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Authors: Merete B. Christensen, MD; Anders Gotfredsen, DMSc; Kirsten Nrgaard, DMSc
Denmark
Corresponding author:
Merete B. Christensen
Department of Endocrinology
Kettegrds All 30
2650 Hvidovre
Denmark
Telephone: +45 23 81 12 64
E-mail: Merete.bechmann.christensen.01@regionh.dk
Fax: +45 38 62 61 34
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/dmrr.2885
inpatient management of non-critically ill patients with type 2 diabetes: A systematic review
longer hospital stays and various insulin regimes are used in the inpatient diabetes
management. In this systematic review and metaanalysis we aimed to assess the efficacy and
safety of basal-bolus insulin therapy in the management of hospitalized non-critically ill type
2 diabetes patients. Five RCTs and seven observational studies comparing basal-bolus insulin
(BBI) therapy to sliding scale insulin (SSI) therapy were included in the review. Meta-
analysis of RCTs showed significantly lower mean daily blood glucose with BBI than SSI,
but basal-bolus insulin therapy was associated with increased risk of mild hypoglycemia.
complications and longer hospital stays. Various insulin regimens are used in the inpatient
diabetes management of non-critically ill patients. We aimed to assess the efficacy and safety
of basal-bolus insulin therapy (BBI) by summarizing evidence from studies of BBI versus
sliding scale insulin therapy (SSI) in the management of hospitalized non-critically ill type 2
diabetes patients.
Methods: We searched MEDLINE, EMBASE, Scopus and the Cochrane Library for studies
comparing BBI therapy with SSI therapy in hospitalized non-critically ill patients with type 2
diabetes. Primary outcome was mean daily blood glucose (BG) during admission. Secondary
outcomes were incidence of hypoglycemia and length of hospital stay. Results of included
randomized controlled trials (RCT) were pooled and meta-analyzed to provide estimates of
Results: Five RCTs and seven observational studies were included in the review. Meta-
analysis of RCTs showed significantly lower mean daily BG with BBI than SSI. Mean
difference in daily BG between the two regimens ranged from 14 29 mg/dl. BBI therapy
was associated with increased risk of mild hypoglycemia (BG70 mg/dl, RR 5.75; 95% CI
2.79-11.83), (BG60 mg/dl, RR 4.21; 95% CI 1.6111.02) compared with SSI therapy. There
was no difference in risk of severe hypoglycemia (BG40 mg/dl) and no difference in mean
length of stay.
lower mean daily BG than sliding scale insulin but is associated with increased risk of mild
hypoglycemia.
INTRODUCTION:
The prevalence of diabetes among hospitalized patients is high. One out of four hospitalized
patients has diabetes [13], thus treating hyper- or hypoglycemia represents an everyday
increased rate of complications [3] and longer hospitals stays [4], hence the inpatient care of
diabetes patients accounts for a substantial proportion of total health costs [5].
The role of glucose control during hospitalization has been a subject of debate recently, as
has the choice of insulin regimens. The first landmark trials on glycemic targets were carried
out in intensive care units. Van den Berge et al. reported that intensive insulin treatment with
a glycemic goal of 110 mg/dl (6.2 mmol/L) reduced in-hospital morbidity and mortality [6]
however, subsequent trials failed to confirm this finding of reduced mortality with intensive
Only few randomized trials have studied glycemic targets in non-critically ill patients. Murad
et al. found in a systematic review and meta-analysis of randomized and observational studies
of non-critically ill patients with hyperglycemia that intensive glycemic control (using a
variable of insulin regimens) reduced the risk of hospital acquired infections but found no
effect on mortality [8]. A target glucose range of 140180 mg/dL (7.810.0 mmol/L) is now
recommended in the recent American Diabetes Association (ADA) guidelines for the
Insulin is the preferred treatment of hospitalized patients with sustained hyperglycemia and
several different insulin regimens are used worldwide. An insulin regimen with basal insulin
1-2 times daily and bolus insulin at the main meals is recommended by ADA for the inpatient
correction insulin when blood glucose is above target, is strongly discouraged. However,
sliding scale insulin is still used in many countries. The reason for the persistent use of
sliding scale insulin regimens is unclear, and may simply be due to clinical inertia.
In this systematic review and meta-analysis we aim to assess the efficacy and safety of basal-
bolus insulin regimens for the inpatient management of non-critically ill patients with type 2
diabetes by summarizing all available evidence from randomized controlled trials (RCT) and
METHODS:
Data Sources and Searches: We searched MEDLINE, EMBASE, Scopus and the Cochrane
Library using the following search terms: Type 2 diabetes, hyperglycemia, hospitalization,
inpatient, insulin, basal-bolus and sliding scale. The complete search for MEDLINE was
Manual searches included scanning of reference lists in relevant papers and conference
Study Selection: Two authors (MC and KN) independently screened all titles and abstracts
identified through the search strategies. Studies included in this meta-analysis and review
were RCTs, observational studies and retrospective studies. We searched for studies
fast-acting insulin) with sliding scale insulin (SSI) for the treatment of hyperglycemia during
hospitalization of non-critically ill patients with type 2 diabetes. SSI was defined as
subcutaneous insulin regimens using fast-acting insulin alone for the treatment of
hyperglycemia. Only studies with adult patients were included and the studies had to measure
the outcomes of interest. Studies were excluded if conducted in intensive care units or in
Data extraction and Quality Assessment: Data were extracted using a standard data
extraction form. Two authors (MC and KN or MC and AG) independently extracted the data
and differences were resolved by consensus. If relevant data were not included in the
published study reports, the authors were contacted for further information. The risk of bias
in RCTs was assessed as recommended in the Cochrane Handbook for Systematic Reviews
incomplete outcome, selective reporting and other) was scored as low risk, unclear or high
risk.
Data Synthesis and Analysis: Primary outcome was mean daily blood glucose. Secondary
outcomes were hypoglycemic events, mean length of stay and total daily insulin dose. Only
RCTs are included in the meta-analysis. Data from observational studies are presented as a
Studies were analyzed using the mean and SD of change for the intervention period of each
study. For the meta-analysis we used both a fixed effect model and a random effects model.
Since no discrepancy was found between the two models, only results from the random
effects model are presented. Heterogeneity was assessed using the I2 statistics, which
heterogeneity rather than sampling error. Data analyses were performed using the software
Review Manager 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration,
Copenhagen, Denmark). Due to the small number of trials we did not conduct meta-
RESULTS:
Study identification: Through electronic literature search 817 studies were identified. Title
and abstract was screened and 756 studies were considered irrelevant. The full texts of the
remaining 61 articles were reviewed. Twelve of these studies met the inclusion criteria and
were eligible for inclusion in the systematic review. The study selection process is illustrated
in Fig. 1.
Study characteristics and quality assessment: Five studies were RCTs [1014], two were
observational, prospective studies with historical controls [15,16] and five were retrospective
studies [1721]. Characteristics of the included studies are presented in Table 1, including
number and mean age of patients, mean admission blood glucose and mean HbA1C. All
studies were done in a non-ICU setting. Six were done in medical wards, three were done in
surgical wards and three reported results from both medical and surgical wards. Eight studies
included only patients with known history of type 2 diabetes. Two studies included a few
patients with type 1 diabetes and four studies also included patients with hyperglycemia
without known history of diabetes. Two studies did not specify type of diabetes. All studies
compared basal-bolus treatment with sliding scale treatment. In some studies sliding scale
on to the patients preadmission therapy which in a few cases included basal insulin. Insulin
glargine was used as basal insulin in seven studies; NPH insulin was used in four studies and
in one retrospective study both types of insulin was used. The total daily starting dose of
insulin for basal-bolus treatment varied from 0.25 U/kg to 0.50 U/kg.
None of the studies were blinded since blinding of patients and study personnel was not
feasible in any of the included studies and all RCTs had a high risk of bias in at least one
domain. The retrospective studies were heterogeneous and had a potential risk of
confounding, however; lack of reported information made it impossible to assess the risk of
Glycemic control: Meta-analysis of mean daily blood glucose in the RCTs showed
significantly lower mean blood glucose in the BBI group than in the SSI group (Fig. 2). The
mean difference in daily blood glucose between the two treatment regimens ranged from 14
to 29 mg/dl (0.8 1.6 mmol/L). Heterogeneity (I2) between the studies was moderate (43%).
Overall basal-bolus therapy reduced the mean daily blood glucose significantly more than
sliding scale insulin therapy in 11 of the 12 included studies. Six studies reported data on the
number of patients achieving glycemic target [1013,15,19]. In all of them significantly more
patients treated with BBI had blood glucose values within the glycemic target range during
their hospital stay than patients treated with SSI (BBI range: 34% - 66%, SSI range: 23% -
50%).
Surgery patients had lower mean daily blood glucose than patients at medical wards,
however; patients at surgical wards generally had lower mean admission blood glucose and
associated with increased risk of mild hypoglycemia (BG 70 mg/dl (3.9 mmol/L), RR 5.75;
95% CI 2.79-11.83), (BG 60 mg/dl (3.3 mmol/l), RR 4.21; 95% CI 1.6111.02) compared
with SSI therapy. No statistical heterogeneity was found (I2 = 1%). There was no significant
difference in the risk of severe hypoglycemia (BG 40 mg/dl (2.2 mmol/L)) between the two
treatment regimens (Fig. 3). However there were only few events of severe hypoglycemia (6
patients out of 633 patients), all of them occurring in the BBI group.
Overall the incidence of hypoglycemia in the included studies ranged from 2 % to 29 %. Six
studies reported significantly more episodes of hypoglycemia in patients treated with basal-
bolus therapy than in patients treated with sliding scale [13,1517,21,22]. Two retrospective
BBI-treated patients [18,21]. The remaining four studies found no significant difference in
hypoglycemic episodes between the two treatment regimens [10,14,16,17]. The definition of
hypoglycemia was not consistent in all included studies. Some studies only reported episodes
of mild hypoglycemia and other studies reported episodes of both mild and severe
hypoglycemia. Three RCTs reported BG values 70 mg/dl (3.9 mmol/L) [1113], and four
RCTs reported BG values 60 mg/dl (3.3 mmol/L) and BG values 40 mg/dl (2.2 mmol/L)
the two treatment groups, but did not report the number of hypoglycemic episodes [14].
Length of stay: The meta-analysis found no overall difference in mean length of stay
between the two treatment regimens. Difference in mean length of stay varied from 0.1 to 0.5
days in the RCTs. Overall two studies found significantly shorter length of stay for BBI-
treated patients than SSI-treated patients [14,20] and one study found significantly shorter
length of stay for SSI-treated patients than BBI-treated patients [15]. One retrospective study
the two groups. The remaining 7 studies found no significant difference in length of stay
wound infection, pneumonia, bacteremia, respiratory failure and acute renal failure [11]. In
contrast Schroeder et al. found no difference in postoperative complication between the BBI
group and the SSI group [14]. Due to the small number of studies no meta-analysis was done
Total daily insulin dose: The total daily insulin dose was higher for the BBI groups than for
the SSI groups. Total daily insulin dose ranged from 12.5 to 55.6 U/kg/day for the BBI
groups and ranged from 3.1 to 35.2 U/kg/day for the SSI groups.
DISCUSSION:
In the present meta-analysis of RCTs we have demonstrated that basal-bolus insulin therapy
significantly reduces mean blood glucose in non-critically ill hospitalized patients with type 2
diabetes and/or hyperglycemia, compared to traditional sliding scale insulin. This result is
supported in all the observational studies, except one retrospective study. As a side effect the
with basal-bolus treatment but no difference in incidence of severe hypoglycemia was found.
also included some patients with type 1 diabetes or patients with hyperglycemia without a
diagnosis of diabetes. However, this heterogeneity might very well reflect the usual clinical
setting in general medical and surgical wards in most hospitals, why it should not be seen as
The insulin algorithm used for basal-bolus insulin treatment and adjustment varied in the
included studies. Insulin starting dose varied from 0.25 U/kg to 0.50 U/kg and different
titration algorithms were used. Both could have a significant influence on mean blood
glucose and the risk of hypoglycemia, but the heterogeneity of these algorithms makes it
our knowledge no studies or reviews have examined the effect of insulin starting dose or
insulin titration algorithm on achieved mean blood glucose during hospitalization. One study
indicated that electronic insulin orders improved mean blood glucose, but different insulin
length of hospital stay. Increased glycemic variability has also been associated with increased
length of stay in patients with type 2 diabetes [23]. In this review we found no consistent
association between insulin regimen and length of stay. SSI treatment might result in greater
glycemic variability than BBI treatment, but none of the included studies have included
continuous glucose monitoring to analyze that aspect. Only two of the included studies
reported outcome on postoperative complications and only one of these found a benefit of
described in several other trials. In a recent randomized controlled trial of coronary artery
bypass grafting (CABG) patients by Umpierrez et al. intensive insulin therapy (target 100 -
140 mg/dl) did not significantly reduce perioperative complications after CABG surgery
Boreland et al. found in their systematic review that maintaining BG levels 200 mg/dl with
continuous insulin infusions in all stages of the perioperative period in cardiac surgery
patients with diabetes reduced the incidence of surgical site infection [25]. The association
patients has only been described in a few studies. In a systematic review and meta-analysis
Murad et al. found that intensive glycemic control was associated with decreased risk of
infections, a finding that was mainly derived from studies in surgical settings [8].
All studies included in this present review reported hypoglycemia as a secondary outcome;
however the definition of hypoglycemia varied between studies. There was a wide range in
the incidence of mild hypoglycemia. Only 3 % of BBI treated patients had an episode of
hypoglycemia in the RABBIT study by Umpierrez et al. In contrast 29% of BBI treated
patients experienced hypoglycemia in the study by Mader et al. The starting insulin dose and
the used insulin titration algorithm might have influenced the risk of hypoglycemia. None of
the included studies reported data on beta cell function and only three studies reported data
on diabetes duration. Diabetes duration was not reported in the RABBIT study, but all
patients were insulin nave. Mader et al. included patients with preadmission therapy with
OADs and/or insulin, and the patients had mean diabetes duration of 13 years. Long diabetes
duration is associated with decreased beta-cell function, which could make the patients more
higher risk of hypoglycemia than others. Factors associated with higher risk of hypoglycemia
include older age, decreased kidney function, low body weight and reduced nutritional intake.
To minimize the risk of hypoglycemia it is important to pay attention to these factors and
insulin regimens, but mortality was reported as an outcome in two studies. In these two
studies only three events occurred (two in BBI group and one in SSI group).
The relationship between hypoglycemia and mortality in critically ill patients at intensive
care units have been described in several studies, but only a few have studied non-critically ill
patients at general wards. One retrospective cohort study by Turhin et al. analyzed data from
4,386 admissions of diabetic patients at general non-ICU wards. They defined hypoglycemia
as BG 50 mg/dl (2.8 mmol/L) and found that inpatient hypoglycemia was associated with
increased length of stay and increased inpatient mortality. Inpatient mortality was 2.96 % for
patients who had at least one hypoglycemic episode during the hospital stay versus 0.82 %
for patients who had no hypoglycemic episodes [26]. However this study did not differentiate
another retrospective cohort study of non-critically ill patients (with and without diabetes) at
general wards that only spontaneous and not drug-associated hypoglycemia (BG 70 mg/dl
(3.9 mmol/L)) was linked to increased mortality risk [27]. After adjustment for patient
eliminated. This suggests that hypoglycemia could be a marker of disease burden rather than
Our systematic review and meta-analysis has several strengths. It is the first review to
evaluate the efficacy and safety of basal-bolus insulin treatment compared to sliding scale
insulin and the first to include a meta-analysis of all RCTs. The strength of this review also
includes the comprehensive literature search which allows us to summarize all the available
information on this topic. Our review also has some limitations. Only few RCTs have been
published and the inclusion of observational studies increases the risk of bias and complicates
the comparison of included studies due to the heterogeneity in study design. The individual
subgroup analysis. Due to the relatively small number of RCTs included in the meta-
The findings of the present study support the need for further trials addressing the problems
aid devices could help to reduce the rate of hypoglycemia with the use of insulin-on-board
calculators, as described in the Gluco-Tab system [28]. The possibility to enter intake of
carbohydrates in the decision-aid device might also be helpful to guide insulin dosage to
patients with reduced nutritional intake. Another approach to reduce the risk of hypoglycemia
could be the use of the new ultra-long acting basal insulins, which in outpatient studies have
shown a reduced risk of nocturnal hypoglycemia [29]. We suggest that future studies could
evaluate these new basal insulins for the inpatient diabetes management and further study
In conclusion, basal-bolus insulin treatment for non-critically ill hospitalized patients with
diabetes efficiently reduces the mean daily blood glucose, but is associated with an increased
risk of mild hypoglycemia. There was no statistical significant difference in the risk of severe
hypoglycemia and no difference in length of hospital stay between the basal-bolus group and
the sliding scale group. Further randomized trials are needed to address the problem of
hypoglycemia.
The authors would like to thank Bianca Hemmingsen for statistical assistance with the meta-
analysis. We also wish to thank Thomas Almdal for helpful comments on an earlier version
of the manuscript.
Funding: None
Author Contributions: MC undertook the literature search. MC, AG and KN reviewed the
abstracts and full articles, extracted data and analyzed data. MC and KN wrote the
manuscript. All authors designed the study, contributed to the discussion and critically
reviewed the final manuscript. KN is the guarantor of this work and, as such, had full access
to all the data in the study and takes responsibility for the integrity of the data and the
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Author/year Population and setting Sample size Mean Mean Mean Intervention Control Glycemic target Mean length
a) a) a)
Diabetes type (Intervention age HbA1C admission Regimen and insulin type Regimen and insulin (mg/dl) of stay
b) b)
Pre-admission treatment group/ (Years) (% BG Insulin starting dose type (days)
c) b)
Setting Control group) (mmol/mol)) (mg/dl) (TDD: Total daily dose) Insulin starting
instructions
Retrospective studies:
a) a) a)
Harbin et al Type 1(17%) + type 2(83%) 46/41 69 9 NR 164 BBI:NPH x 2 + SSI: Insulin type not 90 - 144 BBI: 15.4 14
b)
(2015) Insulin OAD Regularx3 reported (some SSI: 13.0 11
c) b)
Vascular surgery unit Starting dose = pre- patients also received
admission TDD long-acting insulin)
b)
NR
a) a) a)
Chen et al Known history of diabetes, 89/409 69.7 7.5 (58) 195 90 BBI: Glargine/NPH x 1 + SSI: Insulin type not 80 - 150 BBI: 6.2 4
(2010) type unknown Aspart/regular x 3 reported SSI: 7.4 8.7
b) b)
NR NR
c)
Medical ward?
a) a) a)
Patel et al Type 1 + type 2 + 210/121 67.8 7.1 (54) F-BG: BBI: Glargine x 1 + SSI: Insulin type not 80 - 150 NR
(2009) undiagnosed diabetes 183 92 Aspart/regular x 3 reported
b) b)
NR NR
c)
Medical ward
a) a) a)
Akhtar et al Type 2 138/186 51 NR NR BBI: NPH + short acting SSI: Regular NR BBI: 7.8 1.9
b) b)
(2014)* Diet or OAD insulin NR SSI: 15.5 3.6
c)
Medical ward
a) a) a)
Zaman et al Type 2 159/179 NR 11.7 (104) 219 167 BBI: NPH + Actrapid SSI: Actrapid NR Mean for both
b) b)
(2014) NR NR groups: 7.9 6
c)
Medical ward
SSI: Sliding scale insulin, NR: Not reported, OAD: Oral antidiabetic agents.
*These trials have three treatment arms; only BBI and SSI arms are described here.
of severe hypoglycemia (BG 40 mg/dl). BBI: Basal-bolus insulin, SSI: Sliding scale