This article discusses the potential role of glucagon-like peptide-1 (GLP-1) or its analogues in enhancing glycemic control in critically ill adult patients. It notes that intravenous insulin therapy is currently the standard treatment for hyperglycemia in ICU patients but has limitations, including risk of hypoglycemia and difficulties maintaining tight glycemic control. The article reviews studies on insulin therapy and outcomes in ICU patients and discusses factors that can complicate glycemic management. It suggests GLP-1 or its analogues administered intravenously may be a useful alternative or addition to insulin therapy for acute hyperglycemia in ICU patients.

1. review article
Diabetes, Obesity and Metabolism 13: 118–129, 2011.
© 2010 Blackwell Publishing Ltd
article
review
The potential role of glucagon-like peptide-1 or its
analogues in enhancing glycaemic control in critically ill
adult patients
J. Combes, S. Borot, F. Mougel & A. Penfornis
´
Department of Endocrinology-Metabolism and Diabetology-Nutrition, Jean Minjoz Hospital, University of Franche-Comte, Boulevard Fleming, Besancon, France
¸
Intravenous insulin therapy is the gold standard therapy for glycaemic control in hyperglycaemic critically ill adult patients. However,
hypoglycaemia remains a major concern in critically ill patients, even in some populations who are not receiving infused insulin. Furthermore,
the influence of factors such as glycaemic variability and nutritional support may conceal any benefit of strict glycaemic control on morbidity and
mortality in these patients. The recently revised guidelines of the American Diabetic Association/American College of Clinical Endocrinologists
no longer advocate very tight glycaemic control or normalization of glucose levels in all critically ill patients. In the light of various concerns over
the optimal glucose level and means to achieve such control, the use of glucagon-like peptide-1 or its analogues administered intravenously
may represent an interesting therapeutic option.
Keywords: acute hyperglycaemia, exenatide, GLP-1 analogues, glycaemic control, insulin intensive management, intravenous insulin therapy,
type 2 diabetes mellitus
Date submitted 3 January 2010; date of first decision 9 February 2010; date of final acceptance 26 September 2010
Introduction instability of the patients, and the myriad examinations and
treatments that they require. Furthermore, the occurrence of
The prevalence of diabetes among hospitalized adults is poorly
severe hypoglycaemia, the main complication of IIT, is also
documented. In the USA, it is estimated to be between
problematic [7,16,17].
5 and 30–35% [1]. According to various reports, 19–27%
In addition, there is some controversy as to whether there
of patients hospitalized for acute conditions [e.g. severe
is any direct benefit of insulin therapy on morbidity and
infection, surgery or intensive care unit (ICU) admission with
mortality, independently of its effect on glycaemia. We cannot
significant stress response] have documented type 2 diabetes
exclude from this debate the deleterious impact on mortality
mellitus (T2DM), whereas previously undiagnosed diabetes
secondary to severe hypoglycaemia or excessive glycaemic
or stress hyperglycaemia is diagnosed at hospital admission
variability, which could overshadow the survival benefit of
in an additional 12–18% [2–4]. This may be a significant
the insulin therapy [5,13,18–21]. Finally, other factors, such
underestimation of the true incidence of T2DM or prediabetes
as mode of nutritional support or the variability between
in the heterogeneous critically ill population. Several studies
glucose measurement methods also compound the difficulty of
have shown the benefits of tight glycaemic control (TGC),
obtaining TGC [22,23]. These factors constitute obstacles to the
i.e. maintaining glycaemia at normal levels between 80 and
efficacious application of IIT and have probably contributed
110 mg/dl (4.4–6 mmol/l), in certain situations of temporary
to the conflicting evidence about the benefits of TGC on
acute glycaemic imbalance in patients with T2DM or stress
morbidity and mortality rates reported in several studies. The
hyperglycaemia [5–14].
issue of the risk/benefit ratio of TGC and methods to obtain
Continuous intravenous insulin therapy (IIT) represents
it remain at the heart of the current controversy over ideal
a reasonable approach to achieve target blood glucose (BG)
glucose management in the ICU.
levels. However, several obstacles hamper the effective use
Glucagon-like peptide-1 (GLP-1) is one of a family of
of this therapy, particularly in ICUs, where IIT imposes
intestinal factors named incretins, which stimulate insulin
many constraints, as well as an extra workload, as it is time
production in response to nutrient intake. Through its
consuming [15]. Complex glucose management algorithms are
multiple glucose-regulating effects, GLP-1 plays an essential
difficult to apply consistently in these settings, because of the
role in maintaining glucose homeostasis. GLP-1 administered
intravenously rapidly lowers glycaemia without the risk of
Correspondence to: Alfred Penfornis, Department of Endocrinology-Metabolism and hypoglycaemia [24]. The use of GLP-1 or its analogues could
´
Diabetology-Nutrition, Jean Minjoz Hospital, EA 3920, University of Franche-Comte,
Boulevard Fleming, Besancon 25000, France.
¸ become a useful alternative or adjunct to IIT in the future in
E-mail: alfred.penfornis@univ-fcomte.fr acute hyperglycaemic ICU patients.

2. DIABETES, OBESITY AND METABOLISM review article
Intravenous Insulin Therapy Similarly, Goldberg et al. [7,33] estimate that the application
of IIT protocols creates an extra workload of around 5 min/h
Several studies have shown that continuous IIT is the optimal
for nurses (hourly monitoring of BG, modification of insulin
route of administration in certain cases of transitory glycaemic
dose, and data entry in the patient’s file) and this can be
imbalance in patients with T2DM or stress hyperglycaemia.
incompatible with the already high workload in certain ICUs.
Its effect on glycaemic control is more rapid, more stable
Finally, patient testing and procedures, changes in feeding
and more reliable, and hypoglycaemia is less intensive and
protocols, evolution of the initial disease and the possible
less frequent than after repeated subcutaneous injections of
presence of co-morbidities combine to render problematic the
insulin [5]. However, IIT does pose some practical problems
permanent and efficacious implementation of IIT protocols to
in terms of feasibility and hypoglycaemia. BG measurement in
reach TGC. Similarly, Wilson et al. [34] noted a wide variability
this setting requires reliable methods and nutritional support
in practice in this area and concluded that one standard
can complicate the task of reaching target BG levels [22,23]. It
protocol might not be suitable for all patients. According
remains debated whether there is currently sufficient benefit
to Goldberg et al. [7], Kanji et al. [30] and Barth et al.[31],
to IIT with the goal of normalization of glucose levels in the
successful implementation of a protocol aiming at TGC with
setting of hyperglycaemia in the ICU. The factors that influence
IIT requires a considerable investment of time in training,
these results warrant further exploration.
practice and evaluation, and in motivating the entire medical
staff of the unit [33].
Feasibility
Meijering et al. [25] performed a literature review of manage- Benefit of TGC with IIT in Different ICU Populations
ment of patients with stress hyperglycaemia or T2DM using IIT
in certain acute situations. The severity of the initial glycaemic The effect of TGC in the ICU has been investigated in
imbalance, the duration of the IIT, protocols for modification various clinical settings, such as patients with myocardial
of the insulin dosage, target glycaemic levels and the frequency infarction, stroke, septicaemia, trauma, neurosurgical and
of BG monitoring, all varied considerably between studies, cardiac surgical patients, and the heterogeneous medical and
rendering pooled analysis of the results difficult to interpret. surgical population. Results have been conflicting and, to date,
However, one common point was that many of these studies it has not been possible to establish with certainty that TGC is
brought to light considerable difficulties in attaining target BG beneficial in any particular disease setting.
levels, although the frequency of capillary BG monitoring, with The meta-analysis by Wiener et al. included 29 randomized
a view to dose adaptation, ranged from once every 4 h to once studies totalling 8432 patients hospitalized in intensive care
per hour. In two studies in patients with T2DM during the and showed that TGC with IIT is not associated with a signif-
acute phase of myocardial infarction, the average glycaemic icant mortality benefit. Conversely, Griesdale et al. [20], in a
level obtained was reported to be 187 mg/dl (10.3 mmol/l) meta-analysis of 26 studies, concluded that patients in surgical
after 12 h [26] and 150 mg/dl (8.2 mmol/l) after 48 h [27] of ICU yield a benefit from TGC [relative risk (RR) 0.63 (95% CI
IIT, whereas the target range was between 70 and 140 mg/dl 0.44–0.91)] among the 14 trials that reported hypoglycaemia.
(4–8 mmol/l). This meta-analysis did not include all the studies reviewed
In another study of patients with T2DM hospitalized in Wiener’s analysis, but did include the Normoglycemia in
for acute medical conditions, average BG obtained after Intensive Care Evaluation-Survival Using Glucose Algorithm
24 h was 183 mg/dl (10.1 mmol/l), [target 110–130 mg/dl Regulation (NICE-SUGAR) data. In a previous meta-analysis
(6–7 mmol/l)], despite hourly BG monitoring [28]. including 38 randomized studies and published prior to those
Finally, in a further study in patients with diabetes during of Griesdale and Wiener, Pittas et al. [35] also observed a reduc-
the acute phase of stroke, 24% of patients had glycaemic levels tion in mortality in the surgical ICU with TGC [RR 0.58 (95%
above target values [<130 mg/dl (<7 mmol/l)] during the first CI 0.22–0.62)]. Taken together, these data show conflicting evi-
24 h, despite BG monitoring every 2 h [29]. dence and remain difficult to interpret, in view of the numerous
In their respective studies in this field, Kanji et al. [30], biases and the wide variations in methodology between studies.
Goldberg et al. [7] and Barth et al. [31] showed that it is possible
to adequately control glycaemia and maintain BG within target Impact of the Existence of Documented Diabetes
ranges using standardized IIT protocols. However, all these on Morbidity–Mortality Outcomes and on the Benefits
authors underline the difficulty for the nursing staff to apply of TGC in the ICU
such protocols, particularly in the intensive care setting. They
When interpreting the results of the studies mentioned above,
propose four main reasons to explain these difficulties:
it should be noted that there is a potential bias, in that there may
1 Hyperglycaemia is considered to be less important than the have been a number of patients with undiscovered diabetes at
gravity of the initial disease. admission, who were considered as having stress hypergly-
2 Staff are not always aware of the necessity of maintaining caemia. In a meta-analysis of 15 studies in the setting of myocar-
appropriate BG levels. dial infarction in the cardiac ICU, Capes et al. [36] showed that
3 They are not always experienced in applying IIT protocols, the relative risk of in-hospital death in patients without known
although this is changing with the increasing use of these diabetes and with elevated glucose levels was 3.9-fold higher
protocols in the ICU setting [32,33]. than that of patients without diabetes and with lower glucose
4 Fear of hypoglycaemia leads staff to tolerate high BG levels. concentrations. Among patients with known diabetes, for those
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3. review article DIABETES, OBESITY AND METABOLISM
who had BG concentrations above 180 mg/dl (10 mmol/l), the included (532 before and 578 after implementation of TGC with
risk of in-hospital death was moderately increased (RR 1.7) IIT). A significant reduction in mortality was observed among
compared to patients with diabetes and normal glycaemia. The patients without diabetes between the historical era and the era
retrospective Cooperative Cardiovascular Project study [37] of TGC (18.7 vs. 13.5%), whereas there was a non-significant
included 141 680 patients admitted to the ICU for myocardial reduction among patients with diabetes (22.6 vs. 19.2%).
infarction, of whom 30.4% had known diabetes. This study Conversely, in a case-control study of 7285 patients undergo-
showed that elevated BG levels were significantly associated ing IIT in medical and surgical ICUs, Rady et al. [42] observed
with mortality at 30 days in patients without known diabetes a twofold higher mortality in patients without diabetes vs.
vs. those with diabetes. The risk of death began to increase when controls. It is noteworthy that, in these last three studies,
glycaemia exceeded 110 mg/dl (6.1 mmol/l) in patients without hyperglycaemic patients without diabetes included those with
known diabetes, whereas the threshold was higher for patients undiagnosed diabetes or a prediabetic condition. Thus, this
with diabetes. Similarly, Krinsley [38] and Whitcomb et al. [39] may reflect part of what Umpierrez et al. [3] observed in general
also retrospectively noted a relationship between hypergly- hospital patients who were hyperglycaemic, but undertreated
caemia at admission and survival in patients with diabetes in and/or not known to have T2DM on admission, but who had
both medical and surgical ICUs. In Krinsley’s study, the lowest it nonetheless.
hospital mortality (9.6%) was observed among patients with More recently, subgroup analysis in the NICE-SUGAR
mean glucose values between 80 and 99 mg/dl, and increased study [43] did not reveal any significant difference in the
progressively as glucose values increased, reaching 42.5% treatment effect between patients with and without diabetes.
among patients with mean glucose values exceeding 300 mg/dl. Although results are disparate, it appears that patients
In the study by Whitcomb et al., the association between hyper- without diabetes yield greater benefit from intensive glucose
glycaemia on ICU admission and in-hospital mortality was not control with IIT in medical and surgical ICUs than patients
uniform in the study population; hyperglycaemia was an inde- with diabetes, whereas in the setting of cardiac ICU, patients
pendent risk factor only in patients without the history of with diabetes seem to obtain the greatest benefit.
diabetes in the cardiac, cardiothoracic and neurosurgical ICUs.
The HI-5 study [40] compared the benefit of IIT in
myocardial infarction in 116 patients with known diabetes Impact of Glycaemic Variability on Glycaemic Control
and 128 patients with admission glycaemia above 140 mg/dl in the ICU
(7.8 mmol/l) but without documented diabetes. IIT was not The benefit of TGC in the ICU setting with intensive IIT
associated with a reduction in mortality. However, among has been assessed in some reports by the variation in the
patients with diabetes, there was a significant reduction in mean BG levels [44]. Glucose variability may confer an adverse
the risk of re-infarction after >72 h (0 vs. 7.7%, p = 0.04), risk of mortality, independent of absolute glucose level and
and a lower occurrence of the composite endpoint combining indeed is a stronger risk factor for mortality than average
death and any major cardiac event at 3 months (21.9 vs. 40.4%, glucose levels [44,45]. In a study of 5728 patients over 3 years
p = 0.03). in a medical-surgical ICU, Hermanides et al. [46] studied
In a study performed in surgical ICU patients, Van den glycaemic variability using the absolute variation in mean
Berghe et al. [14] found that IIT aiming at TGC reduced mortal- hourly BG, as well as the standard deviation of mean BG,
ity in critically ill patients, regardless of the existence of known which is the usual parameter used to analyse glycaemic
diabetes or hyperglycaemia. However, the effect was more pro- variability. IIT was initiated with a target BG range of
nounced in hyperglycaemic patients without known diabetes. 72–126 mg/dl (4–6.9 mmol/l). This study showed that elevated
The mortality rates were 8.4 vs. 4.7% in the conventional treat- glycaemic variability was associated with a significant increase
ment vs. intensive IIT groups, respectively, in patients without in mortality, while low glycaemic variability exerted a protective
diabetes, compared to 5.8 vs. 4% in patients with diabetes. In effect, even when mean BG remained high.
a further study in 2006, Van den Berghe et al. [13] pooled the In a cohort of >66 000 ICU patients, Bagshaw et al. [47]
data from their two prospective randomized studies in medical observed glycaemic variability [defined as the occurrence of
and surgical ICUs [target glycaemia range of 80–110 mg/dl hypoglycaemia <80 mg/dl (4.5 mmol/l) or hyperglycaemia
(4.4–6.1 mmol/l) in the IIT group]. Among the 2748 patients >220 mg/dl (12 mmol/l) within 24 h of admission] in 2.9%
included, there were 200 patients with diabetes in the conven- of patients. This early glycaemic variability was associated with
tional therapy group and 207 in the intensive therapy group. a significant increase in the risk of ICU or hospital death.
Contrary to the findings observed in patients without diabetes, Patients with glycaemic variability are generally older with
intensive IIT showed no benefit on mortality in the subgroup of more co-morbidities, particularly heart failure and renal
patients with diabetes. Furthermore, risk of death mirrored that dysfunction. They also usually present with the most severe
of patients without diabetes for all strata of BG control, with forms of disease and undergo the most aggressive therapy. These
a non-significant increase in risk among patients with diabetes predisposing factors raise the question of whether glycaemic
when average BG was below 110 mg/day (6.1 mmol/day). variability is a marker of disease severity or rather a risk factor
In a single-centre retrospective cohort study, Krinsley [41] for morbidity and mortality.
compared the outcome in patients admitted to surgical and Similarly, Egi et al. [45] retrospectively analysed 168 337 BG
medical ICUs before and during the era of TGC with IIT. measures in 7049 ICU patients and concluded that glycaemic
Patients with diabetes represented 1110 of the 5365 patients variability (s.d. of mean BG) was independently associated with
120 Combes et al. Volume 13 No. 2 February 2011

4. DIABETES, OBESITY AND METABOLISM review article
longer ICU stay and higher ICU and hospital mortality. This could be explained by a lower risk of hyperglycaemia. Thus,
relation was not observed among the subgroup of 728 patients early enteral nutrition is all the more recommended when IIT
with known diabetes. is initiated in the ICU to treat hyperglycaemia, in order to
In a prospective study of glycaemic variability in 191 patients allow better insulin dose adjustment. Van den Berghe et al.
admitted to the ICUs for sepsis or septic shock, patients under- also underlined that caloric uptake is the main determining
went intensive IIT to maintain BG between 80 and 140 mg/dl factor in deciding to adjust insulin doses, and in 62% of cases,
(4.4–7.7 mmol/l) [48]. Results showed that a standard devia- hypoglycaemia results from non-adjustment of the dose of
tion of BG levels >20 mg/dl (1.1 mmol/l) was associated with insulin when nutritional support is interrupted.
significantly higher mortality than among patients with a stan- Vriesendorp et al. [59] also purport that non-adjustment
dard deviation <20 mg/dl (24 vs. 2.5%, p = 0.0195). Similar of insulin doses, when nutritional support (be it parenteral,
results were observed by Ali et al. [49] in a retrospective study enteral or mixed) is reduced or temporarily interrupted, is one
of patients with sepsis. It would thus appear that glycaemic vari- of the main factors predisposing patients to hypoglycaemia (in
ability has a negative impact on outcome. Strategies to limit gly- 11% of hypoglycaemia cases).
caemic variability should be an integral part of management of In a retrospective analysis of data from a subset of 211
hyperglycaemia in the ICU setting in the future. However, it is of patients included in the ‘Glucontrol’ trial and 393 patients from
note that, in the study by Van den Berghe et al. [13], in patients the Specialized Relative Insulin Nutrition Titration (SPRINT)
hospitalized in mixed medical/surgical ICUs, the IIT did not initiative, Suhaimi et al. [60] showed that glycaemic variability
confer any major impact on improving glucose variability. is greater when insulin protocols do not take into account
carbohydrate administration. Thus, it would appear that nutri-
Impact of Nutritional Support on BG Control in the ICU tional support, particularly when it is modified or interrupted,
may create a favourable environment for the occurrence of
The effects of enteral or parenteral nutritional support on BG
hypoglycaemia and greater glycaemic variability, through inad-
control in ICU patients have been widely studied, but the results
equate adjustment of IIT. This in turn can have a negative
have been discordant. Briefly, it would appear that both forms
impact on glycaemic control in the ICU.
of nutritional support are equivalent, and the most appropriate
In the two studies by Van den Berghe carried out in the
method should be chosen taking into account the advantages
medical [13] and surgical [14] ICU settings, patients initially
and disadvantages in a given clinical situation. It has been shown
received a high dose of glucose by the parenteral route (average
that parenteral nutrition is used in 12–71% of patients, while
160 g/24 h) in the first few days, contrary to subsequent
enteral nutrition is used in 33–92% of ICU patients requiring
studies, whose results were more equivocal. For example,
nutritional support [50–55]. Several factors may explain this
in the NICE-SUGAR study, average glucose administered
wide variability in the use of enteral and parenteral nutrition,
intravenously was approximately 22 g/24 h.
such as local practices, cost issues, nutritional status of the
In a systematic review of trials that studied the impact of
patient, the type and severity of the underlying pathology and
TGC, Marik and Preiser [61] showed a significant relationship
type of surgery.
between the treatment effect of TGC on 28-day mortality and
In a meta-analysis of 13 studies, Gramlich et al. [56] showed
the proportion of calories provided parenterally. Conversely,
that there was no difference in mortality between enteral and
lack of early parenteral nutrition in such situations would
parenteral nutrition in critically ill patients. However, they did
even appear to be associated with an increase in the number
observed a significant reduction in infectious complications
of deaths. Marik and Preiser hypothesize that the difference
in patients receiving enteral nutrition. The higher infectious
between the positive results of Van den Berghe’s two studies
risk observed with parenteral nutrition could be secondary to
and the conflicting results observed thereafter could be at least
the higher incidence of hyperglycaemia with this method, as
partially explained by the use of early parenteral nutrition high
compared with enteral feeding [56,57].
in glucose.
The influence of nutritional support on BG control has
Increased glucose turnover and insulin resistance may allow
been less extensively studied among patients receiving IIT in
the body to provide sufficient supplies of the glucose that
the ICU. Van den Berghe et al. [58] showed, in a prospective,
is vital to certain organs. However, the initiation of IIT
randomized study among 1548 ICU patients, that the benefit of
without administration of additional glucose, by suppressing
strict BG control was similar regardless of whether nutritional
the body’s adaptive response, could have a deleterious effect on
support was enteral, parenteral or mixed. Dan et al. [57]
prognosis [62]. Future studies are needed to identify the impact
observed similar findings in a retrospective study of a mixed
of nutritional support on the effect of strict glycaemic control
medical–surgical ICU.
in the ICU and to elucidate whether there is a benefit from
Van den Berghe et al. [58] observed that with similar levels of
early parenteral high-glucose nutritional support associated
nutritional support, the insulin doses required to normalize BG
with intensive IIT.
[target 80–100 mg/dl (4.4–6 mmol/l)] were 26% higher when
nutritional support was by the parenteral route, as compared
to the enteral route, because of the incretin effects. According Hypoglycaemia
to Van den Berghe, parenteral nutrition incurs a higher risk of In intervention studies among patients with diabetes in
hyperglycaemia through insufficient or delayed adaptation of various acute situations where IIT aiming at TGC is used,
insulin doses. These same authors also indicate that the benefit hypoglycaemia is not always reported [9,25,26]. When it is
of early initiation of enteral nutrition observed in certain studies recorded, the incidence varies widely from one study to another,
Volume 13 No. 2 February 2011 doi:10.1111/j.1463-1326.2010.01311.x 121

5. review article DIABETES, OBESITY AND METABOLISM
ranging from 0 to 17.7% [40,63–71]. Analysis and comparison In a retrospective study, Krinsley and Grover [73] also
of these figures are difficult, as the duration of therapy, identified diabetes and sepsis as predisposing factors for hypo-
glycaemia targets and insulin protocols differ significantly glycaemia, but further observed that mechanical ventilation,
between studies. renal insufficiency and severity of illness were also risk factors
The diabetes and insulin–glucose infusion in acute myocar- for hypoglycaemia.
dial infarction (DIGAMI) 1 and DIGAMI 2 studies, which Heightened awareness of the predisposing factors for
included a large number of T2DM patients during the acute hypoglycaemia, combined with more frequent BG controls
phase of myocardial infarction, used robust methodology to in the population at risk, could help to reduce the incidence of
illustrate that even with staff who are well trained in the applica- hypoglycaemia.
tion of IIT protocols, and despite average BG results often above However, in a retrospective multicentre cohort study
target levels with frequent monitoring, hypoglycaemia remains including 7820 patients hospitalized with acute myocardial
frequent [11,66]. In DIGAMI 1 [66], 46 of the 306 patients with infarction and who were hyperglycaemic on admission, while
T2DM (15%) in the group treated by IIT in the first 24 h were hypoglycaemia was associated with increased mortality, this
reported to have hypoglycaemia, although BG monitoring was risk was confined to patients who developed hypoglycaemia
performed every 1 or 2 h, target levels were between 130 and spontaneously [74]. In contrast, iatrogenic hypoglycaemia after
180 mg/dl (7–10 mmol/l) and average BG in the first 24 h was insulin therapy was not associated with higher mortality risk.
174 ± 60 mg/dl (9.6 ± 3.3 mmol/l). In DIGAMI 2 [11], in the
two groups of T2DM patients (n = 474 and 473, respectively) Benefit of TGC by IIT on Morbidity and Mortality in
treated by IIT during the first 24 h, with the same target BG Intensive Care
levels and the same monitoring frequency as above, the rate The meta-analysis by Wiener et al. [19], published in 2008,
of hypoglycaemia was 12.7 and 9.6%, respectively. Average BG included 29 randomized studies totalling 8432 patients
during the first 24 h was 165 mg/dl (9.1 mmol/l). In the two hospitalized in intensive care and showed that TGC by IIT
studies by Van den Berghe et al. in the surgical [14] and med- is not associated with a significant reduction in mortality, but is
ical [13] ICU setting, hypoglycaemia was reported to occur in associated with a significantly increased risk of hypoglycaemia.
5.1 and 18.7%, respectively. Two multicentre studies, namely The recently published randomized NICE-SUGAR study [43]
the Efficacy of Volume Substitution and Insulin Therapy in included over 6000 patients in intensive care and showed a
Severe Sepsis (VISEP) [18] and Glucontrol [72] studies, were significant increase in cardiovascular and all-cause mortality
prematurely stopped. In both these studies, the target glycaemia at 90 days in the group with intensive BG control [target
levels were the same as those used in the two Van den Berghe 81–108 mg/dl (4.4–5.9 mmol/l)] compared to the control
studies, that is, 80–110 mg/dl (4.4–6.1 mmol/l) [13,14]. The group [target 180 mg/dl or less (10 mmol/l)]. This finding
VISEP study included 537 patients, of whom 163 had dia- was also observed in the subgroups of patients hospitalized in
betes [18]. The trial was stopped because of the increased rate of medical and surgical ICUs. The results of the NICE-SUGAR
severe hypoglycaemia in the group receiving intensive insulin study are at odds with those observed in previous studies in
treatment (12.1 vs. 2.1% in the conventional therapy group, critical care [14], surgery [13] and the paediatric setting [75].
p < 0.01) and there was no significant difference between This discrepancy in the results could be explained by differences
groups in terms of morbidity and mortality at 28 and 90 days. in parameters such as inclusion criteria, the methods used to
The Glucontrol study [72] was prematurely stopped after the measure BG, staffing ratios, patient populations, incidence
inclusion of 1101 patients because of a high rate of unintended of diabetes and, in particular, the intervention itself, that is,
protocol violations (based on the evaluation of available BG the method used to obtain strict BG control. In addition,
measures). Although ICU mortality was similar in the two the results of the single-centre randomized controlled trial of
groups (15.3% in the intermediate BG control group vs. 17.2% intensive IIT by Van den Berghe et al. in 2001 have given rise to
in the intensive IIT group), higher rates of severe hypoglycaemia some debate. This unblinded study concluded that ‘intensive
were observed in the intensive therapy arm. insulin therapy to maintain BG at or below 110 mg/dl reduces
In the NICE-SUGAR study, a significantly higher rate morbidity and mortality among critically ill patients in the
of hypoglycaemia was also observed in the group receiving surgical ICU’. Among the several limitations of this study
intensive IIT as compared to the conventional therapy group that have been raised [76], it is of note that the study was
(6.8 vs. 0.5%, p < 0.001) [43]. strongly biased towards postoperative cardiothoracic surgical
The incidence of hypoglycaemia is reportedly similarly in patients, and mainly showed benefits for patients in the ICU for
medical and surgical ICU patients [59] and hypoglycaemia >5 days. Furthermore, all patients initially received a high dose
remains an independent risk factor for mortality in ICU of glucose by the parenteral route, followed by initiation of
patients. Certain predisposing factors for hypoglycaemia in either total parenteral nutrition, enteral feeding or combined
the ICU have been identified. Vriesendorp et al. [59] analysed feeding, which is a highly unusual practice. A recent meta-
data from a cohort of 2272 patients admitted to the ICU, analysis [20] including 26 randomized studies, with a total of
and identified the following predisposing factors: reduction of 13 567 patients in intensive care, including the NICE-SUGAR
nutrition without a corresponding adjustment of insulin ther- data, showed, as in Wiener’s meta-analysis, that intensive IIT
apy, documented diabetes, sepsis, use of inotropic medication increases the risk of hypoglycaemia sixfold, without any benefit
or octreotide and venovenous haemofiltration with bicarbonate on mortality, except in the subgroup of patients admitted to
substitution fluid. surgical intensive care.
122 Combes et al. Volume 13 No. 2 February 2011

6. DIABETES, OBESITY AND METABOLISM review article
In light of the NICE-SUGAR data, the American Diabetes
Association (ADA) and American Association of Clinical
Endocrinologists (AACE) [77] recently revised their guidelines
on inpatient glycaemic control. Although the previous
ADA guidelines advocated initiation of insulin infusion for
ICU patients in the aim of maintaining BG <140 mg/dl
(7.7 mmol/l), and if possible <110 mg/dl (6 mmol/l) for
patients in surgical intensive care, the revised guidelines
now recommend that for critically ill patients, BG should
be maintained between 140 and 180 mg/dl (7.7–9.9 mmol/l),
aiming preferably to approach the lower end of this range.
Lower BG levels may be appropriate in selected patients. In the
recent revision of the ‘Surviving Sepsis’ guidelines, initiation
of glycaemic control is recommended, targeting BG levels
<150 mg/dl after initial stabilization for the management of
patients with severe sepsis or septic shock [78]. However,
target BG <110 mg/dl (<6 mmol/l) is not recommended in
any circumstances.
We cannot exclude the hypothesis that a certain proportion Figure 1. Glucagon-like peptide-1 (GLP-1) secretion and metabolism.
of deaths may be caused by unidentified severe hypoglycaemia Bioactive GLP-1(7-36) amide and GIP (1–42) are released from the
(such as in patients with consciousness disorders, often small intestine after meal ingestion and enhance glucose-stimulated
under sedation and whose mechanisms of hormonal counter- insulin secretion (incretin action). Dipeptidyl peptidase-4 (DPP-4) rapidly
converts GLP-1 to its inactive metabolite GLP-1(9-36) in vivo. Inhibition
regulation are altered). Such an excess could mask the benefit
of DPP-4 activity prevents GLP-1 degradation, thereby enhancing incretin
of TGC on mortality [13,18–21,59]. action. GIP (glucose-dependent insulinotropic polypeptide) is another
In addition, the practical obstacles associated with the use incretin. Adapted with permission from Ref. [107].
of IIT outlined above underline how difficult it is to obtain
appropriate and stable BG control. Indeed, in the NICE-
SUGAR study, even with a complex and computerized IIT
protocol, investigators reported that, on average, patient BG
levels were within the target range only 40% of the time [43].
Therefore, it would seem that, at present, the benefit of
TGC for patients in intensive care may be concealed by the
lack of reliable tools for IIT that can effectively maintain
target BG levels without danger of excess hypoglycaemia. The
CGAO-REA study (impact of computerized glucose control in
critically ill patients), which is currently ongoing, may provide
new information in this setting.
Incretin–GLP-1
Physiological Data
GLP-1 is a gut hormone produced by the proglucagon gene in Figure 2. Chemical structure of native human glucagon-like peptide-1.
Adapted with permission from Ref. [108].
the L-cells located predominantly in the distal small intestine.
It is secreted in response to nutrient intake (figure 1). The
main circulating form in humans is the GLP-1(7-36) amide
• GLP-1 dose dependently inhibits glucagon secretion, but
(figure 2). The half-life of GLP-1 is extremely short (1–2 min)
because it is rapidly inactivated by the ubiquitous, non- without preventing hormonal counter-regulation at BG levels
specific enzyme dipeptidyl peptidase-4 (DPP-4), leading to below 65 mg/dl (3.5 mmol/l).
• It slows gastric emptying, reduces intestinal peristalsis and
the formation of its inactive metabolite (figure 1) [79,80].
reduces secretory activity in the upper digestive tract through
GLP-1 Possesses Several Important Pharmacodynamic Properties. mechanisms initiated by the vagal nerve and the autonomic
It stimulates insulin secretion in a dose-dependent manner, nervous system [82].
but this effect disappears when BG levels are below 80 mg/dl • Finally, GLP-1 promotes satiety, which can lead to reduced
(4.4 mmol/l) as the insulinotropic activity of GLP-1 is strictly food intake and weight loss [83]. This effect could be
glucose-dependent [79]. On top of the insulinotropic effects, mediated by vagal afferent activity or could result from a
GLP-1 stimulates insulin production and exerts a trophic effect direct action of circulating GLP-1 on areas of the central
on β cells (differentiation of progenitor cells, reduction of nervous system with receptors that are not protected by the
apoptosis and proliferation of β cells) (figure 3) [81]. blood–brain barrier.
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7. review article DIABETES, OBESITY AND METABOLISM
Figure 3. Glucagon-like peptide-1 (GLP-1) action in peripheral tissues. The majority of the effects of GLP-1 are mediated by direct interaction with
GLP-1 receptors on specific tissues. However, the actions of GLP-1 in liver, fat and muscle most probably occur through indirect mechanisms. Adapted
with permission from Ref. [107].
GLP-1 in the Treatment of T2DM Intravenous (IV) Administration of GLP-1
GLP-1 possesses two essential characteristics that enhance Efficacy. Several studies have shown that continuous IV
its potential as a treatment for T2DM. First, the majority infusion of GLP-1 makes it possible to normalize fasting
of its effects are exerted very rapidly in the presence and postprandial (PP) glycaemia in patients with T2DM
of hyperglycaemia and cease as soon as BG returns to suffering from moderate to severe glycaemic imbalance (apart
normal levels. Second, in patients with T2DM, secretion of from episodes of acute decompensation) [85,86]. Similar
GLP-1 may be diminished, but sensitivity to GLP-1 remains efficacy is observed regardless of whether patients were
unchanged. These particular characteristics combine to make initially treated with sulphonylurea [86,87], metformin [88]
GLP-1 a focus of research for the treatment of T2DM in or pioglitazone [89]. Normalization of fasting BG in T2DM
situations of acute hyperglycaemia. However, in the case patients can be obtained within approximately 4 h after the
of ICU patients, hyperglycaemia is often stress-induced and start of GLP-1 infusion. When fasting glycaemia is above
patients are not known to have T2DM. Also, with counter- 270 mg/dl (15 mmol/l), normalization may take longer [90].
regulatory hormones potentially altered during critical illness
and altered gluconeogenesis or glycogenolysis (e.g. in those Dosage and Side Effects. In most studies, the most efficacious
with decompensated liver or relative starvation), the global and best tolerated dose of GLP-1 when administered by infusion
potential of GLP-1 remains to be elucidated through further is from 1 to 1.2 pmol/kg/min. This does not increase the risk of
research. hypoglycaemia [85,86,91–95]. There exists a dose-dependent
relationship between the dose of GLP-1 administered and
deceleration of gastric emptying which may cause digestive side
Subcutaneous Injection of GLP-1 effects after food intake. Higher doses improve BG levels consid-
Subcutaneous injection of high doses of GLP-1 (1.5 nmol/kg) erably, but also significantly increase the rate of side effects [87].
makes it possible to rapidly normalize BG levels in patients However, Meier et al. [91] showed in a recent study that nor-
with T2DM. However, the effect is of short duration, because malization of fasting and PP glycaemia (test meal of 250 kcal)
of the rapid inactivation of GLP-1, and therefore regular in patients with T2DM was not dose-dependent at doses lower
subcutaneous injections every 2 h are required to maintain than 1.2 pmol/kg/min. GLP-1 administered at doses of 0.4, 0.8
BG levels within the normal range [84]. or 1.2 pmol/kg/min by overnight infusion, or started 1 h before
124 Combes et al. Volume 13 No. 2 February 2011

8. DIABETES, OBESITY AND METABOLISM review article
a meal, normalized BG levels in the same manner both in the observed from week 1 and persisted till 6 weeks, with a reduc-
fasting state and 4 h after the meal. However, unlike the lower tion of 1.3% (12 mmol/mol) in HbA1c. At this dose, BG levels
doses of GLP-1, gastric emptying was almost completely inhib- were thus not normalized, but tolerance was good [98].
ited 4 h after meal intake at the 1.2 pmol/kg/min dose. These Over a period of 3 months, subcutaneous administration of
adverse effects of GLP-1 activity on intestinal motility and diges- GLP-1 in elderly patients (75 ± 2 years) with T2DM at a dose
tive secretions may compound the reduction in gastric empty- of 2.4 pmol/kg/min was shown to be as efficacious as treatment
ing frequently observed in ICU patients. This renders the use of by oral antidiabetic agents (metformin and/or sulphonylurea
GLP-1 difficult in medical–surgical patients with gastrointesti- treatment) to maintain HbA1c at 7% (53 mmol/mol), with
nal or pancreatic diseases as well as in patients with diabetic gas- good tolerance and without the risk of hypoglycaemia
troparesis. Whether GLP-1-based therapies might increase the observed with secretagogues [97]. However, it is unlikely
risk of aspiration and alter gastrointestinal tract caloric intake, that subcutaneous administration, whether continuous or
because of the changes they can induce in gastric emptying and not, would be a viable option for ICU patients, because of
food absorption, should be closely monitored in these critical the absorption difficulties linked to the frequent presence of
situations. However, Deane et al. [96] have shown, in critically vasoconstriction or peripheral oedema, and the potential for
ill mechanically ventilated patients, without known diabetes, haematoma or infection in or around the sites of recurrent
that exogenous GLP-1 slows gastric emptying only when the lat- subcutaneous infusions or injections in frail patients.
ter is normal, but not when it is already spontaneously delayed.
Controlled Intervention Studies
Continuous or Discontinuous Infusion. Infusion of 1 pmol/kg/
Although it has been shown that continuous IV infusion of
min of GLP-1 for 4 h in patients with T2DM in the fasting state,
GLP-1 at doses of 1–1.2 pmol/kg/min makes it possible to
with average initial BG of 210 ± 16 mg/dl (11.7 ± 0.9 mmol/l),
rapidly normalize fasting and PP BG levels with good tolerance
normalizes glycaemia at the end of infusion [87 ± 7 mg/dl
in diabetic patients with severe, transitory glycaemic imbalance
(4.8 ± 0.4 mmol/l)] and for up to 4 h afterwards if patients
(apart from episodes of acute decompensation), there is a
remain fasting [92,93]. If food is given after the interruption
paucity of controlled intervention studies in this setting. In
of GLP-1 infusion, then BG rises within 1 h to levels similar to
particular, data are lacking about the use of GLP-1 in the highly
those observed after the infusion of placebo [95]. However, if
complex, dynamic and often unstable ICU patient who may
food is ingested while maintaining an infusion of GLP-1, BG
have little hepatic or pancreatic reserve.
remains normal [91,94].
In a randomized study of eight patients with T2DM,
In patients with poorly controlled T2DM and normal food
Schmoelzer et al. [99] observed that GLP-1 infusion at a dose
intake of 3 meals/day, only a continuous infusion of GLP-1
of 1.2 pmol/kg/min over 8 h normalized BG to the same extent
made it possible to maintain normal BG levels over a 24-h
as IIT, with a more rapid effect, without dose adaptation and
period. Interruption of the infusion for 6 h during the night
without hypoglycaemia.
resulted in elevated fasting BG levels, similar to those observed
In a study among eight patients with T2DM who had
under 24-h placebo infusion. The beneficial effect on BG levels
undergone major surgery, Meier et al. [24] observed that with
can persist for up to 1 week if continuous IV infusion of GLP-1
infusion of GLP-1 over 8 h at a dose of 1.2 pmol/kg/min
is maintained [87].
between the second and eighth postoperative day, a
normoglycaemic fasting BG range was reached within 150 min,
with good tolerance and without hypoglycaemia. In a
Continuous Subcutaneous Infusion of GLP-1
randomized study of GLP-1 IV infusion vs. placebo in 20
The therapeutic use of GLP-1 for the long term is hampered patients during the postoperative phase, Sokos et al. showed
by the necessity of IV administration. In this context, studies that in the 12 h preceding and the 48 h following coronary
have been carried out to test continuous subcutaneous pump artery bypass graft surgery, GLP-1 at a dose of 1.5 pmol/kg/min
infusion over periods ranging from 48 h [90] to 3 months [97]. achieved better glycaemic control, with less frequent use of IIT,
Administration by the subcutaneous route achieves circulating and 45% less insulin was required to obtain the same glycaemic
GLP-1 concentrations that are more or less equivalent to those control compared to when IV insulin was used. Furthermore,
obtained by the IV route by radio-immunological dosing, but GLP-1 achieved comparable haemodynamic recovery, with
for reasons that remain to be identified, the therapeutic efficacy less use of inotropic and anti-arrhythmic medication [100].
and the side effects are less. Thus, doses of 2.4–4.8 pmol/kg/min These beneficial effects are in line with the GLP-1-induced
are necessary by subcutaneous administration, compared to improvements in left ventricular ejection fraction in mice
doses of 0.4–1.2 pmol/kg/min by the IV route to obtain a subjected to ischaemia–reperfusion [101].
significant therapeutic effect [90,97,98]. In another randomized study of GLP-1 IV infusion vs. IIT
In a parallel group study of 20 patients with poorly among 20 patients with T2DM over the 12 h following coronary
controlled T2DM [HbA1c 9.2 ± 1.8% (77 ± 17 mmol/mol)], artery bypass graft surgery, GLP-1 at a dose of 3.6 pmol/kg/min
Zander et al. showed that GLP-1 administered by subcutaneous obtained normalized glycaemia levels as efficaciously as IIT,
infusion at a dose of 4.8 pmol/kg/min for 6 weeks lowered fast- with good tolerance and no reported hypoglycaemia [102].
ing BG from 261 to 183 mg/dl (14.4–10.1 mmol/l), and average A further study showed that infusion of GLP-1 over 4 h
plasma BG as assessed by an 8-h profile of BG concentrations makes it possible to normalize BG levels in severely ill patients
was reduced by 100 mg/dl (5.5 mmol/l). These effects were hyperglycaemic during total parenteral nutrition [103].
Volume 13 No. 2 February 2011 doi:10.1111/j.1463-1326.2010.01311.x 125

9. review article DIABETES, OBESITY AND METABOLISM
Finally, Deane et al. [104] assessed the effect of exogenous the apparently inferior efficacy as compared to insulin and the
GLP-1 on the glycaemic response to enteral nutrition need for insulin–GLP-1 combination therapy in some patients.
in patients with critical illness-induced hyperglycaemia. In Intervention studies with exenatide are currently ongoing
this randomized double-blind placebo-controlled crossover [see http://clinicaltrials.gov: IV exenatide (Byetta®) for the
study, seven mechanically ventilated critically ill patients, treatment of perioperative hyperglycaemia, NCT00882050; IV
not previously known to have diabetes, received two IV exenatide in coronary ICU patients, NCT00736229], which may
infusions of GLP-1 (1.2 pmol/kg/min) and placebo over answer some of these outstanding questions and subsequently
270 min, while a mixed nutrient liquid was infused via help evaluate the potential benefit of GLP-1 therapy on
a postpyloric feeding catheter. Acute, exogenous GLP-1 morbidity and mortality.
infusion markedly attenuated the glycaemic response to enteral
nutrition in all these critically ill patients, with reduced overall Acknowledgement
glycaemic response during enteral nutrient stimulation and
reduced peak BG [GLP-1 (10.1 ± 0.7 mmol/l) vs. placebo We would like to thank Fiona Ecarnot for translation and
(12.7 ± 1.0 mmol/l); p < 0.01]. The same authors, in a similar editorial assistance.
study design, showed that exogenous GLP-1 lowers PP
glycaemia in 25 critically ill patients after intragastric feeding. Conflict of Interest
This may occur, at least in part, by reducing the rate of J. C. and A. P. took the decision to write this review and were
carbohydrate absorption [96]. responsible for writing the manuscript. All authors contributed
to the research and analysis of literature and drafting and
GLP-1 Analogues revising the manuscript. Prof. Penfornis reports receiving an
investigator-initiated research grant and honoraria for speaking
As the therapeutic use of GLP-1 is considerably limited by its engagements from Eli Lilly. No other potential conflicts of
very short half-life, GLP-1 receptor agonists (GLP-1 analogues), interest relevant to this review were reported.
which are active for longer, have been developed.
Exendin-4 or exenatide (Byetta®, Amylin Pharmaceuticals
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