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Correspondence: Mikko T. Honkasalo, Nurmijärvi Health Centre, Network of Academic Health Centres, University of Helsinki, Unit of General Practice,
University Hospital of Helsinki, Finland. E-mail: mikko.honkasalo@saunalahti.fi
(Rece ived 3 Ju ne 2010; accepted 4 Ap ril 2011)
ORIGINAL ARTICLE
Severe hypoglycaemia in drug-treated diabetic patients needs attention:
A population-based study
MIKKO T. HONKASALO1, OUTI M. ELONHEIMO2 & TIMO SANE3
1Nurmijär vi Health Centre; Network of Academic Health Centres, University of Helsinki; Unit of General Practice,
University Hospital of Helsinki, 2Network of Academic Health Centres, University of Helsinki; Unit of General Practice,
University Hospital of Helsinki, and 3Department of Endocrinology, University Hospital of Helsinki, Helsinki, Finland
Abstract
Objective. To study one-year incidence and risk factors of severe hypoglycaemias (SH) in adult drug-treated diabetic patients
living in two Finnish communities. Design. The episodes of SH and their risk factors were identifi ed from local ambulance reg-
isters, from the databases of local health care units, and from patient questionnaires. Setting. The target population consisted
of all drug-treated diabetic patients from the two middle-sized communities in southern Finland, altogether 1776 patients.
The study was retrospective. Subjects. A total of 1469 patients (82.7% of the target population) gave informed consent for the
use of their medical records and 1325 patients (74.6% of the target population) returned the detailed 36-item questionnaire.
Results. Of type 1 and type 2 insulin-treated diabetic patients, 14.6% and 1.0%, respectively, needed ambulance or emer-
gency room care (incidence of 30.5 and 3.0 per 100 patient years). However, 31.0% of type 1 and 12.3% of type 2 diabetic
patients reported at least one episode of SH (incidence of 72.0 and 27.0 per 100 patient years). Of all insulin-treated patients,
53 (7.8%) reported three or more episodes of SH. Signifi cant independent risk factors for SH were depression, daily exercise,
and nephropathy but not glycaemic control. Conclusion. The incidence of SH was high in both types of insulin-treated diabetic
patients. However, the recurrent episodes of SH were clustered in a small minority of insulin-treated patients with diabetes.
The risk of SH should be considered when assessing the treatment target for an individual diabetic patient.
Key Words: Insulin-treated diabetes, oral antidiabetic therapy, severe hypoglycaemia, type 1 diabetes, type 2 diabetes
The risk of severe hypoglycaemias (SH) or the fear
of them poses the greatest obstacle to achieving good
glucose control in insulin-treated diabetic patients [1,2].
The population-based studies of the epidemiology of
SH in patients with both type 1 and type 2 diabetes
are quite limited and somewhat controversial [3–7].
Intensive antihyperglycaemic therapy and unaware-
ness of hypoglycaemic symptoms increase the risk of
SH in patients with type 1 diabetes [8–11], although
this has not been the case in all studies [12,13].
Recent prospective clinical trials with very inten-
sive glucose lowering have also shown an increased risk
of SH in patients with type 2 diabetes [14,15], although
some clinical trials have suggested that the risk of SH
is not a problem in insulin-treated patients with type
2 diabetes [16–19] and may be related to the insulin
regimen used [7]. Use of sulphonylureas may increase
the risk of SH, especially in old patients [7].
In our retrospective population-based study we
analysed the rate and risk factors of SH episodes,
which were either self-reported or resulted in ambulance
or emergency room care among diabetic residents of
two Finnish communities during a one-year period.
Material and methods
Study patients
The study was carried out in two medium-sized com-
munities. In the city of Kouvola (31 399 inhabitants;
data from 2004), the primary diabetes care was based
on family doctors. In Nurmijärvi (35 922 inhabitants;
data from 2004), type 1 diabetic patients and most
of the type 2 diabetic patients undergoing intensive
treatment were treated by one primary care doctor. From
the Reimbursement Register of the Social Insurance
Scandinavian Journal of Primary Health Care, 2011; 29: 165–170
ISSN 0281-3432 pri nt/ISSN 1502 -7724 onl ine © 2011 Informa Hea lthcare
DOI : 10. 3109 / 0281 343 2. 2011.5 80 090
166 M.T. Honkasalo et al.
Adult population with reimbursement
for antidiabetic drug therapy living in
two study communities (n=1776)
Informed consent obtained for
collection of data from ambulance
registers and health care units
(Cohort 1, n=1469)
n=760 using insulin
Questionnaire with self-reported
episodes of severe hypoglycaemia
(Cohort 2, n=1325)
Informed consent
not obtained (n=307)
Questionnaire not
returned (n=144)
n=686 using insulin n=639 on oral agents
n=709 on oral agents
Figure 1. The study cohort: insulin-treated diabetic patients living
in the study communities.
The risk of severe hypoglycaemia (SH) has not
been thought to be a problem in the treatment
of type 2 diabetes.
In this population-based study cohort severe •
hypoglycaemias in both type 1 and type 2
insulin-treated diabetic patients seemed to be
more common than previously thought.
Severe hypoglycaemias seem, however, to be •
clustered in a small minority of insulin-treated
diabetic patients.
The risk of severe hypoglycaemia should be •
considered when assessing the treatment target
for an individual diabetic patient.
Institution of Finland we identifi ed 1776 diabetic
patients over 18 years of age and living either in Kou-
vola (951) or Nurmijärvi (827), who were eligible for
reimbursement payments for antidiabetic medication.
Of this target population (1776 subjects), 1469 (cohort
1: 82.7% of the eligible study population) provided
their written consent for the use of their clinical data
from different sources. Of these, 1325 study patients
(cohort 2: 74.6% of the eligible population) also returned
a questionnaire in which they reported the number
of severe hypoglycaemias during the preceding 12
months (year 2005) and data on the risk factors for SH.
The numbers of insulin-treated patients in cohorts 1
and 2 are shown in Figure 1. At the time of the study,
glargine insulin was practically the only long-acting
insulin analogue available and reimbursed and was used
by 56.6% of the study patients with type 1 diabetes.
The demographic data of the study patients as well as
their diabetes type are given in Table I. Of type 1 diabetic
patients 78.7% and almost all (97.7%) with type 2
diabetes were followed-up in primary health care.
Survey of severe hypoglycaemia episodes
SH was defi ned as a condition for which the patient
needs the assistance of another person to recover
from a hypoglycaemic episode as used by the UK
Hypoglycaemia Study Group [20]. In cohort 1 (1469
patients) data on the episodes of SH during 2005
were collected from the patient records used in the
two primary health care centres and in the local hos-
pitals with 24-hour emergency room service, and from
the 24-hour ambulance service registers of these
communities. In cohort 2 (1325 patients) the study
patients were asked to report the number of SH epi-
sodes by answering the following question: “Have
you needed help from another person to recover
from an episode of low blood glucose concentra-
tion (hypoglycaemia or ‘insulin shock’) during the
latest 12 months (year 2005)” using answer options
“No or Yes, __ times”.
Measurement of HbA1c
The HbA1c value used in the data analysis was the
mean of all HbA1c measurements of a patient during
the year 2005. HbA1c was measured in local labora-
tories with immunological assays (Olympus analyzer®
in Nurmijärvi and Roche Integra 800® analyzer in
Kouvola). The correlation coeffi cient between the two
assays was 0.96, but the assay used in Kouvola gave
on average 0.6% units lower HbA1c values than the
assay used in Nurmijärvi as reported earlier [21].
Evaluation of risk factors for severe hypoglycaemia
In the 36-item questionnaire, the study patients
reported data on weight, smoking status (current
smoker or non-smoker), the weekly use of alcohol (the
number of 15 g alcohol doses during a week), living
status (alone or with other people), physical activity
(sedentary, medium, or active), profession (agricul-
ture/labour, white-collar, not in work), depression
(no depression or self-reported feelings of depression
or therapy for depression), the place of residence, the
place of diabetes care (primary health care or hospi-
tal diabetes outpatient unit), the latest doctor’s visit
because of diabetes during the past 12 months (yes
or no). Constant microalbuminuria (recurrent over-
night albumin excretion ⱖ 20 μg/min) or more advanced
renal disease (macroproteinuria or consistently elevated
serum creatinine value) indicated nephropathy. The
level of physical activity was grouped by the number
of weekly episodes of exercise lasting at least half an
Severe hypoglycaemia in drug-treated diabetic patients 167
hour and causing at least slight shortness of breath
or sweating. The level of physical activity was consid-
ered “active” (exercise daily), “medium” (number of
weekly exercise episodes from 2 to 6), or “sedentary”
(exercise less than twice a week). The prevalence of
depression was evaluated by asking the study patients:
“Have you felt depressed during the latest year (2005)
either (1) the whole time, (2) most part of time, (3)
a notable part of the time, (4) sometimes, (5) only a
little part of time, or (6) not at all?” Options 1–4 were
regarded as showing a depressed mood. Current use
of antidepressant medication was collected from
patient records.
Statistics
All the data are given as mean ⫾ standard deviation
(SD). We used Student’s t-test and a chi-squared test
for between-group comparisons. The independent
role of the risk factors for self-reported episodes of SH
was analysed by using multivariate stepwise logistic
regression analysis.
Ethics
The Ethics Committee of the Department of Inter-
nal Medicine in Helsinki Uusimaa Hospital District
approved the study protocol.
Results
Severe hypoglycaemia requiring ambulance or
emergency room care
From the ambulance registers and the patient
records of local hospitals and health care centres we
found altogether 100 episodes of SH in 47 patients
(3.2% of all patients in cohort 1), of whom 46 were
on insulin therapy (6.1% of all insulin-treated
patients in cohort 1, Table II). Ambulance person-
nel treated 72 of 91 SH episodes on site, whereas
19 patients were subsequently transferred to emer-
gency room care.
Self-reported episodes of severe hypoglycaemia
The total number of self-reported SH episodes in the
study year was 340, of which 302 episodes occurred
among 132 insulin-treated patients, and 38 episodes
among 24 patients on oral therapy (see Table II).
Altogether 31.0% of the patients with type 1 diabetes
and 12.3% of those with type 2 diabetes reported at
least one SH episode (the incidence rates are given
in Table II). Of all study patients the recurrent epi-
sodes of SH were clustered among 56 (4.2%) patients,
of whom 33, 20, and three had type 1, type 2, and sec-
ondary diabetes, respectively. There was no signifi -
cant difference in the incidence of SH among patients
living in the two communities studied.
Table I. Demographic data of the study patients (mean ⫾ SD).
Kouvola Nurmijärvi All patients
No. of patients eligible for the study 951 827 1776
No. of patients with informed consent (cohort 1) 686 (72%)1783 (95%)11469 (83%)1
No. of patients with returned questionnaire (cohort 2) 588 (62%)1737 (89%)11325 (75%)1
Age, years (cohort 2) 62.7 ⫾ 13.7 60.8 ⫾ 13.3 61.6 ⫾ 13.5
Age at time of diabetes diagnosis (cohort 2, data from patient records) 46.1 ⫾ 18.0 49.4 ⫾ 17.0 48.5 ⫾ 17.3
Duration of diabetes, years (cohort 2; data from questionnaires) 13.3 ⫾ 10.6 12.4 ⫾ 11.2 12.8 ⫾ 11.0
No. of patients with type 1/type 2 diabetes2 (cohort 2) 104/479 135/586 239/1065
No. of patients on insulin therapy (cohort 2) 274 (46.6%) 412 (55.9%) 686 (51.8%)
HbA1c (cohort 2)
all diabetic patients
Type 1
Type 2 with oral therapy
Type 2 with insulin therapy
7.34 ⫾ 1.20
8.21 ⫾ 1.27
6.83 ⫾ 0.89
7.76 ⫾ 1.21
7.45 ⫾ 1.25
8.21 ⫾ 1.25
6.69 ⫾ 0.83
7.96 ⫾ 1.18
7.41 ⫾ 1.23
8.21 ⫾ 1.26
6.76 ⫾ 0.86
7.89 ⫾ 1.19
1Percentage of eligible patients; 221 patients with diabetes secondary to pancreatitis, pancreatic trauma, or resection of pancreas were not
included in these fi gures.
Table II. Number and incidence (per 100 patient years) of
episodes of severe hypoglycaemia (SH) grouped by diabetes
type and mode of treatment.
Type of diabetes
Self-reported
episodes of SH
No. of episodes
Incidence
(patients)
SH episodes
needing
ambulance or
emergency care
No. of episodes
Incidence
(patients)
Type 1 diabetes 172 (74) 72.0 73 (35) 30.5
Type 2 diabetes, all
Insulin treated
Oral treated
154 (77)
116 (53)
38 (24)
14.4
27.0
6.0
14 (11)
13 (10)
1 (1)
1.3
3.0
0.2
Secondary diabetes 14 (5) 66.7 13 (1) 61.9
168 M.T. Honkasalo et al.
Severe hypoglycaemia in relation to diabetes type and
quality of basal insulin
The absolute number of self-reported SH episodes
was almost equal to both major types of diabetes (see
Table II) although 73% of SH episodes needing ambu-
lance or emergency room service occurred in patients
with type 1 diabetes. There was no statistically signifi -
cant difference in the occurrence of SH between type
1 diabetic patients using either NPH (neutral protamine
Hagedorn) or glargine insulin as basal insulin (data
not shown).
Risk factors of severe hypoglycaemia
In the logistic multivariate analysis independent risk
factors of SH were nephropathy, depression, active
physical exercise, and follow-up of diabetic patients
in secondary or tertiary care hospitals (Table III). In
contrast, HbA1c (OR [odds ratio] 1.063; 95% CI
(confi dence interval) 0.874–1.293), smoking or even
alcohol use were not independent risk factors for SH.
Other variables included in the multivariate analysis
were the duration of the diabetes, the living status of
the patient (alone or with other people), the place of
residence (Kouvola vs. Nurmijärvi), diabetes controls
by a doctor during the year (yes or no), diabetes type,
and the mode of diabetes care (oral therapy, insulin,
or their combination). It is worth noting that 11 (19%)
diabetic patients with recurrent episodes (three or more)
of SH were outliers of any diabetes care, since they
had no diabetes-related visits to any doctor during the
observation year [22].
Discussion
In this population-based study, we have found that
31% of the patients with type 1 diabetes and 12% of
the insulin-treated patients with type 2 diabetes had
at least one episode of severe hypoglycaemia during
a one-year period. The number of ambulance or
emergency room treated SH episodes comprised just
the tip of the iceberg, since only 6% of all insulin-
treated patients needed intensive treatment for SH.
Recurrent episodes of SH occurred in 8% of the
insulin-treated patients. Of patients with type 2 dia-
betes using oral therapy only 4% reported a single
episode of SH and only one patient needed ambu-
lance care.
The strength of our study is the use of three dif-
ferent data sources to cover all possible episodes of
SH in an unselected population. Moreover, data were
collected from an observation period of one year. We
found no difference in the overall incidence rate of
SH between the communities although the primary
health care of the insulin-treated patients was orga-
nized differently. Due to the retrospective nature of
the study it is possible that patients under-reported
or even over-reported the episodes of SH, and the
understanding of the SH defi nition may have varied.
Inaccuracy of recall of the rate of hypoglycaemia has
previously been documented [23], therefore the exact
incidence of SH may still remain in the dark. Of all the
SH episodes, the majority received treatment from
another person without any action by health care per-
sonnel. Therefore, in everyday care, the majority of
SH episodes may go undocumented in clinical data-
bases. Of patients with recurrent SH, 19% were out-
liers of standard medical care (i.e. they had no visits
to a doctor during the observation year because of
their diabetes) although they seemed to have remark-
able problems with their glycaemic control. Patients
requiring ambulance care received treatment mostly
at the hands of on-site ambulance personnel as has
been shown previously [24].
The overall incidence of SH among type 1 dia-
betic patients was much higher than observed in the
Diabetes Control and Complications Trial (DCCT)
and some other clinical trials [4,6]. This may be exp-
lained by the clustering of SH in patients who
appeared to receive no structured diabetes care. Of
note is that 69% of type 1 and 88% of insulin-treated
type 2 diabetic patients did not experience a single
SH episode. At the time of data collection, the use of
long-acting insulin analogues started in Finland and
was eligible for reimbursement only among type 1 dia-
betic patients. However, we observed no lower risk
for SH among patients using long-acting insulin ana-
logues than among those using NPH insulin as expected
on the basis of clinical trials [25]. At the time of the
study all insulin-treated patients with type 2 diabetes
still received NPH insulin.
The international guidelines for the treatment of
diabetes have brought the goals of HbA1c levels closer
to normoglycaemia in both type 1 and type 2 diabetes
although recent data suggest that intensive therapy
Table III. Risk factors for severe hypoglycaemia.
Variant OR 95.0% CI
Age 1.0 0.9–1.0
Depression 1.6 1.0–2.6
Daily exercise 2.5 1.1–5.6
Nephropathy 2.0 1.2–3.5
Follow-up in secondary or
tertiary care hospitals
2.1 1.0–4.3
Duration of diabetes
Less than 10 years
From 10 to 30 years
Over 30 years
0.8
1.6
1.1
0.4–1.7
0.9–2.8
0.5–2.6
Oral therapy only 0.2 0.1–0.5
Insulin therapy only 2.5 0.6–10.1
Combination therapy 0.8 0.4–1.6
Severe hypoglycaemia in drug-treated diabetic patients 169
for type 2 diabetes may even increase mortality [15].
Some have considered the occurrence of SH to be a
minor problem in type 2 diabetes compared with
type 1 diabetes [16,18], although observational studies
have yielded contradictory results [4,6]. In line with
these data, we found the rate of SH among insulin-
treated type 2 diabetic patients to be about one-third
to half of the rate of type 1 patients, but the absolute
number of SH episodes was nearly equal within the
two major types of diabetes.
Unawareness of hypoglycaemia, long diabetes dura-
tion, previous episodes of SH, strict glycaemic con-
trol, and male gender are well-known risk factors for
SH [7,11,26,27]. We did, however, not fi nd any neg-
ative correlation between the HbA1c level and the risk
of SH, even if insulin-treated patients were analysed
separately. This may be explained by the fact that SH
episodes were clustered in some poorly controlled
patients with high HbA1c. One weakness of our study
was that we did not record data on awareness of hypo-
glycaemia in our patients.
Interestingly, depression and high daily physical
activity turned out to be independent risk factors of
SH. The connections between SH risk and depres-
sion as well as SH risk and abundant physical activ-
ity are fi ndings not often reported in previous studies.
Although the presence and severity of depression were
evaluated only with one question in our 36-item ques-
tionnaire, we found an independent positive correla-
tion between SH and depression. It still remains
uncertain whether the depression is a partial cause
or a consequence of the labile glycaemic control. A
link between diabetes in general and depression has
recently been found in other studies [28–30] or com-
mon aetiological factors may exist behind these two
disorders [30]. Physically very active diabetic patients
seemed to have a 2.5-fold increased risk of SH. Vary-
ing level of physical activity may be a challenge for
tailoring personal insulin therapy [31].
In conclusion, our population-based study revealed
a high incidence of SH among both type 1 and insulin-
treated type 2 diabetic patients. The recurrent
episodes of SH were clustered in a minority of insulin-
treated patients, many of them being outliers of any
diabetes care. The risk of SH must always be con-
sidered among insulin-treated patients and the avoid-
ance of hypoglycaemia should be a major target in
their treatment.
Acknowledgements
This study benefi ted from the support of the Finnish
Diabetes Research Foundation. The authors would
like to thank the nurses at the Kouvola and Nurmi-
järvi Health Centres who participated in gathering
the data.
Declaration of competing interests
Nothing to declare.
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