sliding-scale regimen alone. A BG target below 140
mg/dl was achieved in 66% of patients in the glargine plus glulisine
J Clin Endocrinol Metab, February 2009, 94(2):564 –569
group and 38% in the sliding-scale group. Only two patients (3%)
in the glargine/glulisine group and in the sliding-scale regimen developed a BG below 60 mg/dl, and no patients had a BG below 40
mg/dl during the hospital stay. In this study, the frequency of hypoglycemia with detemir/aspart and NPH/regular insulin was
higher than that reported with the use of glargine and glulisine in the
Rabbit-2 trial. This could be explained in part by the fact that the
Rabbit trial included insulin-naive patients, whereas 56% of subjects in this trial were treated with insulin before admission. In this
study, about 25% of insulin-naive patients and 37% of those
treated with insulin before admission developed one or more episodes of hypoglycemia during the hospital stay.
Several outpatient studies have shown that basal/bolus insulin
regimens facilitate glycemic control with lower rates of hypoglycemic events than NPH/regular insulin (35–38). It is hypothesized that
the use of a long-lasting basal insulin and rapid-acting mealtime
insulin is more physiological and may represent a better alternative
to the use of intermediate and short-acting insulin regimen in hospitalized subjects with type 2 diabetes (9, 12, 18, 39). This study,
however, failed to demonstrate differences in glycemic control between a basal/bolus regimen using detemir/aspart insulin and NPH/
regular regimen in hospitalized subjects with type 2 diabetes. In this
study, less than half of patients in either treatment group achieved
a target BG below 140 mg/dl before meals. The relatively low rate
of BG readings within target could be the result of a relatively high
rate of hypoglycemic events, or in the case of detemir because the
algorithm did not include an option for twice daily dosing of insulin
detemir. Based on the reported pharmacodynamic profile of detemir (about 16-h duration, and a peak from 4 – 8 h), the use of
detemir twice daily may have facilitated a more rapid insulin dose
titration resulting in further improvements in glycemic control.
In summary, treatment with a basal/bolus regimen of detemir
once daily and aspart before meals and a standard split-mixed regimen of NPH and regular insulin results in similar glycemic control
and hypoglycemia outcomes in hospitalized patients with type 2
diabetes. Both regimens may be appropriate alternatives, and the
choice depends on the physician’s preferences, hospital formulary
options, cost considerations, and adequate nursing support.
Acknowledgments
Address all correspondence and requests for reprints to: Guillermo E.
Umpierrez, M.D., Professor of Medicine, Emory University School of
Medicine, 49 Jesse Hill Jr Drive, Atlanta, Georgia 30303. E-mail:
[email protected].
This investigator-initiated study was supported by an unrestricted
grant from Novo Nordisk Pharmaceuticals (Princeton, NJ). G.E.U. is
supported by research a grant from the American Diabetes Association
(7-03-CR-35), National Institutes of Health (NIH) Grant R03
DK073190-01, and General Clinical Research Center Grant M01 RR00039. D.S. is supported by a research grant from the NIH (K12
RR-017643).
The sponsors of the study were not involved in the study design, data
collection, analysis or interpretation of the results, or preparation of the
manuscript.
Disclosure Statement: G.E.U. has received research support from
Novo Nordisk and Sanofi-Aventis. He has received honoraria from
Novo Nordisk and Sanofi-Aventis and is a member of the speakers’
J Clin Endocrinol Metab, February 2009, 94(2):564 –569
bureau for Sanofi-Aventis. D.S. has received honoraria and lecture fees
from Sanofi-Aventis. C.N. is a member of the speakers’ bureau and has
received honoraria and lecture fees from Sanofi-Aventis. T.H. and D.B.
have received grant support from Novo Nordisk. D.B. has received honoraria and lecture fees from Novo Nordisk and from Sanofi-Aventis. The
other authors have nothing to disclose.
References
1. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE 2002
Hyperglycemia: an independent marker of in-hospital mortality in patients
with undiagnosed diabetes. J Clin Endocrinol Metab 87:978 –982
2. Capes SE, Hunt D, Malmberg K, Gerstein HC 2000 Stress hyperglycaemia and
increased risk of death after myocardial infarction in patients with and without
diabetes: a systematic overview. Lancet 355:773–778
3. Estrada CA, Young JA, Nifong LW, Chitwood Jr WR 2003 Outcomes and
perioperative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting. Ann Thorac Surg 75:1392–1399
4. Pomposelli JJ, Baxter 3rd JK, Babineau TJ, Pomfret EA, Driscoll DF, Forse RA,
Bistrian BR 1998 Early postoperative glucose control predicts nosocomial
infection rate in diabetic patients. JPEN J Parenter Enteral Nutr 22:77– 81
5. Kitabchi AE, Freire AX, Umpierrez GE 2008 Evidence for strict inpatient blood
glucose control: time to revise glycemic goals in hospitalized patients. Metabolism 57:116 –120
6. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz
M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R 2001 Intensive insulin
therapy in the critically ill patients. N Engl J Med 345:1359 –1367
7. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC 2001 Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 32:2426 –2432
8. Williams LS, Rotich J, Qi R, Fineberg N, Espay A, Bruno A, Fineberg SE,
Tierney WR 2002 Effects of admission hyperglycemia on mortality and costs
in acute ischemic stroke. Neurology 59:67–71
9. Clement S, Braithwaite SS, Magee MF, Ahmann A, Smith EP, Schafer RG,
Hirsh IB 2004 Management of diabetes and hyperglycemia in hospitals. Diabetes Care 27:553–597
10. Levetan CS, Magee MF 2000 Hospital management of diabetes. Endocrinol
Metab Clin North Am 29:745–770
11. Schnipper JL, Barsky EE, Shaykevich S, Fitzmaurice G, Pendergrass ML 2006
Inpatient management of diabetes and hyperglycemia among general medicine
patients at a large teaching hospital. J Hosp Med 1:145–150
12. Umpierrez GE, Maynard G 2006 Glycemic chaos (not glycemic control) still
the rule for inpatient care. J Hosp Med 1:141–144
13. Queale WS, Seidler AJ, Brancati FL 1997 Glycemic control and sliding scale
insulin use in medical inpatients with diabetes mellitus. Arch Intern Med 157:
545–552
14. Baldwin D, Villanueva G, McNutt R, Bhatnagar S 2005 Eliminating inpatient
sliding-scale insulin: a reeducation project with medical house staff. Diabetes
Care 28:1008 –1011
15. Umpierrez GE, Palacio A, Smiley D 2007 Sliding scale insulin use: myth or
insanity? Am J Med 120:563–567
16. Owens DR, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R 2000 Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection
sites. Diabetes Care 23:813– 819
17. Heinemann L 2002 Variability of insulin absorption and insulin action. Diabetes Technol Ther 4:673– 682
18. Inzucchi SE 2006 Clinical practice. Management of hyperglycemia in the hospital setting. N Engl J Med 355:1903–1911
jcem.endojournals.org
569
19. Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M, Puig A,
Mejia R 2007 Randomized study of basal-bolus insulin therapy in the inpatient
management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care
30:2181–2186
20. Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA 2006 Hyperglycemic
crises in adult patients with diabetes: a consensus statement from the American
Diabetes Association. Diabetes Care 29:2739 –2748
21. Finney SJ, Zekveld C, Elia A, Evans TW 2003 Glucose control and mortality
in critically ill patients. JAMA 290:2041–2047
22. Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL 2002 Is
blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era? J Am Coll Cardiol 40:1748 –1754
23. Norhammar AM, Ryden L, Malmberg K 1999 Admission plasma glucose.
Independent risk factor for long-term prognosis after myocardial infarction
even in nondiabetic patients. Diabetes Care 22:1827–1831
24. Montori VM, Bistrian BR, McMahon MM 2002 Hyperglycemia in acutely ill
patients. JAMA 288:2167–2169
25. Stranders I, Diamant M, van Gelder RE, Spruijt HJ, Twisk JW, Heine RJ,
Visser FC 2004 Admission blood glucose level as risk indicator of death after
myocardial infarction in patients with and without diabetes mellitus. Arch
Intern Med 164:982–988
26. Umpierrez GE, Kitabchi AE 2004 ICU care for patients with diabetes. Curr
Opin Endocrinol 11:75– 81
27. Wexler DJ, Meigs JB, Cagliero E, Nathan DM, Grant RW 2007 Prevalence of
hyper- and hypoglycemia among inpatients with diabetes: a national survey of
44 U.S. hospitals. Diabetes Care 30:367–369
28. Baldwin D, Braithwaite S, Arnold P, Selig P, Brake H, Cuny J, Cerese J 2006
The University Health System Consortium (UHC) Benchmarking Project: evaluation of hospital glycemic control at academic medical centers (AMC). Diabetes 55(Suppl 1):104
29. Cook CB, Castro JC, Schmidt RE, Gauthier SM, Whitaker MD, Roust LR,
Argueta R, Hull BP, Zimmerman RS 2007 Diabetes care in hospitalized noncritically ill patients: more evidence for clinical inertia and negative therapeutic
momentum. J Hosp Med 2:203–211
30. Ben-Ami H, Nagachandran P, Mendelson A, Edoute Y 1999 Drug-induced
hypoglycemic coma in 102 diabetic patients. Arch Intern Med 159:281–284
31. Varghese P, Gleason V, Sorokin R, Senholzi C, Jabbour S, Gottlieb JE 2007
Hypoglycemia in hospitalized patients treated with antihyperglycemic agents.
J Hosp Med 2:234 –240
32. Krinsley JS, Grover A 2007 Severe hypoglycemia in critically ill patients: risk
factors and outcomes. Crit Care Med 35:2262–2267
33. Van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M,
Vlasselaers D, Ferdinande P, Lauwers P 2003 Outcome benefit of intensive
insulin therapy in the critically ill: insulin dose versus glycemic control. Crit
Care Med 31:359 –366
34. 2005 Defining and reporting hypoglycemia in diabetes: a report from the
American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care
28:1245–1249
35. Gerich JE 2004 Insulin glargine: long-acting basal insulin analog for improved
metabolic control. Curr Med Res Opin 20:31–37
36. Kiess W, Raile K, Galler A, Kapellen T 2004 Insulin detemir offers improved
glycemic control compared with NPH insulin in people with type 1 diabetes.
Diabetes Care 27:2567–2568
37. Hermansen K, Madsbad S, Perrild H, Kristensen A, Axelsen M 2001 Comparison of the soluble basal insulin analog insulin detemir with NPH insulin:
a randomized open crossover trial in type 1 diabetic subjects on basal-bolus
therapy. Diabetes Care 24:296 –301
38. Riddle MC, Rosenstock J, Gerich J 2003 The treat-to-target trial: randomized
addition of glargine or human NPH insulin to oral therapy of type 2 diabetic
patients. Diabetes Care 26:3080 –3086
39. Michota F 2007 What are the disadvantages of the sliding scale? J Hosp Medicine 2(Suppl 1):20 –22