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Title: Does severe hypoglycaemia influence microvascular complications in Type1 diabetes? An analysis of the Diabetes Control and Complications Trial database

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DIABETICMedicine
DOI: 10.1111/j.1464-5491.2012.03612.x

Short Report: Complications
Does severe hypoglycaemia influence microvascular
complications in Type 1 diabetes? An analysis of the
Diabetes Control and Complications Trial database
E. S. Kilpatrick1, A. S. Rigby2, S. L. Atkin3 and B. M. Frier4
1
Department of Clinical Biochemistry, Hull Royal Infirmary, 2Academic Department of Cardiology, University of Hull, 3Department of Diabetes, Hull York Medical
School, Hull and 4Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK

Accepted 10 February 2012

Abstract
Aims Severe hypoglycaemia may have a role in aggravating micro- and macrovascular disease in diabetes. Data from the
Diabetes Control and Complication Trial have been reanalysed to ascertain whether the frequency of severe hypoglycaemia
exerted an influence on the development and progression of retinopathy or nephropathy in people with Type 1 diabetes.

Using binary longitudinal multiple logistic regression, HbA1c at study baseline, mean HbA1c throughout the study
and the number of severe hypoglycaemic episodes during the trial were compared to examine the risk of development ⁄ progression of retinopathy and nephropathy.

Methods

Average HbA1c during the study and ⁄ or HbA1c at baseline were independently predictive of retinopathy and
nephropathy both in the intensively and the conventionally treated patients (all P £ 0.001). However, the number of
hypoglycaemic episodes did not add to HbA1c in predicting retinopathy [odds ratio (95% CI) 0.99 (0.96–1.01), P = 0.51 in
intensively treated patients, 0.94 (0.89–1.00), P = 0.05, conventional] or nephropathy [odds ratio (95% CI) 0.98 (0.95–
1.01), P = 0.48 intensive, 1.03 (0.98–1.10), P = 0.17 conventional].

Results

Conclusions The frequency of exposure to severe hypoglycaemia did not predict a different risk of developing retinopathy
or nephropathy in either treatment group of the Diabetes Control and Complications Trial at any given HbA1c.

Diabet. Med. 29, 1195–1198 (2012)
Keywords glycated haemoglobin, hypoglycaemia, nephropathy, retinopathy, Type 1 diabetes

Introduction
The main barrier to achieving optimal glycaemia targets in
patients with diabetes is the constant risk of hypoglycaemia.
These targets were derived from studies such as the Diabetes
Control and Complications Trial (DCCT) in Type 1 diabetes
and the UK Prospective Diabetes Study (UKPDS) in Type 2
diabetes, both of which supported an exponential relationship
between rising blood glucose and the risk of either developing
or worsening retinopathy, nephropathy and neuropathy [1–4].
Following these studies, the challenge has been to maintain
near-normal glycaemia while avoiding hypoglycaemia [5].

Correspondence to: Prof. Eric S. Kilpatrick, Department of Clinical Biochemistry, Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ, UK.
E-mail: eric.kilpatrick@hey.nhs.uk

ª 2012 The Authors.
Diabetic Medicine ª 2012 Diabetes UK

The neuroglycopenic effects of hypoglycaemia are well
recognized and their consequences can vary from causing psychological, quality-of-life, driving and employment issues to
substantial physical morbidity [6] and occasional mortality [7]
in people with Type 1 diabetes. More recently, results from the
Action to Control Cardiovascular Risk in Diabetes (ACCORD)
trial and the Action in Diabetes and Vascular Disease: Preterax
and Diamicron Modified Release Controlled Evaluation (ADVANCE) study have focused attention on the possibility that
hypoglycaemia may lead to an increase in macrovascular
disease and events in patients with Type 2 diabetes [10,11]. Of
further interest, the ADVANCE study found hypoglycaemia to
also be associated with a 1.8-fold increase in the development
of new or worsening nephropathy or retinopathy [12]. This
raised the possibility that severe hypoglycaemia could accelerate the development of both macro- and microvascular disease
in Type 2 diabetes.

1195

DIABETICMedicine

Plausible mechanisms for linking severe hypoglycaemia and
the progression of both macro- and microvascular disease have
been suggested [13]. For microvascular disease, it has been
hypothesized that excess free radical production may be a
unifying link in the development of this complication [14].
Hypoglycaemia increases circulating inflammatory markers
[15–17] and may exaggerate the overproduction of reactive
oxygen species that occurs during short-term glycaemic
excursions [18], especially as rebound hyperglycaemia often
follows over-treatment of severe hypoglycaemia.
By comparison with Type 2 diabetes, little evidence is
available to relate hypoglycaemia to the development of vascular disease in Type 1 diabetes, although a a direct association
between the frequency of severe hypoglycaemia and the severity
of macrovascular disease has recently been described [19]. This
present study aimed to establish if any association exists
between hypoglycaemia and microvascular complications in
Type 1 diabetes by re-examining data from the 1441 subjects
who participated in the DCCT.

Subjects and methods
The data sets

We used the publicly accessible data sets collected by the
DCCT and stored in the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK). The DCCT was a
9-year follow-up study of 1441 participants with Type 1
diabetes comparing the effect of intensive vs. conventional
blood glucose management on the development of the microvascular complications of diabetes [1]. At randomization
patients were stratified into one of two cohorts. The primary
prevention cohort (n = 726) had no evidence of retinopathy by
fundus photography and a urinary albumin excretion rate
< 40 mg ⁄ 24 h (28 lg ⁄ min). The secondary prevention cohort
(n = 715) had only minimal retinopathy and an albumin
excretion rate < 200 mg ⁄ 24 h (140 lg ⁄ min). The study
participants were randomized into intensive (n = 711) or
conventional (n = 730) treatment groups.

Definition of hypoglycaemia and microvascular complications

Severe hypoglycaemia was defined as an episode that required
the assistance of another person and was associated with a
blood glucose < 2.78 mmol ⁄ l (< 50 mg ⁄ dl) or prompt recovery following intravenous glucose, glucagon or oral carbohydrate [20]. During a typical year, approximately 27% of
patients in the intensive group and 10% in the conventional
group experienced at least one episode of severe hypoglycaemia.
The development and progression of sustained retinopathy
was defined as a change from baseline of three or more units in
the 25-point Early Diabetic Retinopathy Treatment Study
(EDRTS) interim score on any two successive annual evaluations as predefined by the DCCT investigators [1]. During the

1196

Hypoglycaemia and microvascular risk • E. S. Kilpatrick et al.

9 years of follow-up, 242 people developed sustained retinopathy, 67 of whom were in the intensive treatment group.
Nephropathy was defined as the development of an albumin
excretion rate ‡ 40 mg ⁄ 24 h (28 lg ⁄ min) on any annual
evaluation, providing that the baseline albumin excretion rate
was < 40 mg ⁄ 24 h (28 lg ⁄ min).

Statistical methods

The generalized estimating equation with a logit link was used
to assess the effect of severe hypoglycaemia and other covariates on the development of microvascular complications over
repeated time points [21,22]. The generalized estimating
equation logistic regression method [23], implemented in the
Stata statistical computer package [24], allows for the correlation between repeated measurements on the same patient.
Covariates included in the models were age (years), gender,
disease duration prior to the DCCT (months), HbA1c at
baseline, HbA1c averaged across the study, systolic blood
pressure (mmHg) at baseline, randomization treatment
(intensive vs. conventional, where appropriate) and intervention group (primary vs. secondary). The size, direction and
statistical significance of relationships were estimated by odds
ratios with 95% confidence intervals. The odds ratio
approximates the relative risk [25]. For continuous measurements, the odds ratio is calculated per unit increase; for
example, per 11-mmol ⁄ mol (1%) change in HbA1c. For
categorical variables, one of the categories is set to a reference
of 1.0. A nominal level of 5% statistical significance (twotailed) was assumed.
We related an increasing number of hypoglycaemic episodes
to small vessel disease risk. As the presence of one or more
hypoglycaemic episodes (vs. none) has previously been found to
be associated with microvascular risk [12], we also examined
the effect of this amongst participants in the DCCT.

Results
In the Supporting Information, Table S1 shows simple demographic data for those patients who did, and those who did
not, experience severe hypoglycaemia during the study. There
were 3788 completed reports of severe hypoglycaemia experienced by just under half (n = 720) of the study participants.
The median number of episodes was three (interquartile range
1–6).
Table 1 shows the effect of HbA1c and the number of severe
hypoglycaemia episodes on the risk of retinopathy and
nephropathy development ⁄ progression in intensively treated
patients, conventionally treated patients and in both groups
combined. A further analysis, looking solely at the presence or
absence of severe hypoglycaemia during the study, irrespective
of multiple episodes in the same patient, produced very similar
findings (see also Supporting Information, Table S2). With the
exception of the presence of hypoglycaemia in conventionally
treated patients, each analysis showed little evidence to support

ª 2012 The Authors.
Diabetic Medicine ª 2012 Diabetes UK

Original article

DIABETICMedicine

Table 1 Relating the number of episodes of severe hypoglycaemia to the risk of microvascular complications*
Intensive
Variable
Retinopathy
HbA1c (baseline)
HbA1c (average)
Number of hypos
Nephropathy
HbA1c (baseline)
HbA1c (average)
Number of hypos

Conventional

All data

Odds ratio (95% CI)

P-value

Odds ratio (95% CI)

P-value

Odds ratio (95% CI)

P-value

1.27 (1.13–1.43)
1.47 (1.22–1.78)
0.99 (0.96–1.01)

< 0.001
< 0.001
0.51

1.37 (1.25–1.50)
1.20 (1.07–1.35)
0.94 (0.89–1.00)

< 0.001
0.007
0.05

1.44 (1.30–1.59)
1.51 (1.31–1.74)
0.97 (0.94–1.00)

< 0.001
< 0.001
0.06

1.11 (0.96–1.30)
1.46 (1.16–1.84)
0.98 (0.95–1.01)

0.19
0.001
0.48

1.23 (1.07–1.42)
1.33 (1.11–1.58)
1.03 (0.98–1.10)

0.003
0.001
0.17

1.21 (1.04–1.40)
1.58 (1.28–1.96)
0.99 (0.95–1.03)

0.011
< 0.001
0.81

*Covariates included in the models were age (years), gender, disease duration prior to the Diabetes Control and Complications Trial
(months), HbA1c per 11 mmol ⁄ mol (1%) change at baseline, HbA1c averaged across the study, systolic blood pressure (mmHg) at
baseline, randomization treatment (intensive vs. conventional, where appropriate) and intervention group (primary vs. secondary).

a role for severe hypoglycaemia compounding microvascular
risk or for there to be a dose–response relationship between the
number of episodes of hypoglycaemia and microvascular
complication development.

Discussion
A relationship between the occurrence and frequency of severe
hypoglycaemia in people with Type 1 diabetes and the development and progression of either retinopathy or nephropathy
was not found in the present analysis of data collected in the
DCCT, after adjustment had been made for the study baseline
and mean HbA1c of each subject. This lack of association is
indirectly consistent with two previous analyses of the DCCT
data set. One showed that increasing glucose variability was
independently predictive of severe hypoglycaemia in the study
[26], while another did not find a relationship between large
glycaemic excursions and the development of microvascular
complications [27].
However, this negative finding per se does not completely
refute a putative relationship between hypoglycaemia and
progression of microangiopathy. It is possible that the overall
frequency of exposure to severe hypoglycaemia of the participants in the DCCT may have been insufficient to reveal a
relationship with microvascular disease within the time course
of the study. Unfortunately, the subsequent record of severe
hypoglycaemia in these patients when followed further within
the Epidemiology of Diabetes Interventions and Complications
(EDIC) study was neither sufficiently comprehensive nor robust
to allow an analysis over a longer period of time [28].
Certainly, from a statistical perspective, the negative result is
unlikely to have been attributable to a lack of statistical power,
as we can estimate from our data that, even taking the worst
case scenario (an odds ratio of 0.84 for retinopathy in the
Supporting Information, Table S2), there is a < 35% chance of
this being a false negative.
When the ADVANCE study found a 1.8-fold increase in the
development of new or worsening nephropathy or retinopa-

ª 2012 The Authors.
Diabetic Medicine ª 2012 Diabetes UK

thy, the analysis was unable to determine with certainty
whether there is a causal link between hypoglycaemia and
diabetes complications or whether a propensity to severe
hypoglycaemia identified an individual as also being susceptible to a poor outcome [12]. With respect to the latter, the
investigators speculated that the relationship between severe
hypoglycaemia and microvascular disease could more readily
be explained by the presence of risk factors common to both,
such as older age and longer duration of diabetes. The present
analysis would tend to support this suggestion as no relationship has been found in the much younger group of individuals with Type 1 diabetes in the DCCT (mean age 27 vs.
66 years) who had a shorter average duration (4 vs. 8 years)
of known disease.
In conclusion, this analysis of DCCT data has failed to
provide any evidence to support the role of exposure to hypoglycaemia in the worsening of microvascular complications in
patients with Type 1 diabetes.

Competing interests
Nothing to declare.

Acknowledgements

The Diabetes Control and Complications Trial (DCCT) and its
follow-up the Epidemiology of Diabetes Interventions and
Complications (EDIC) study were conducted by the
DCCT ⁄ EDIC Research Group and supported by National
Institute of Health grants and contracts and by the General
Clinical Research Center Program, NCRR. This manuscript
was not prepared under the auspices of the DCCT ⁄ EDIC study
and does not represent analyses or conclusions either of the
DCCT ⁄ EDIC study group or the National Institute of Health.
We wish to thank the DCCT ⁄ EDIC investigators for making
their trial data set public and therefore allowing independent
investigators to analyse their work for the benefit of patients
with Type 1 diabetes.

1197

Hypoglycaemia and microvascular risk • E. S. Kilpatrick et al.

DIABETICMedicine

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Supporting Information
Additional Supporting Information may be found in the online
version of this article:
Table S1. Baseline characteristics of patients with and without
severe hypoglycaemia.
Table S2. Relating one or more severe hypoglycaemic episodes
to the risk of microvascular complications.
Please note: Wiley-Blackwell are not responsible for the content
or functionality of any supporting materials supplied by the
authors. Any queries (other than for missing material) should
be directed to the corresponding author for the article.

ª 2012 The Authors.
Diabetic Medicine ª 2012 Diabetes UK


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