Intensive glucose control versus conventional glucose control

for type 1 diabetes mellitus (Protocol)

Fullerton B, Berghold A, Jeitler K, Siebenhofer A

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane
Library 2011, Issue 5
[Link]

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol)
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) i
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Intensive glucose control versus conventional glucose control

for type 1 diabetes mellitus

Birgit Fullerton1 , Andrea Berghold2 , Klaus Jeitler3 , Andrea Siebenhofer1

1 Institute for General Practice, Goethe University, Frankfurt am Main, Germany. 2 Institute for Medical Informatics, Statistics and

Documentation, Medical University of Graz, Graz, Austria. 3 Department of Internal Medicine and Institute for Medical Informatics,
Statistics and Documentation, EBM Review Center, Medical University of Graz, Graz, Austria

Contact address: Andrea Siebenhofer, Institute for General Practice, Goethe University, Theodor-Stern-Kai 7, Frankfurt am Main,
60590, Germany. [Link]@[Link].

Editorial group: Cochrane Metabolic and Endocrine Disorders Group.

Publication status and date: New, published in Issue 5, 2011.

Citation: Fullerton B, Berghold A, Jeitler K, Siebenhofer A. Intensive glucose control versus conventional glucose control for type 1
diabetes mellitus. Cochrane Database of Systematic Reviews 2011, Issue 5. Art. No.: CD009122. DOI: 10.1002/14651858.CD009122.

Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

The primary objective of this review is to assess the effects of different blood glucose treatment targets in terms of long-term complications
and determine whether very low, near normoglycaemic values are of additional benefit.

BACKGROUND To date, no cure has been found and treatment consists of life-
long blood sugar control through insulin replacement. Long-term
complications include neuropathy, nephropathy, retinopathy and
cardiovascular disease.
Description of the condition
For more detailed information on diabetes mellitus, the reader
Type 1 diabetes can be acquired at any age and accounts for about is referred to Additional information on the Metabolic
five to ten percent of all diabetes mellitus cases (Daneman 2006). It and Endocrine Disorders Group in The Cochrane Library
is a metabolic disease caused by a cellular-mediated auto-immune (see About the Cochrane Collaboration, Collaborative Review
destruction of pancreatic cells which results in a deficiency of Groups-CRGs). For an explanation of methodological terms, see
insulin secretion. What causes the pathological autoimmune re- the main glossary in The Cochrane Library.
sponse is not yet fully understood but includes genetic suscepti-
bility in combination with an environmental trigger (Field 1997;
Maahs 2010; van der Werf 2007). The incidence of type 1 diabetes
varies geographically, being highest in Northern Europe where it
Description of the intervention
can be higher than 30 cases per 100 000 per year (Karvonen 1993). Since high blood glucose is associated with long-term complica-
Over the years, a worldwide increase in incidence has been ob- tions (Nordwall 2009), many efforts are made to reduce blood
served, the reasons for which are not yet clear (Onkamo 1999; glucose as low as possible. Different types of approaches could
Pitkaniemi 2004). be taken when aiming for a low glucose target: for example, one
Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 1
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
could change to a different insulin regimen, which might be more with type 1 diabetic patients, e.g. in the Diabetes Control and
effective lowering blood sugar levels than another regimen or one Complications Trial (DCCT) (DCCT 1993), the term intensive
could switch to a different type of insulin, which could poten- therapy has often implied much more than just a lower glucose
tially be more successful than other types. In general, all these ef- treatment target. In fact, intensive treatment usually refers to a
forts should be nested in patient counselling and education efforts, multi-factorial intervention with an intensified treatment regimen
which are further factors helping to achieve good glycaemic con- and additional factors such as patient education, individual coun-
trol (Aschner 2010). The primary research question for this review selling and increased frequency of blood glucose monitoring com-
is to assess the effects of different blood glucose treatment targets pared to the conventional treatment. The results of these studies
and determine whether very low, near normoglycaemic values are can only be attributed to a combination of factors rather than the
of additional benefit. To answer this question, ideally only stud- effects of different glycaemic targets alone.
ies targeting different glycaemic levels, but using identical insulin Table1: Glycaemic targets for type 1 diabetes mellitus in dif-
regimens in the treatment groups (e.g. multiple daily injections in ferent treatment guidelines
both groups) should be considered. However, in previous studies

Country Guideline Year HbA1c

Canada Canadia Diabetes Association 2008 7.0%

(Canadian 2008)

Germany Deutsche Diabetes Gesellschaft ( 2007 < 7.0%

Martin 2007)

UK National Institute for Health and Clin- 2010 < 7.5% (in case of increased
ical Excellence (NICE) (NICE 2010) arterial disease risk: < 6.5%)

USA American Association of Clinical En- 2007 6.5%

docrinologists (AACE) (Rodbard
2007)

USA American Diabetes Association (ADA) 2010 < 7.0%

(ADA 2010)

Since the results of the DCCT became known, intensive insulin

therapy has become the standard therapy recommended by most all number of events was small so that the power of the study
clinical guidelines for patients with type 1 diabetes. In addition, might have not been high enough for the effect to reach statistical
most clinical guideline recommendations (see table 1) today take significance (DCCT 1995a). A recently published meta-analysis
their evidence from the results (based on the achieved glycosylated (Stettler 2006), which combined the effects of eight randomised
haemoglobin A1c (HbA1c)) of the DCCT, in which the HbA1c trials, however, came to the conclusion that an improvement of
treatment target of the intervention group was 6.05%. This tar- glycaemic control reduces the risk of macrovascular complications.
get, however, was only reached by less than 5% of the patients. In addition, in the long-term follow-up observation of the DCCT/
On average, the HbA1c in this group could be reduced by 1.8% EDIC (Epidemiology of Diabetes Interventions and Complica-
from 9.1% at baseline to a mean level of 7.1% throughout the tions) trial a substantial reduction in cardiovascular disease in the
randomised follow-up period in the intervention group (DCCT former intensive treatment group compared to the former conven-
1993; DCCT 1995). The results showed a substantial reduction in tional treatment group was shown (Nathan 2005), which further
the risk of developing microvascular complications during the fol- supports the assumption that intensive glucose control not only
low-up period in the intervention group compared to the control reduces microvascular but macrovascular complications as well.
group. The results regarding macrovascular complications were Those studies aiming for the same glucose targets in both groups
less clear. Although the number of macrovascular events was higher (or if no targets were specified) will be excluded from this review,
under conventional treatment than intensive treatment, the over- because any effect must be attributed to the treatment regimen and

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 2
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
cannot have been caused by setting different treatment targets. in highly motivated selected patients treated under optimal con-
It is generally agreed that achieving good glycaemic control with ditions, close-to-normal HbA1c levels are extremely difficult to
concurrent avoidance of hypoglycaemic episodes should be the reach. The HbA1c target in the DCCT intervention group was
primary treatment goal for type 1 diabetic patients. It is not yet less than 6.05%, which is - according to the DCCT-HbA1c stan-
completely clear how good glycaemic control should be defined. dard - close to the upper end of the range of a non-diabetic person
Should it be the goal to get as close as possible to the HbA1c (HbA1c: approx. 4% to 6%). In the EDIC cohort, the observa-
level of a healthy person, or could a higher level be a better target tional continuation of the DCCT, the mean HbA1c increased to
to achieve optimal long-term outcomes when all the benefits and 7.8% and several observational studies on the general population
risks associated with tight blood glucose control are considered? in Europe show that the percentage of patients with type 1 di-
abetes who reach an HbA1c lower than 7.5% is less than 50%
Adverse effects of the intervention
(Calvert 2009; Mortensen 1997; Nordrheinische Gemeinsame
Einrichtung 2008). Considering the difficulty of achieving recom-
For patients with type 2 diabetes, a recent study has raised con-
mended treatment targets, it is even more important to not only
cerns that aiming for very strict glycaemic targets could potentially
look at the benefits of an intervention aiming at strict metabolic
cause more harm than benefit. The ACCORD study (Gerstein
control, but to also carefully consider all possible adverse effects.
2007; Gerstein 2008), which had an HbA1c target of less than
Hypoglycaemic episodes are a relatively common problem in type
6.0% in the intervention group had to be discontinued due to
1 diabetic patients. The event rates for severe hypoglycaemic
an increase in mortality in this group. This effect, however, was
episodes in type 1 diabetic patients reported in various studies lie
not found by other similar trials recently published such as the
between 62 and 320 events per 100 patient-years, whereby a severe
ADVANCE or the VADT trial (Abraira 1997; Duckworth 2009).
episode is defined as one requiring assistance of another person
The reason for this increase in mortality in some studies but not
(Desouza 2010). To what extent frequent hypoglycaemia can have
others has not yet been clearly understood, but it is suggested that
negative long-term effects is not yet fully understood. Recent epi-
patient circumstances such as age, cardiovascular risk factors, type
demiological studies have suggested a link between hypoglycaemia
of antiglycaemic agents and duration of diabetes could potentially
and cardiovascular risk (Desouza 2003; Gill 2009). Other stud-
affect the balance of risks and benefits of tight blood sugar control.
ies have found an association in type 2 diabetic persons between
In addition, as shown in previously published meta-analyses, none
hypoglycaemia and cognitive dysfunction (Whitmer 2009). Fur-
of the trials examining different treatment targets could demon-
thermore, physiological counter-regulation mechanisms triggered
strate a clear superiority of lower glucose target levels regarding
by low blood sugar levels can hinder achieving stable blood glu-
micro- or macrovascular complications. Only for non-fatal my-
cose control and it has been shown that frequent hypoglycaemic
ocardial infarction, a small, but clinically non-relevant reduction
episodes can lead to hypoglycaemia unawareness (Cryer 2008;
in the intervention group was observed (Montori 2009; Turnbull
Zoungas 2010).
2009; Yudkin 2010).
Several trials have shown that intensive glucose control increases
Whether similar concerns could apply to tight blood sugar con-
the risk of hypoglycaemic episodes (DCCT 1993; Shalitin 2008).
trol in individuals with type 1 diabetes is not yet clear. An ob-
In the DCCT, the incidence of severe hypoglycaemia was 68% in
servational analysis of the HbA1c values within the intervention
the intervention group compared to 35% in the control group (
group of the DCCT in relation to the reduction of risk regard-
DCCT 1993), however, no increase in risk of cardiovascular events
ing the development of microvascular complications could not
or other clinical outcomes associated with this higher frequency
identify a threshold or turning point under which a lower HbA1c
of hypoglycaemic episodes has been reported. Another reported
level would be associated with an increase in risk (DCCT 1995b;
adverse effect of tight blood sugar control is weight gain (Conway
DCCT 1996). However, this analysis has not been performed with
2010). Also in the DCCT, the risk of weight gain was increased
regard to macrovascular outcomes. Furthermore, it is problematic
under intensive treatment resulting in 12.7% overweight cases
to assign causality to an observational association between HbA1c
compared to 9.3% cases under conventional treatment (DCCT
and risks. From this association one can not necessarily conclude
1993).
that an intervention that causes a reduction of the HbA1c would
Furthermore, intensive insulin therapy is associated with an in-
show a similar effect.
creased insulin dose compared to conventional insulin therapy
Observational studies show that blood sugar control varies widely
(DCCT 1993). In animal studies, exogenous hyperinsulinaemia
among type 1 diabetic patients (Calvert 2009; Mortensen 1997;
resulted in a thickening of arterial walls, raising concerns that
Thomsett 1999). While some of this variation can be attributed to
higher insulin use might increase the risk of atherosclerosis. How-
behavioural factors, there are also biological influences that make
ever, in human studies the effects of exposure to high levels of in-
control easier for some patients compared to others. For example,
sulin levels on cardiovascular disease remains controversial (Muis
hormonal changes during puberty are thought to be one factor
2005).
contributing to particularly poor control observed in adolescents
Also, potential effects of tight blood sugar control on patients
(Amiel 1986). The results of the DCCT clearly show that even

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 3
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
quality of life should not be ignored. For many patients, achiev- The recommended glycaemic target for type 1 diabetic patients
ing close to normal HbA1c levels might only be possible by ad- varies between less than or equal to 6.5% and less than 7.5% in
hering to a strict treatment plan, which might involve major re- different clinical guidelines (see table 1). Considering that more
strictions on the patients lifestyle, for example through adhering than 50% of type 1 diabetic patients do not achieve the highest
to a strict diet, frequent blood glucose measurements and insulin target of less than 7.5%, as well as evidence from studies on type
injections or the careful documentation of blood measurements, 2 diabetes that strict glucose control could potentially lead to an
insulin doses and food intake, which can be very time-consuming increased mortality risk, the balance of all harms and benefits re-
(Davidson 2004). Not being able to achieve ambitious treatment lated to interventions aiming at lowering glycaemic levels should
targets could also have an effect on the emotional well-being of be carefully evaluated. To date the risks of strict glycaemic control
the patient by creating a feeling of failure or by raising fear about in type 1 diabetic patients are not yet fully understood and might
possible future health complications (Herzer 2010; Ingerski 2010; differ depending on factors such as duration of diabetes, age, hy-
McGrady 2009). poglycaemic unawareness, baseline HbA1c levels, and cardiovas-
cular risk factors. Therefore, a thorough evaluation of the poten-
Why it is important to do this review tial benefits and harms depending on these factors is important.
At the heart of this review lies this question: Considering that with
Recent studies on type 2 diabetes suggest that the effects of tight
current treatment very few type 1 diabetic patients achieve gly-
blood-glucose control on cardiovascular risk is more complex than
caemic levels close to that of a healthy person, should the optimal
originally assumed and might depend on a variety of factors such
treatment always consist of aiming for a lower HbA1c; or could,
as age, diabetes duration, gender and cardiovascular risk factors
depending on different patient factors, a higher glycaemic level
(Desouza 2010). To date it is not clear whether the situation could
be considered optimal when taking into account all harms and
be similar in type 1 diabetes. A meta-analysis from 2006 has found
benefits?
a decrease of long-term clinical outcomes associated with strict
glycaemic control (Stettler 2006). However, in this analysis little
attention was paid to differences regarding age, study duration and
diabetes duration. Furthermore, this meta-analysis only analysed
the risk of macrovascular disease, but did not consider any other OBJECTIVES
outcomes. It also did not study adverse effects of tight blood sugar The primary objective of this review is to assess the effects of dif-
control, such as hypoglycaemia, weight gain, or a potential bur- ferent blood glucose treatment targets in terms of long-term com-
den on the quality of life. In contrast to our review, Stettler et al. plications and determine whether very low, near normoglycaemic
(2006) did not focus on the effects of different treatment targets. values are of additional benefit.
They included all trials that compared regimens with the aim to
improve glycaemic control compared to conventional treatment.
Whether different treatment targets were set for the intensive and
METHODS
conventional treatment was not an inclusion criterion. Further-
more, the search strategy of this meta-analysis has not been doc-
umented; therefore it is difficult to know whether relevant older
studies might have been overlooked. Since 2006, no meta-analysis Criteria for considering studies for this review
has been published on this topic, so it is possible that new results
have been published since.
Since the completion of the DCCT in 1993 intensive insulin ther- Types of studies
apy as well as other treatment innovations, such as new insulin Randomised controlled clinical trials with a parallel group design
analogues (Siebenhofer 2006), have become widely available to comparing different glycaemic treatment targets in people with
many type 1 diabetic patients. In addition, there have been im- type 1 diabetes, which assess any of the outcome measures of
provements regarding the treatment of co-morbidities such as hy- interest for this review and have a follow-up period of at least one
pertension. These factors had a significant impact on the clinical year.
course of type 1 diabetes so that patients prospects today are much
better than what they have been in the past (Nathan 2009). This,
however, also implies that in the future many more type 1 dia- Types of participants
betic patients might reach old age and it will become an important Females and males with type 1 diabetes mellitus of any age will be
question whether the treatment goals, which are predominantly considered. The diagnosis should be based on clearly described cri-
based on relatively young patients, can be applied to an older age teria, which should be consistent with world-wide accepted stan-
group. An analysis of different age subgroups as part of this meta- dards at the time of study initiation (for example ADA 1999; ADA
analysis could potentially provide further insight. 2010; Alberti 1998)

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 4
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of interventions EMBASE
All included trials should (prior to patient allocation) have a pre- We will also search databases of ongoing trials (http://
defined more intensive treatment target in the intervention group [Link]/ with links to several databases and
in comparison with the control group. Ideally, studies with the [Link] We will provide informa-
same treatment regimens in both treatment groups will be in- tion including trial identifier about recognized studies in the sec-
cluded in the review. For studies using different treatment regi- tion Outcomes in the Characteristics of included studies table.
mens (e.g. multiple daily injections versus conventional therapy), For detailed search strategies please see under Appendix 1 (searches
inclusion will be accepted if a difference in glycaemic target can be will not be older than six months at the moment the final review
obviously identified. Trials aiming for the same treatment targets draft is checked into the Cochrane Information and Management
or unspecified treatment targets in the different groups, although System for editorial approval).
achieving differences in glycosylated haemoglobin A1c (HbA1c) If additional key words of relevance are detected during any of the
at follow-up, will be excluded from this review. Either HbA1c (or electronic or other searches we will modify the electronic search
equivalent such as total glycosylated haemoglobin) target levels or strategies to incorporate these terms. We will include studies pub-
target levels measured by fasting blood or plasma glucose or post- lished in any language.
prandial blood or plasma glucose must be presented to fulfil the We will send results of electronic searches to the Editorial Base of
criteria for inclusion. the Cochrane Metabolic and Endocrine Disorders Group.

Types of outcome measures Searching other resources

We will try to identify additional studies by searching the reference
lists of included trials and (systematic) reviews, meta-analyses and
Primary outcomes
health technology assessment reports noticed.
macrovascular complications (nonfatal and fatal myocardial
infarction, stroke);
microvascular complications (manifestation and
progression of retinopathy, nephropathy, neuropathy and end-
Data collection and analysis
stage renal disease);
severe hypoglycaemic episodes.
Selection of studies
Studies will be selected based on the following criteria:
Secondary outcomes the study is a randomised controlled trial;
health-related quality of life; the target population are patients with type 1 diabetes;
adverse events (e.g. hypoglycaemic episodes, ketoacidosis, the intervention of the study aims to achieve an
weight gain); improvement in glycaemic control;
death from any cause; different glycaemic targets have been specified for the
costs. intervention and control group;
outcome measures of interest to our review are recorded as
part of the study.
Timing of outcome measurement
All publications identified by the search strategy will first be anal-
Outcomes will be assessed as short-term (less than two years) and
ysed based on the title and abstract. If the abstract and title do
long-term (two years or more) measurements.
not provide sufficient information, the full-text article will be ob-
tained. All potentially relevant articles will be investigated as full
text. Two authors (B.F., A.S.) will independently assess studies
Search methods for identification of studies according to the selection criteria. Where differences in opinion
exist, they will be resolved by a third party. If resolving disagree-
ment is not possible, the article will be added to those awaiting
Electronic searches assessment and we will contact authors for clarification.
We will use the following sources for the identification of trials: The selection process will be plotted in a flow diagram (Figure
The Cochrane Library 1) in accordance with the PRISMA (preferred reporting items for
MEDLINE systematic reviews and meta-analyses) statement (Liberati 1999).

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 5
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 1. Study flow diagram.

are willing to answer questions regarding their trials. The results

Data extraction and management
of this survey will be published in Appendix 6. Thereafter, we will
Study characteristics will be assessed independently by two authors seek relevant missing information on the trial from the original
(B.F., A.S.) and entered into standard data extraction templates. author(s) of the article, if required.
The data extracted from the identified studies include information
on the study participants, the design of the trial, details of the in-
tervention, and the assessed outcomes. For details see Character-
Dealing with duplicate publications
istics of included studies table, Table 1, Appendix 2, Appendix 3,
Appendix 4, Appendix 5. Disagreements will be resolved by a third If we find several articles related to the same trial, they will be eval-
reviewer and relevant missing information will be sought from the uated together to extract the maximum amount of information.
original authors of the study. We will send an email request to In case of an unresolvable conflict between two articles, we will
contact persons of published studies to enquire whether authors contact the authors.

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 6
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Repeated observations Dealing with missing data
In case of repeated observations on the same participants, the We will obtain relevant missing data from authors, if feasible, and
outcome assessed after the longest follow-up period will be used. carefully perform evaluation of important numerical data such as
screened, randomised patients as well as intention-to-treat (ITT),
as-treated and per-protocol (PP) populations. We will investigate
Assessment of risk of bias in included studies attrition rates, for example drop-outs, losses to follow up and
withdrawals and critically appraise issues of missing data and im-
Two authors (B.F., A.S.) will assess each trial independently. Pos- putation methods (for example last-observation-carried-forward
sible disagreements will be resolved by consensus, or with consul- (LOCF)).
tation of a third party. In cases of disagreement, the rest of the
group will be consulted and a judgement will be made based on
consensus.
We will assess risk of bias using the Cochrane Collaborations tool Assessment of heterogeneity
(Higgins 2011). We will use the following bias criteria: In the event of substantial clinical or methodological or statistical
random sequence generation (selection bias); heterogeneity we will not report study results as meta-analytically
allocation concealment (selection bias); pooled effect estimates. We will identify heterogeneity by visual
blinding (performance bias and detection bias), separated inspection of the forest plots and by using a standard Chi2 test
for blinding of participants and personnel and blinding of with a significance level of = 0.1, in view of the low power of
outcome assessment; this test. We specifically will examine heterogeneity employing the
incomplete outcome data (attrition bias); I2 statistic which quantifies inconsistency across studies to assess
selective reporting (reporting bias); the impact of heterogeneity on the meta-analysis (Higgins 2002;
other bias. Higgins 2003), where an I2 statistic of 75% and more indicates a
considerable level of inconsistency (Higgins 2011).
We will judge risk of bias criteria as low risk, high risk or unclear
When heterogeneity is found, we will attempt to determine po-
risk and use individual bias items as described in the Cochrane
tential reasons for it by examining individual study and subgroup
Handbook for Systematic Reviews of Interventions (Higgins 2011).
characteristics.
We will attach a risk of bias graph figure and risk of bias summary
We expect the following characteristics to introduce clinical het-
figure.
erogeneity:
We will assess the impact of individual bias domains on study
age;
results at endpoint and study levels.
gender;
The overall quality of evidence for each outcome will be assessed
cardio-vascular risk factors;
using the GRADE approach and summarised in the summary of
hypoglycaemia unawareness;
finding table (Guyatt 2008; Higgins 2011). Planned prioritisation
duration of disease;
of evaluated outcomes is provided in the summary of findings
primary versus secondary prevention;
table.
duration of follow-up.

Measures of treatment effect

Assessment of reporting biases
Data analysis will be performed with Review Manager 5.1. For
continuous outcome variables, results will be presented as differ- We will use funnel plots to assess for the potential existence of small
ences in means with 95% confidence intervals (CI). If certain out- study bias. There are a number of explanations for the asymmetry
comes are measured differently across studies, the standardized of a funnel plot (Sterne 2001) and we will carefully interpret the
mean difference will be used instead. For binary outcome vari- results (Lau 2006).
ables, results will be described by relative risks or odds ratios with
95% CI.
Data synthesis
We will primarily summarise low-risk of bias data by means of a
Unit of analysis issues
random-effects model. We will perform statistical analyses accord-
We will take into account the level at which randomisation oc- ing to the statistical guidelines referenced in the newest version
curred, such as cluster-randomised trials and multiple observations of the Cochrane Handbook for Systematic Reviews of Interventions
for the same outcome. (Higgins 2011).

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 7
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Subgroup analysis and investigation of heterogeneity beneficial effects if the baseline HbA1c levels were higher and
potentially less adverse effects.
We will mainly carry out subgroup analyses of the primary out-
come parameters (see above) and investigate interaction. Sensitivity analysis
The following subgroup analyses are planned and the direction of
We will perform sensitivity analyses in order to explore the influ-
the subgroup effect is anticipated as follows (Sun 2010):
ence of the following factors on effect size:
different age groups: we expect stronger effects for adverse
restricting the analysis to published studies;
events in the older age group;
restricting the analysis taking account risk of bias, as
gender: we expect to see no gender differences;
specified above;
duration of diabetes: we expect stronger beneficial effects if
restricting the analysis to very long or large studies to
the duration of diabetes at the time of intervention was shorter;
establish how much they dominate the results;
primary or secondary prevention of micro- and
restricting the analysis to studies using the following filters:
macrovascular endpoints: we expect stronger beneficial effects in
diagnostic criteria, language of publication, source of funding
the primary prevention group;
(industry versus other), country.
specific patient populations (patients with hypoglycaemia
unawareness, patients with cardiovascular risk factors): we expect We will also test the robustness of the results by repeating the
a higher risk of adverse events in patients with hypoglycaemia analysis using different measures of effect size (relative risk, odds
unawareness or cardiovascular risk factors; ratio etc.) and different statistical models (fixed-effect model and
different baseline HbA1c levels: we expect stronger random-effects model).

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Affairs Cooperative Study on Glycemic Control and Calvert 2009
Complications in Type II Diabetes. Archives of Internal Calvert M, Shankar A, McManus RJ, Lester H, Freemantle
Medicine 1997;157(2):1818. N. Effect of the quality and outcomes framework on
ADA 1999 diabetes care in the United Kingdom: retrospective cohort
The Expert Committee on the Diagnosis and Classification study. British Medical Journal (Clinical Research Ed.) 2009;
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the diagnosis and classification of diabetes mellitus. Diabetes Canadian 2008
Care 1999;22(Suppl 1):S519. Canadian Diabetes Association. Clinical practice guidelines
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ADA 2010
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Indicates the major publication for the study

ADDITIONAL TABLES
Table 1. Overview of study populations

Study ID Interven- [n] screened [n] [n] safety [n] ITT [n] finishing study [%] of randomised
tion(s) & con- randomised participants
trol(s) finishing study

ID1 I1: e.g. met- I1: I1: I1: I1: I1: I1:
formin C1: C1: C1: C1: C1: C1:
C1: e.g. T: T: T: T: T: T:
placebo

ID2 I1: I1: I1: I1: I1: I1: I1:

C1: C1: C1: C1: C1: C1: C1:
T: T: T: T: T: T:

ID3 I1: I1: I1: I1: I1: I1: I1:

C1: C1: C1: C1: C1: C1: C1:
T: T: T: T: T: T:

ID3 I1: I1: I1: I1: I1: I1: I1:

C1: C1: C1: C1: C1: C1: C1:
T: T: T: T: T: T:

ID4 I1: I1: I1: I1: I1: I1: I1:

C1: C1: C1: C1: C1: C1: C1:
T: T: T: T: T: T:

ID5 I1: I1: I1: I1: I1: I1: I1:

C1: C1: C1: C1: C1: C1: C1:
T: T: T: T: T: T:

ID6 I1: I1: I1: I1: I1: I1: I1:

C1: C1: C1: C1: C1: C1: C1:
T: T: T: T: T: T:

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 11
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Overview of study populations (Continued)

ID7 I1: I1: I1: I1: I1: I1: I1:

C1: C1: C1: C1: C1: C1: C1:
T: T: T: T: T: T:

ID8 I1: I1: I1: I1: I1: I1: I1:

C1: C1: C1: C1: C1: C1: C1:
T: T: T: T: T: T:

ID9 I1: I1: I1: I1: I1: I1: I1:

C1: C1: C1: C1: C1: C1: C1:
T: T: T: T: T: T:

Total I1: I1:

C1: C1:
T: T:
./. : not reported
C: control; I: intervention; ITT: intention-to-treat; T: Total

APPENDICES

Appendix 1. Search strategies

Search terms

Unless otherwise stated, search terms are free text terms; MeSH = Medical subject heading (MEDLINE medical index term); exp =
exploded MeSH; the dollar sign ($) stands for any character(s); the question mark (?) substitutes one or no characters; tw = text word;
pt = publication type; sh = MeSH; adj = adjacent (i.e. number of words within range of search term)
The Cochrane Library:
#1 MeSH descriptor Diabetes mellitus, type 1 explode all trees
#2 (IDDM in All Text or T1DM in All Text or T1D in All Text)
#3 ( (insulin* depend* in All Text or insulindepend* in All Text) and not (non insulin* depend* in All Text or non insulin-
depend* in All Text) )
#4 (typ? 1 diabet* in All Text or typ?1 diabet* in All Text or typ? I diabet* in All Text or typ?I diabet* in All Text)
#5 (child* in All Text near/2 diabet* in All Text)
#6 (acidos* in All Text near/2 diabet* in All Text)
#7 (labil* in All Text near/2 diabet* in All Text)
#8 (britt* in All Text near/2 diabet* in All Text)
#9 (keto* in All Text near/2 diabet* in All Text)
#10 (juvenil* in All Text near/2 diabet* in All Text)
#11 (autoimmun* in All Text near/2 diabet* in All Text)
#12 (auto in All Text and (immun* in All Text near/2 diabet* in All Text) )

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 12
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

#13 (sudden in All Text and (onset in All Text near/2 diabet* in All Text) )
#14 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13)
#15 (intensiv* in All Text near/3 control* in All Text)
#16 (conventional* in All Text near/3 control* in All Text)
#17 (regular in All Text near/3 control* in All Text)
#18 (tight* in All Text near/3 control* in All Text)
#19 (usual in All Text near/3 control* in All Text)
#20 (routin* in All Text near/3 control* in All Text)
#21 (standard* in All Text near/3 control* in All Text)
#22 (intensiv in All Text near/3 therap* in All Text)
#23 (conventional* in All Text near/3 therap* in All Text)
#24 (regular in All Text near/3 therap* in All Text)
#25 (tight* in All Text near/3 therap* in All Text)
#26 (usual in All Text near/3 therap* in All Text)
#27 (routin* in All Text near/3 therap* in All Text)
#28 (standard* in All Text near/3 therap* in All Text)
#29 (intensiv* in All Text near/3 treatment* in All Text)
#30 (conventional* in All Text near/3 treatment* in All Text)
#31 (regular in All Text near/3 treatment* in All Text)
#32 (tight* in All Text near/3 treatment* in All Text)
#33 (usual in All Text near/3 treatment* in All Text)
#34 (routin* in All Text near/3 treatment* in All Text)
#35 (standard* in All Text near/3 treatment* in All Text)
#36 (intensiv* in All Text near/3 intervention* in All Text)
#37 (conventional in All Text near/3 intervention* in All Text)
#38 (regular in All Text near/3 intervention* in All Text)
#39 (tight* in All Text near/3 intervention* in All Text)
#40 (usual in All Text near/3 intervention* in All Text)
#41 (routin* in All Text near/3 intervention* in All Text)
#42 (standard* in All Text near/3 intervention* in All Text)
#43 (intensiv* in All Text near/3 management* in All Text)
#44 (conventional* in All Text near/3 management* in All Text)
#45 (regular in All Text near/3 management* in All Text)
#46 (tight* in All Text near/3 management* in All Text)
#47 (usual in All Text near/3 management* in All Text)
#48 (routin* in All Text near/3 management* in All Text)
#49 (standard* in All Text near/3 management* in All Text)
#50 (#15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30)
#51 (#31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #
48 or #49)
#52 (#50 or #51)
#53 (#14 and #52)
MEDLINE:
1 exp Diabetes Mellitus, Type 1/
2 exp Diabetic Ketoacidosis/
3 exp Diabetes Complications/
4 (IDDM or T1DM or T1D).tw,ot.
5 ((insulin* depend* or insulin?depend*) not (non-insulin* depend* or non insulindepend*)).tw,ot.
6 (typ? 1 diabet* or typ? I diabet* or typ?1 diabet* or typ?I diabet*).tw,ot.

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 13
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

7 ((acidos* or juvenil* or child* or keto* or labil* or britt*) adj2 diabet*).tw,ot.

8 ((auto-immun* or autoimmun* or sudden onset) adj2 diabet*).tw,ot.
9 (insulin* defic* adj2 absolut*).tw,ot.
10 or/1-9
11 exp Diabetes Insipidus/
12 diabet* [Link],ot.
13 11 or 12
14 10 not 13
15 ((intensiv* or conventional* or regular or tight* or usual or routin* or standard) adj3 (control* or therap* or treatment* or
intervention* or management*)).tw,ot.
16 14 and 15
17 randomized controlled [Link].
18 controlled clinical [Link].
19 randomi?[Link].
20 [Link].
21 drug [Link].
22 [Link].
23 [Link].
24 [Link].
25 or/17-24
26 [Link].
27 exp Technology Assessment, Biomedical/
28 exp Meta-analysis/
29 exp Meta-analysis as topic/
30 [Link],ot.
31 (health technology adj6 assessment$).tw,ot.
32 (meta analy$ or metaanaly$ or meta?analy$).tw,ot.
33 ((review$ or search$) adj10 (literature$ or medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo
or psyclit or healthstar or biosis or current content$ or systemat$)).tw,ot.
34 or/26-33
35 25 or 34
36 (comment or editorial or historical-article).pt.
37 35 not 36
38 16 and 37
39 (animals not (animals and humans)).sh.
40 38 not 39
EMBASE:
1 exp insulin dependent diabetes mellitus/
2 exp diabetic ketoacidosis/
3 (IDDM or T1DM or T1D).tw,ot.
4 ((insulin* depend* or insulin?depend*) not (non insulin* depend* or non insulin?depend*)).tw,ot.
5 ((typ? 1 or typ? I or typ?1 or typ?I) adj2 diabet*).tw,ot.
6 ((acidos* or juvenil* or child* or keto* or labil* or britt*) adj2 diabet*).tw,ot.
7 ((auto-immun* or autoimmun* or sudden onset) adj2 diabet*).tw,ot.
8 (insulin* defic* adj2 absolut*).tw,ot.
9 or/1-8
10 exp diabetes insipidus/
11 diabet* [Link],ot.
12 10 or 11

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 14
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

13 9 not 12
14 ((intensiv* or conventional* or regular or tight* or usual or routin* or standard*) adj3 (control* or therap* or treatment* or
intervention* or management*)).tw,ot.
15 13 and 14
16 exp Randomized Controlled Trial/
17 exp Controlled Clinical Trial/
18 exp Clinical Trial/
19 exp Comparative Study/
20 exp Drug comparison/
21 exp Randomization/
22 exp Crossover procedure/
23 exp Double blind procedure/
24 exp Single blind procedure/
25 exp Placebo/
26 exp Prospective Study/
27 ((clinical or control$ or comparativ$ or placebo$ or prospectiv$ or randomi?ed) adj3 (trial$ or stud$)).ab,ti.
28 (random$ adj6 (allocat$ or assign$ or basis or order$)).ab,ti.
29 ((singl$ or doubl$ or trebl$ or tripl$) adj6 (blind$ or mask$)).ab,ti.
30 (cross over or crossover).ab,ti.
31 or/16-30
32 exp meta analysis/
33 (metaanaly$ or meta analy$ or meta?analy$).ab,ti,ot.
34 ((review$ or search$) adj10 (literature$ or medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo
or psyclit or healthstar or biosis or current content$ or systematic$)).ab,ti,ot.
35 exp Literature/
36 exp Biomedical Technology Assessment/
37 [Link],ot.
38 (health technology adj6 assessment$).tw,ot.
39 or/32-38
40 31 or 39
41 (comment or editorial or historical-article).pt.
42 40 not 41
43 15 and 42
44 limit 43 to human

Appendix 2. Description of interventions

Charac- study ID1 study ID2 study ID3 study ID4 study ID5 study ID6 study ID7 study ID8 study ID9
teristic

Interven- intensive
tion(s) glucose
[route, fre- control
quency, to-
tal dose/
day]

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 15
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Control(s) conven-
[route, fre- tional glu-
quency, to- cose con-
tal dose/ trol
day]

Footnotes
./. : not reported

Appendix 3. Baseline characteristics

Charac- study ID1 study ID2 study ID3 study ID4 study ID5 study ID6 study ID7 study ID8 study ID9
teristic

Interven- intensive
tion(s) glucose
control

Control(s) conven-
tional glu-
cose con-
trol

Participat-
ing popu-
lation

Sex I: I: I: I: I: I: I: I: I:
[female%] C: C: C: C: C: C: C: C: C:
T: T: T: T: T: T: T: T: T:

Age [mean I: I: I: I: I: I: I: I: I:
years (SD)] C: C: C: C: C: C: C: C: C:
T: T: T: T: T: T: T: T: T:

HbA1c I: I: I: I: I: I: I: I: I:
[mean % C: C: C: C: C: C: C: C: C:
(SD)] T: T: T: T: T: T: T: T: T:

BMI I: I: I: I: I: I: I: I: I:
[mean kg/ C: C: C: C: C: C: C: C: C:
m2 (SD)] T: T: T: T: T: T: T: T: T:

Dura- I: I: I: I: I: I: I: I: I:
tion of dis- C: C: C: C: C: C: C: C: C:
ease [mean T: T: T: T:

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 16
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

years (SD)] T: T: T: T: T:

Ethnic I: I: I: I: I: I: I: I: I:
groups [%] C: C: C: C: C: C: C: C: C:
T: T: T: T: T: T: T: T: T:

Dura- I: I: I: I: I: I: I: I: I:
tion of in- C: C: C: C: C: C: C: C: C:
terven- T: T: T: T: T: T: T: T: T:
tion [mean
... (SD)]

Duration I: I: I: I: I: I: I: I: I:
of follow C: C: C: C: C: C: C: C: C:
up [mean . T: T: T: T: T: T: T: T: T:
.. (SD)]

Co-medi- I: I: I: I: I: I: I: I: I:
cations C: C: C: C: C: C: C: C: C:
T: T: T: T: T: T: T: T: T:

Co-inter- I: I: I: I: I: I: I: I: I:
ventions C: C: C: C: C: C: C: C: C:
T: T: T: T: T: T: T: T: T:

Co-mor- I: I: I: I: I: I: I: I: I:
bidities C: C: C: C: C: C: C: C: C:
T: T: T: T: T: T: T: T: T:

Footnotes
./. : not reported
BMI: body mass index; C: control; HbA1c: glycosylated haemoglobin A1c; I: intervention; SD: standard deviation; T: total

Appendix 4. Matrix of study endpoints

Charac- study ID1 study ID2 study ID3 study ID4 study ID5 study ID6 study ID7 study ID8 study ID9
teristic

Interven- intensive
tion(s) glucose
control

Control(s) conven-
tional glu-
cose con-
trol

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 17
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Primary
1
endpoint
(s)

Secondary
2
endpoint
(s)

Other
3
endpoint
(s)

Footnotes
1,2 verbatim statement in the publication; 3 not explicitly stated as primary or secondary endpoint(s) in the publication

./. : not reported

Appendix 5. Adverse events

Charac- study ID1 study ID2 study ID3 study ID4 study ID5 study ID6 study ID7 study ID8 study ID9
teristic

Interven- intensive
tion(s) glucose
control

Control(s) conven-
tional glu-
cose con-
trol

Deaths [n / I: I: I: I: I: I: I: I: I:
N] C: C: C: C: C: C: C: C: C:
T: T: T: T: T: T: T: T: T:

All adverse I: I: I: I: I: I: I: I: I:
events [n / C: C: C: C: C: C: C: C: C:
%] T: T: T: T: T: T: T: T: T:

Severe / se- I: I: I: I: I: I: I: I: I:
ri- C: C: C: C: C: C: C: C: C:
ous adverse T: T: T: T: T: T: T: T: T:
events [n /
%]

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 18
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Drop- I: I: I: I: I: I: I: I: I:
outs due to C: C: C: C: C: C: C: C: C:
adverse T: T: T: T: T: T: T: T: T:
events [n /
%]

Hospital- I: I: I: I: I: I: I: I: I:
isation [n / C: C: C: C: C: C: C: C: C:
%] T: T: T: T: T: T: T: T: T:

Out-pa- I: I: I: I: I: I: I: I: I:
tient treat- C: C: C: C: C: C: C: C: C:
ment [n / T: T: T: T: T: T: T: T: T:
%]

All hypo- I: I: I: I: I: I: I: I: I:
glycaemic C: C: C: C: C: C: C: C: C:
episodes [n T: T: T: T: T: T: T: T: T:
/ %]

Severe / se- I: I: I: I: I: I: I: I: I:
ri- C: C: C: C: C: C: C: C: C:
ous hypo- T: T: T: T: T: T: T: T: T:
glycaemic
episodes [n
/ %]

Defini-
tion of se-
vere / seri-
ous hypo-
glycaemia

Noctur- I: I: I: I: I: I: I: I: I:
nal hypo- C: C: C: C: C: C: C: C: C:
glycaemic T: T: T: T: T: T: T: T: T:
episodes [n
/ %]

Definition
of noctur-
nal hypo-
glycaemia

Symptoms I: I: I: I: I: I: I: I: I:
[n / %] C: C: C: C: C: C: C: C: C:
T: T: T: T: T: T: T: T: T:

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 19
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Footnotes
./. : not reported
C: control; I: intervention; T: total

Appendix 6. Survey of authors reactions to provide information on trials

Charac- study ID1 study ID2 study ID3 study ID4 study ID5 study ID6 study ID7 study ID8 study ID9
teristic

Study au-
thor con-
tacted

Study au-
thor
replied

No
communi-
cation pos-
sible

Footnotes
n: no; y: yes

HISTORY
Protocol first published: Issue 5, 2011

CONTRIBUTIONS OF AUTHORS
BIRGIT FULLERTON: protocol draft, search strategy development, acquirement of trial copies, trial selection, data extraction, data
analysis, data interpretation, review draft, update draft.
ANDREA BERGHOLD: protocol draft, data analysis, data interpretation, review draft, update draft.
KLAUS JEITLER: protocol draft, search strategy development, data interpretation, review draft, update draft.
ANDREA SIEBENHOFER: protocol draft, search strategy development, acquirement of trial copies, trial selection, data extraction,
data analysis, data interpretation, review draft, update draft.

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 20
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DECLARATIONS OF INTEREST
None known.

Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus (Protocol) 21
Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.