American Journal of Therapeutics 0, 1–8 (2019)

Insulin Therapy in Hospitalized Patients

Antonio Perez, MD,PhD,1,2,3* Analia Ramos, MD,PhD,1,2

and Gemma Carreras, MD,PhD2,4

Background: Hyperglycemia is prevalent and is associated with an increase in morbidity and mor-
tality in hospitalized patients. Insulin therapy is the most appropriate method for controlling glyce-
mia in hospital, but is associated with increased risk of hypoglycemia, which is a barrier to achieving
glycemic goals.

Areas of Uncertainty: Optimal glycemic targets have not been established in the critical and non-
critical hospitalized patients, and there are different modalities of insulin therapy. The primary
purpose of this review is to discuss controversy regarding appropriate glycemic targets and sum-
marize the evidence about the safety and efficacy of insulin therapy in critical and noncritical care
settings.

Data Sources: A literature search was conducted through PubMed with the following key words
(inpatient hyperglycemia, inpatient diabetes, glycemic control AND critically or non-critically ill
patient, Insulin therapy in hospital).

Results: In critically ill patient, blood glucose levels .180 mg/dL may increase the risk of hospital
complications, and blood glucose levels ,110 mg/dL have been associated with an increased risk of
hypoglycemia. Continuous intravenous insulin infusion is the best method for achieving glycemic
targets in the critically ill patient. The ideal glucose goals for noncritically ill patients remain unde-
fined and must be individualized according to the characteristics of the patients. A basal-bolus
insulin strategy resulted in better glycemic control than sliding scale insulin and lower risk of
hypoglycemia than premixed insulin regimen.

Conclusions: Extremes of blood glucose lead to poor outcomes, and target glucose range of 110–
180 mg/dL may be appropriate for most critically ill patients and noncritically ill patients.
Insulin is the most appropriate pharmacologic agent for effectively controlling glycemia in
hospital. A continuous intravenous insulin infusion and scheduled basal-bolus-correction insu-
lin are the preferred modalities for glycemic control in critically and noncritically ill hospitalized
patients, respectively.

Key Words: diabetes, inpatient, insulin therapy, critically ill, insulin infusion, basal-bolus insulin

1
Department of Endocrinology and Nutrition, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; 2Universitat Autònoma de Barcelona,
Barcelona, Spain; 3CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain; and 4Department of
Pediatrics, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
A. Perez has served as a consultant for or received research support, lecture fees or travel reimbursement from Sanofi Aventis, Almirall, Novo
Nordisk, Eli Lilly, MSD, Boehringer Ingelheim, Esteve, Gilead, Novartis, Amgen, Menarini, and Astra Zeneca. A. Ramos received research
support or travel reimbursement from Sanofi Aventis and Novo Nordisk. G. Carreras has received research support or travel reimbursement
from Sanofi and Pfizer.
*Address for correspondence: Hospital de la Santa Creu I Sant Pau, C/Mas Casanovas 90, 08041 Barcelona, Spain. E-mail: aperez@santpau.
cat

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 2 Pe rez et al
BACKGROUND
Hyperglycemia is prevalent in hospitalized people,
even among those without a previous history of dia-
betes. It is estimated that approximately 25%–40% of
hospitalized patients have pre-existing diabetes, while
12%–20% of patients experience hyperglycemia with-
out history of diabetes before admission.1 In critically
ill patient populations, approximately 50% of patients
experience hyperglycemia.
The mechanism underlying hyperglycemia is com-
plex and includes metabolic and hormonal changes
associated with increased circulating counterregula-
tory hormones and proinflammatory cytokines and
administration of exogenous corticosteroids, vasopres-
sors, and enteral and parenteral nutrition.2,3
Hyperglycemia in hospitalized patients, with or with-
out known diabetes, is associated with an increase in
complications and mortality, and a longer hospital stay
in patients admitted for surgery or with infections, con-
gestive heart failure, myocardial infarction, and stroke.2,4
The risk of complications and mortality is related to the
severity of hyperglycemia and is even higher in patients
without known diabetes, especially in those with hyper-
glycemia of stress. Moreover, most clinical trials have
reported, in critically ill and in noncritically ill medicine
and surgery patients with hyperglycemia and diabetes,
that improved glycemic control during admission can
reduce the risk of multiorgan failure and systemic infec-
tions, short- and long-term mortality, as well as length of
stay and cost.5–9 However, intensive insulin therapy is
associated with increased risk of hypoglycemia, which
has been independently associated with increased mor-
bidity and mortality in hospitalized patients.9–11 There-
fore, inpatient goals should include the prevention of
both hyperglycemia and hypoglycemia.
The use of oral antidiabetic agents is generally not
recommended in hospitalized patients due to the lim-
ited data available on their safety and efficacy and the
lack of flexibility in adjusting the dose in accordance
with clinical status. Thus, insulin is considered the
most appropriate pharmacologic agent for effectively
controlling glycemia in hospital because it has no abso-
lute contraindications, and it is potent, rapidly effec-
tive, and easily titrated. According to these data,
current clinical guidelines recommend continuous
intravenous insulin infusion in critical care setting
and basal-bolus insulin regimens in noncritical care
setting as the standard of care for hospitalized patients
with hyperglycemia and diabetes.12
In this review, we will discuss controversy regarding
appropriate glycemic targets as well as the insulin
American Journal of Therapeutics (2019) 0(0)
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regimens for the management of patients with hypergly-
cemia and diabetes in critical and noncritical care setting.
MANAGEMENT OF
HYPERGLYCEMIA IN CRITICAL
CARE SETTING
Glycemic targets
During the past 2 decades, glucose goals for critically
ill patients have been moving targets. In the early
2000s, published study by van den Berghe et al,8 inten-
sive intravenous insulin therapy aimed at maintenance
of blood glucose concentration of 80–110 mg/dL in
critically ill adults in surgical intensive care units dem-
onstrated improvements in mortality and morbidity.
However, subsequent studies in medical and mixed
medical/surgical intensive care units showed potential
harm with this approach.7,9,13,14
The 2009 NICE-SUGAR study,9 which examined the
outcomes of 6.104 mixed-type intensive care units pa-
tients, showed that a blood glucose target of 81–108
mg/dL (mean 115 mg/dL) versus 140–180 mg/dL
(mean 144 mg/dL) was associated with increased mor-
tality (27.5% vs. 24.9%) and a higher incidence of
severe hypoglycemia (6.8%. vs. 0.5%). Studies in criti-
cally ill children were also unable to demonstrate any
benefits from tight glucose control and confirm ele-
vated hypoglycemia rates despite measures such as
continuous glucose monitoring and computer-guided
decision making to reduce hypoglycemia.15–18 In
response to data from the NICE-SUGAR study, the
American Diabetes Association and American Associ-
ation of Clinical Endocrinologists have recommended
maintaining glucose levels between 140 and 180 mg/
dL for most critically ill patients,12,19 and lower goals
of 110–140 mg/dL may be reasonable for selected pa-
tients, particularly those undergoing cardiac proce-
dures, if this can be achieved without significant
hypoglycemia.
There is agreement that blood glucose levels .180
mg/dL may increase the risk of hospital complications
and maintaining a blood glucose levels ,180 mg/dL is
considered a safe target. The lower limit for the blood
glucose target is less well established but generally is
recommendable 110 mg/dL to minimize the risks of
hypoglycemia. The GLUCO-CABG study,20 in cardiac
surgery diabetic and nondiabetic patients, has not
shown differences in the rate of complications or mor-
tality comparing intensive glucose target of 100–140
mg/dL to a conservative target of 141–180 mg/dL,
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Hospital Hyperglycemia
but found a significant reduction in complications
among patients without diabetes treated in the inten-
sive glucose target group. Finally, the results of Krins-
ley et al21 support a blood glucose target of 80–140
mg/dL for patients without diabetes and with diabe-
tes when HbA1c was ,7%, but 110–160 mg/dL in
those with A1C levels $7%. In this context, the data
from the van den Berghe study demonstrated that the
benefit of tight glycemic control by intensive insulin
therapy was restricted to patients without diabetes.22
These data, like the established for outpatient diabetes
management, support a potential benefit of a personal-
ized glycemic target in critically ill patients. Additional
prospective interventional studies using continuous
monitoring of blood glucose values are needed to
answer this important question.
Insulin therapy
Critically-ill patients present metabolic instability and
tendency to sudden and important changes in insulin
requirements, which, together with the risk of devel-
oping tissue hypoperfusion, limits the treatment with
subcutaneous insulin. Intravenous infusion of regular
insulin or rapid-acting insulin analogues is the pre-
ferred method of insulin administration in critical care
setting because its immediate onset and short duration
of action allow matching insulin requirements to rap-
idly changing glucose levels.
Continuous intravenous insulin infusion has been
shown to be the best method for achieving glycemic
targets and should be administered based on validated
written or computerized protocols.19,23–25 Several pub-
lished insulin infusion protocols seem to be effective,
but head-to-head comparisons are rare, and efficacy
and safety are difficult to determine because of differ-
ing patient populations, glycemic targets, metrics for
evaluation, and definitions of hypoglycemia used in
the various protocols.26 However, those that use
dynamic scales for the administration of insulin ac-
cording to glycemia usually offer better results in
terms of glycemic control and low frequency of hypo-
glycemia. Areas of variation between protocols include
differences in initiation and titration of insulin, use of
bolus dosing, requirements for calculation in adjust-
ment of the insulin infusion, and method of insulin
protocol adjustments. The main factor that contributes
to the safety of the protocol is the frequency of glyce-
mic monitoring, but there are also other important
ones, such as the use of relatively low infusion rates
in the range of glucose levels close to euglycemia, set
a less stringent goal, at least initially, and contemplate
the action in case of hypoglycemia. Important aspects
to establish a protocol in a specific center include adapt
the protocol to the characteristics of each hospital,
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3
training of physicians and especially nurses in the effi-
cient use of the protocol, identify the blood glucose
threshold to start the infusion and the initial rate of
infusion or initial insulin algorithm, titration based
on both current blood glucose level and rate of change
and predefined adjustments before important changes
in blood glucose and/or situations in which corticoids,
vasopressors, parenteral nutrition, etc., are removed or
added, and a plan for transition to subcutaneous insu-
lin. The protocols that do not need a calculation of
insulin doses (printed with decision columns and com-
puterized protocols) are preferable to those that
require calculations to decide the dose. The protocol
we established in our hospital for all critically care
units is shown in Figure 1.25,27–29 It was adapted from
a protocol initially published by Markovitz et al30 and
consists of 6 algorithms or tables that consider empir-
ically the insulin sensitivity of the patient. Each algo-
rithm consists of a decision table that indicates the
infusion rate of insulin according to the level of blood
glucose. For safety, most patients started in the algo-
rithm 1, and patients with high insulin requirements
started in the algorithm 2. Subsequently, according to
the glycemic response, the same algorithm will be
maintained or it will be changed to a algorithm with
lower or higher insulin infusion rate: to a higher one if
the blood glucose exceeds the established objectives
(140 or 180 mg/dL) for 2 hours and decreases less than
50 mg in 1 hour and to a lower one if the blood glucose
is below the targets (,100 or 120 mg/dL) or lowering
of the glycemia .80 mg/dL in 1 hour. Protocol allows
nurses to immediately implement treatment of hypo-
glycemia without additional orders. The insulin
infusion will be temporarily stopped, glucose admin-
istered, and when adequate glycemia is reached, insu-
lin infusion is restarted at a lower rate. In the future,
combined use of computer-guided therapeutic algo-
rithms and a continuous blood glucose sensor will
likely improve glycemic control without increasing
hypoglycemia and mortality rates.
Transition from intravenous to subcutaneous insulin
therapy
Transfer from intravenous to subcutaneous insulin will
be recommended when the patient is clinically stable,
and transition protocols have been published.27,31–35
The initial dose of subcutaneous insulin at the time
of transition can be determined as 60%–80% of the
intravenous insulin administered the preceding 24
hours. To avoid rebound hyperglycemia after transi-
tion, a sufficient duration of overlap with the insulin
infusion and the subcutaneous insulin is required.
Short-acting insulin can be administered 1–2 hours
American Journal of Therapeutics (2019) 0(0)
 4 Pe rez et al
FIGURE 1. Example of a protocol for hyperglycemia treatment in critically ill patients, adapted from Pe
and long-acting insulin 2–3 hours before intravenous
insulin discontinuation.
MANAGEMENT OF
HYPERGLYCEMIA IN NONCRITICAL
CARE SETTING
Most of studies have demonstrated that inpatient
hyperglycemia, in patients with and without diabetes,
is associated with increased morbidity and mortality in
noncritically ill hospitalized people.2,36–39 However,
the evidence regarding appropriate glycemic targets
is lower, and insulin therapy can be provided by dif-
ferent strategies.
Glycemic targets
The ideal glucose goals for noncritically ill patients
remain undefined, and current recommendations are
based mostly on retrospective studies, clinical experi-
ence, and judgment. Premeal and fasting glycemic tar-
gets are defined as blood glucose values ,140 mg/dL
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rez et al.25
with maximal random blood glucose ,180 mg/dL.1,19
These objectives must be individualized according to
the characteristics of the patients. More stringent tar-
gets may be appropriate in stable patients with pre-
vious tight glycemic control, as long as this can be
achieved without significant hypoglycemia, while
higher glucose ranges may be acceptable in patients
who are at high risk of hypoglycemia or who have
limited life expectancy, as a way of minimizing risk
of hypoglycemia and symptomatic hyperglycemia.1,40
Insulin therapy
There are very limited data available about the efficacy
and safety of noninsulin agent in hospitalized patients
and restricted to dipeptidyl peptidase 4 inhibitors.41–44
Thus, although dipeptidyl peptidase 4 inhibitors in
combination with basal insulin may represent an alter-
native in some patients,41–44 subcutaneous insulin is
the preferred therapeutic agent for glucose control in
general medicine and surgery patients admitted to
outside of critical care units.
Several regimens have been demonstrated to be
effective for maintaining glycemic control, but basal-
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Hospital Hyperglycemia
bolus insulin regimen with reduction or withdrawal of
bolus (prandial) component in people who are not eat-
ing regularly is the preferred method for achieving
and maintaining glucose control in noncritically ill pa-
tients.5,12,45–50 Sliding scale insulin strategy refers to
the administration of the premeal short-acting insulin
dose based on the blood sugar level before the meal.
This kind of rigid application does not deliver insulin
in a physiologic manner and may be associated hypo-
glycemia and hyperglycemia.5,45,51–53 Although sliding
scale insulin is still widely used, prolonged sole use in
the hospital setting is strongly discouraged.51,52,54 Pre-
mixed insulin regimens are not routinely recommen-
ded for in-hospital use due to the increased risk of
hypoglycemia.46
A basal-bolus insulin strategy results in better gly-
cemic control in general medical and surgery patients
with type 2 diabetes compared with sliding scale insu-
lin.5,45 Moreover, basal-bolus treatment reduced hos-
pital complications compared with sliding scale
insulin in general surgery patients with type 2 diabe-
tes.5 A recent study that compared basal-bolus insulin
with glargine and glulisine versus premixed insulin
(70/30 neutral protamine Hagedorn (NPH)/regular
insulin) showed comparable glycemic control but
was stopped early because of a tripling of the rate of
hypoglycemia in the premixed insulin group.46
The basal-bolus regimen with insulin analogues
resulted in equivalent glycemic control and fre-
quency of hypoglycemia compared to treatment
with human insulin in general medicine hospital-
ized patients with diabetes. 47,48 However, NPH
insulin-based basal-bolus regimen has been largely
supplanted by analogue insulin because of a per-
ceived lower risk of hypoglycemia and that NPH
insulin usually cannot be administered once daily.
A small study found that the frequency of nocturnal
hypoglycemia was significantly lower with insulin
glargine 300 units/mL than with insulin glargine
100 units/mL in hospitalized type 2 diabetic pa-
tients.55 Finally, in type 2 diabetic patients treated
with diet, oral antidiabetic agents, or low-dose insu-
lin, basal plus regimen with glargine once daily and
supplemental doses of glulisine for correction of
hyperglycemia compared with a standard basal-
bolus regimen resulted in similar improvement in
glycemic control and in the frequency of hypogly-
cemia.50 Therefore, an insulin regimen with basal,
prandial, and correction components is the pre-
ferred treatment for noncritically ill hospitalized pa-
tients with good nutritional intake and basal insulin
or a basal plus correction for patients with poor oral
intake or those in which oral intake cannot be
assured.12
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5
Patients with insulin-treated diabetes and most of
those with stress-related hyperglycemia require
scheduled in-patient insulin therapy, according their
home diabetes treatment and current nutritional sta-
tus (Figure 2). In patients with type 2 diabetic patients
treated with diet or those with stress-related hyper-
glycemia, scheduled insulin therapy should be insti-
tuted if the preprandial blood glucose concentration
persistently exceeds 180 mg/dL. The starting dose of
basal and nutritional insulin can be calculated based
on home insulin dose, in patients treated with basal-
bolus or premixed insulin regimen or based on body
weight at 0.3–0.5 units/kg/d.5,25,39,45,49,50,56 In thin
elderly patients and those with renal insufficiency,
the initial insulin dose should be lower (#0.3 units/
kg) to reduce the risk of hypoglycemia. Then, the
calculated total daily dose is divided into a 50% as
basal and a 50% as bolus insulin doses. The nutri-
tional component can be divided into 3 equivalent
premeal insulin doses, and correction doses of the
bolus insulin are provided to cover glycemic excur-
sions above the desired range. Daily review of blood
glucose measurements is required to allow for mod-
ification of insulin doses, to achieve the blood glucose
targets.
Type 1 diabetes and CSII therapy in the hospital
Basal-bolus subcutaneous insulin administration is the
most common insulin regimen used on outpatient set-
ting, to mimic the physiological insulin secretion, and
it is also the preferred method for achieving and main-
taining glucose control in case of noncritically ill hos-
pitalization.57 Continuous subcutaneous insulin
infusion (CSII) therapy is being used with increased
frequency in type 1 diabetic patients, and, when these
patients are admitted to the hospital for reasons other
than diabetes, they are often eager to maintain pump
therapy and diabetes self-managing. Current literature
indicates that this practice can be safety and it can be
allowed in some cases.58,59 Hospitals need to deter-
mine whether allow this practice, or it is better to re-
move the pump on admission and deliver the insulin
using an alternative method. At the time of admission,
if the patient requests to continue using the CSII, he or
she must be alert and be able to properly administer
the pump during hospitalization. In addition, it should
be assessed the patient’s ability to calculate and deliver
bolus, to change basal rate, set a temporary rate, and
suspend insulin infusion, as well as their glucose con-
trol before hospitalization. The patient must sign a con-
sent form/agreement that delineates self-management
responsibilities. An endocrinologist or an inpatient
diabetes managing service should verify within 12
hours of admission the insulin pump setting and the
American Journal of Therapeutics (2019) 0(0)
 6 Pe rez et al
FIGURE 2. Initiation of insulin in noncritically ill hyperglycemic patients, adapted from Pe
doses.
patient’s competence with using the pump. If the
patient is not able to self-management or if appropriate
supports are not available, CSII may be discontinued
and a basal-bolus insulin regimen or intravenous insu-
lin infusion may be initiated. An insulin pump should
not be exposed to electromagnetic fields or ionizing
radiation and should be removed before any radiolog-
ical study. If the procedure is expected to be shorter
than 1 hour, the infusion can be temporarily sus-
pended and resume afterward, but if the pump can
be off for a longer period, an alternative insulin deliv-
ery has to be prescribed.
CONCLUSIONS
Improvement of glycemic control can reduce compli-
cations associated with hyperglycemia in hospitalized
patients. Although there is controversy regarding opti-
mal glycemic targets for inpatients, it is clear that ex-
tremes of blood glucose lead to poor outcomes, and
that insulin is the most appropriate pharmacologic
agent for effectively controlling glycemia in hospital.
A continuous intravenous insulin infusion and sched-
uled basal-bolus-correction insulin are the preferred
American Journal of Therapeutics (2019) 0(0)
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rez et al.25 TDD, total daily
modalities for glycemic control in critically and non-
critically ill hospitalized patients, respectively.
The use of insulin infusion protocols with proven
safety and appropriate blood glucose
monitoring minimizes the risk of hypoglycemia. Using
a computerized infusion protocol and a continuous
blood glucose sensor may allow for tighter glycemic
control without increasing hypoglycemia, but addi-
tional prospective interventional studies are needed
to answer this important question and to determine
the potential benefit of individualized glycemic goals
according diabetes characteristics and underlying
condition.
In noncritically ill hospitalized patients, the use of
correction-only (sliding scale) insulin should be dis-
couraged, and the use of noninsulin agents is very
limited. Basal-bolus-correction insulin is the preferred
regimen for patients with good nutritional intake and
basal insulin or basal plus correction for patients with
poor oral intake. Further investigations are needed to
evaluate the efficacy and safety of new basal and pran-
dial insulin analogues during hospitalization and after
hospital discharge and to confirm that implementation
of a computerized decision support system increase
adherence to guidelines and reduce prescription error.
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Hospital Hyperglycemia
REFERENCES
1. Umpierrez GE, Hellman R, Korytkowski MT, et al. Man-
agement of hyperglycemia in hospitalized patients in
non-critical care setting: an endocrine society clinical
practice guideline. J Clin Endocrinol Metab. 2012;97:16–38.
2. Umpierrez GE, Isaacs SD, Bazargan N, et al. Hypergly-
cemia: an independent marker of in-hospital mortality in
patients with undiagnosed diabetes. J Clin Endocrinol
Metab. 2002;87:978–982.
3. Vasa F. Systematic strategies for improved outcomes for
the hyperglycemic hospitalized patient with diabetes
mellitus. Am J Cardiol. 2005;96(4 suppl):41–46.
4. Everett E, Mathioudakis N. Inpatient glycemic manage-
ment of non-cardiac CVD: focus on stroke and PVD.
Curr Diab Rep. 2018;18:49.
5. Umpierrez GE, Smiley D, Jacobs S, et al. Randomized
study of basal-bolus insulin therapy in the inpatient
management of patients with type 2 diabetes undergoing
general surgery (RABBIT 2 surgery). Diabetes Care. 2011;
34:256–261.
6. Furnary AP, Gao G, Grunkemeier GL, et al. Continuous
insulin infusion reduces mortality in patients with dia-
betes undergoing coronary artery bypass grafting.
J Thorac Cardiovasc Surg. 2003;125:1007–1021.
7. Van den Berghe G, Wilmer A, Hermans G, et al. Inten-
sive insulin therapy in the medical ICU. N Engl J Med.
2006;354:449–461.
8. van den Berghe G, Wouters P, Weekers F, et al. Intensive
insulin therapy in critically ill patients. N Engl J Med.
2001;345:1359–1367.
9. NICE-SUGAR Study Investigators, Finfer S, Chittock
DR, Su SYS, et al. Intensive versus conventional glucose
control in critically ill patients. N Engl J Med. 2009;360:
1283–1297.
10. NICE-SUGAR Study Investigators, Finfer S, Liu B, Chit-
tock DR, et al. Hypoglycemia and risk of death in criti-
cally ill patients. N Engl J Med. 2012;367:1108–1118.
11. Griesdale DEG, de Souza RJ, van Dam RM, et al. Inten-
sive insulin therapy and mortality among critically ill
patients: a meta-analysis including NICE-SUGAR study
data. CMAJ. 2009;180:821–827.
12. Association AD. 15. Diabetes care in the hospital: stand-
ards of medical care in diabetes—2019. Diabetes Care.
2019;42(suppl 1):S173–S181.
13. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin
therapy and pentastarch resuscitation in severe sepsis. N
Engl J Med. 2008;358:125–139.
14. Preiser J-C, Devos P, Ruiz-Santana S, et al. A prospective
randomised multi-centre controlled trial on tight glucose
control by intensive insulin therapy in adult intensive
care units: the Glucontrol study. Intensive Care Med.
2009;35:1738–1748.
15. Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin
therapy for patients in paediatric intensive care: a pro-
spective, randomised controlled study. Lancet. 2009;373:
547–556.
www.americantherapeutics.com
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
7
16. Agus MSD, Steil GM, Wypij D, et al. Tight glycemic
control versus standard care after pediatric cardiac sur-
gery. N Engl J Med. 2012;367:1208–1219.
17. Agus MSD, Wypij D, Hirshberg EL, et al. Tight glycemic
control in critically ill children. N Engl J Med. 2017;376:
729–741.
18. Macrae D, Grieve R, Allen E, et al. A randomized trial of
hyperglycemic control in pediatric intensive care. N Engl
J Med. 2014;370:107–118.
19. Moghissi ES, Korytkowski MT, DiNardo M, et al. Amer-
ican Association of Clinical Endocrinologists and Amer-
ican Diabetes Association consensus statement on
inpatient glycemic control. Endocr Pract. 2009;15:353–369.
20. Umpierrez G, Cardona S, Pasquel F, et al. Randomized
controlled trial of intensive versus conservative glucose
control in patients undergoing coronary artery bypass
graft surgery: GLUCO-CABG trial. Diabetes Care. 2015;
38:1665–1672.
21. Krinsley JS, Preiser JC, Hirsch IB. Safety and efficacy of
personalized glycemic control in critically ill patients:
a 2-year before and after intervention trial. Endocr Pract.
2017;23:318–330.
22. Van den Berghe G, Wilmer A, Milants I, et al. Intensive
insulin therapy in mixed medical/surgical intensive care
units: benefit versus harm. Diabetes. 2006;55:3151–3159.
23. Inzucchi SE. Clinical practice. Management of hypergly-
cemia in the hospital setting. N Engl J Med. 2006;355:
1903–1911.
24. Goldberg PA, Siegel MD, Sherwin RS, et al. Implemen-
tation of a safe and effective insulin infusion protocol in
a medical intensive care unit. Diabetes Care. 2004;27:461–
467.
25. Perez Perez A, Conthe Gutierrez P, Aguilar Diosdado M,
et al. Hospital management of hyperglycemia [in Span-
ish]. Med Clin (Barc). 2009;132:465–475.
26. Wilson M, Weinreb J, Hoo GWS. Intensive insulin ther-
apy in critical care a review of 12 protocols. Diabetes Care.
2007;30:1005–1011.
27. Ramos A, Zapata L, Vera P, et al. Transition from intra-
venous insulin to subcutaneous long-acting insulin in
critical care patients on enteral or parenteral nutrition.
Endocrinol Diabetes Nutr. 2017;64:552–556.
28. Paniagua P, Perez A. Repercusiones y manejo de la hi-
perglucemia peroperatoria en cirugía cardiaca. Rev Esp
Anestesiol Reanim. 2009;56:299–311.
29. Zapata L, Vera Artazcoz P, Betbese AJ, et al. Effects of an
IIT protocol in critically ill patients. Intensive Care Med.
2007;33:190.
30. Markovitz LJ, Wiechmann RJ, Harris N, et al. Description
and evaluation of a glycemic management protocol for
patients with diabetes undergoing heart surgery. Endocr
Pract. 2002;8:10–18.
31. Schmeltz LR, DeSantis AJ, Schmidt K, et al. Conversion
of intravenous insulin infusions to subcutaneously
administered insulin glargine in patients with hypergly-
cemia. Endocr Pract. 2006;12:641–650.
32. Bode BW, Braithwaite SS, Steed RD, et al. Intravenous
insulin infusion therapy: indications, methods, and
American Journal of Therapeutics (2019) 0(0)
 8 Pe rez et al
transition to subcutaneous insulin therapy. Endocr Pract.
2004;10(suppl 2):71–80.
33. Avanzini F, Marelli G, Donzelli W, et al. Transition from
intravenous to subcutaneous insulin: effectiveness and
safety of a standardized protocol and predictors of out-
come in patients with acute coronary syndrome. Diabetes
Care. 2011;34:1445–1450.
34. Jacobson LA, Jerguson K, Spiva L, et al. Evaluation of an
intensive insulin transition protocol in the intensive care unit
setting: a before and after study. Pharm Pract. 2012;10:45–51.
35. Olansky L, Sam S, Lober C, et al. Cleveland Clinic car-
diovascular intensive care unit insulin conversion proto-
col. J Diabetes Sci Technol. 2009;3:478–486.
36. McAlister FA, Majumdar SR, Blitz S, et al. The relation
between hyperglycemia and outcomes in 2,471 patients
admitted to the hospital with community-acquired pneu-
monia. Diabetes Care. 2005;28:810–815.
37. Evans NR, Dhatariya KK. Assessing the relationship
between admission glucose levels, subsequent length of
hospital stay, readmission and mortality. Clin Med
(Lond). 2012;12:137–139.
38. Falciglia M, Freyberg RW, Almenoff PL, et al.
Hyperglycemia-related mortality in critically ill patients
varies with admission diagnosis. Crit Care Med. 2009;37:
3001–3009.
39. Lansang MC, Umpierrez GE. Inpatient hyperglycemia
management: a practical review for primary medical
and surgical teams. Cleve Clin J Med. 2016;83(5 suppl
1):S34–S43.
40. Association AD. 14. Diabetes care in the hospital: stand-
ards of medical care in diabetes—2018. Diabetes Care.
2018;41(suppl 1):S144–S151.
41. Umpierrez GE, Gianchandani R, Smiley D, et al. Safety
and efficacy of sitagliptin therapy for the inpatient man-
agement of general medicine and surgery patients with
type 2 diabetes: a pilot, randomized, controlled study.
Diabetes Care. 2013;36:3430–3435.
42. Pasquel FJ, Gianchandani R, Rubin DJ, et al. Efficacy of
sitagliptin for the hospital management of general med-
icine and surgery patients with type 2 diabetes (Sita-
Hospital): a multicentre, prospective, open-label, non-
inferiority randomised trial. Lancet Diabetes Endocrinol.
2017;5:125–133.
43. Vellanki P, Rasouli N, Baldwin D, et al. Glycaemic effi-
cacy and safety of linagliptin compared to basal-bolus
insulin regimen in patients with type 2 diabetes under-
going non-cardiac surgery: a multicenter randomized
clinical trial. Diabetes Obes Metab. 2018. doi:10.
1111/dom.13587 [Epub ahead of print].
44. Umpierrez GE, Cardona S, Chachkhiani D, et al. A ran-
domized controlled study comparing a DPP4 inhibitor
(linagliptin) and basal insulin (glargine) in patients with
type 2 diabetes in long-term care and skilled nursing
facilities: linagliptin-LTC trial. J Am Med Dir Assoc.
2018;19:399–404.e3.
45. Umpierrez GE, Smiley D, Zisman A, et al. Randomized
study of basal-bolus insulin therapy in the inpatient
American Journal of Therapeutics (2019) 0(0)
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
management of patients with type 2 diabetes (RABBIT
2 trial). Diabetes Care. 2007;30:2181–2186.
46. Bellido V, Suarez L, Rodriguez MG, et al. Comparison of
basal-bolus and premixed insulin regimens in hospital-
ized patients with type 2 diabetes. Diabetes Care. 2015;38:
2211–2216.
47. Bueno E, Benitez A, Rufinelli JV, et al. Basal-bolus regimen
with insulin analogues versus human insulin in medical
patients with type 2 diabetes: a randomized controlled
trial in Latin America. Endocr Pract. 2015;21:807–813.
48. Umpierrez GE, Hor T, Smiley D, et al. Comparison of
inpatient insulin regimens with detemir plus aspart ver-
sus neutral protamine hagedorn plus regular in medical
patients with type 2 diabetes. J Clin Endocrinol Metab.
2009;94:564–569.
49. Perez A, Reales P, Barahona MJ, et al; HOSMIDIA Study
Group. Efficacy and feasibility of basal-bolus insulin reg-
imens and a discharge-strategy in hospitalised patients
with type 2 diabetes—the HOSMIDIA study. Int J Clin
Pract. 2014;68:1264–1271.
50. Umpierrez GE, Smiley D, Hermayer K, et al. Random-
ized study comparing a Basal-bolus with a basal plus
correction insulin regimen for the hospital manage-
ment of medical and surgical patients with type 2 dia-
betes: basal plus trial. Diabetes Care. 2013;36:2169–
2174.
51. Hirsch IB. Sliding scale insulin—time to stop sliding.
JAMA. 2009;301:213–214.
52. Lee YY, Lin YM, Leu WJ, et al. Sliding-scale insulin used
for blood glucose control: a meta-analysis of randomized
controlled trials. Metabolism. 2015;64:1183–1192.
53. Umpierrez GE, Palacio A, Smiley D. Sliding scale
insulin use: myth or insanity? Am J Med. 2007;120:
563–567.
54. Baldwin D, Villanueva G, McNutt R, et al. Eliminating
inpatient sliding-scale insulin. Diabetes Care. 2005;28:
1008–1011.
55. Okajima F, Nakamura Y, Yamaguchi Y, et al. Basal-bolus
insulin therapy with Gla-300 during hospitalization re-
duces nocturnal hypoglycemia in patients with type 2
diabetes mellitus: a randomized controlled study. Diabe-
tes Ther. 2018;9:1049–1059.
56. Mader JK, Neubauer KM, Schaupp L, et al. Efficacy,
usability and sequence of operations of a workflow-
integrated algorithm for basal-bolus insulin therapy in
hospitalized type 2 diabetes patients. Diabetes Obes
Metab. 2014;16:137–146.
57. Yogi-Morren D, Lansang MC. Management of patients
with type 1 diabetes in the hospital. Curr Diab Rep. 2014;
14:458.
58. Wallia A, Umpierrez GE, Rushakoff RJ, et al. Consensus
statement on inpatient use of continuous glucose moni-
toring. J Diabetes Sci Technol. 2017;11:1036–1044.
59. Thompson B, Korytkowski M, Klonoff DC, et al. Consen-
sus statement on use of continuous subcutaneous insulin
infusion therapy in the hospital. J Diabetes Sci Technol.
2018;12:880–889.
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