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An Evaluation of Methods of Assessing Impaired Awareness of Hypoglycemia in Type 1 Diabetes

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Jacqueline Geddes
Jacqueline Geddes
Jacqueline Geddes
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Rohana J Wright
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Nicola N Zammitt at NHS Lothian
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Ian Deary at University of Edinburgh
Ian Deary
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Abstract

Subjective recognition of the warning symptoms of hypoglycemia is fundamental to allow self-treatment and prevent progression to severe hypoglycemia (1,2). Recognition of the onset of these premonitory symptoms constitutes awareness of hypoglycemia (3). With increasing duration of insulin therapy, many people with type 1 diabetes experience a change in their hypoglycemia awareness associated with either a reduction in symptom intensity or a change in symptom profile or both (3–6). Impaired awareness of hypoglycemia (IAH) is associated with a sixfold greater frequency of severe hypoglycemia and is a recognized risk factor for this problem (7,8). Accurate identification of individuals with IAH is important to allow modification of glycemic targets and to adjust insulin therapy to minimize hypoglycemia risk. Three methods have been proposed to assess awareness of hypoglycemia for clinical application (7–9) but to date have not been compared directly. The present study was performed in a randomly selected cohort of individuals with type 1 diabetes to assess the concordance between these methods in ascertaining the prevalence of IAH and whether the methods have equivalent sensitivity in identifying affected individuals. A total of 140 participants were recruited; 80 completed the study. Those who completed the study were significantly older than those who did not ( n = 60) (mean ± SD age 47.6 ± 12.7 vs. 41.1 ± 12.6 years, respectively, P = 0.04). No differences in duration of diabetes ( P = 0.7) or in glycemic control ( P = 0.35) were observed between these two groups. All completed a questionnaire to assess awareness of hypoglycemia using each of the methods presented by Gold et al. …
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AN EVALUATION OF METHODS OF ASSESSING IMPAIRED
AWARENESS OF HYPOGLYCEMIA IN TYPE 1 DIABETES
Received for publication 26 December 2006 and accepted in revised form 28 March
2007.
J Geddes
a
MRCP (UK), RJ Wright
a
MRCP (UK), NN Zammitt
a
MRCP (UK),
IJ Deary
b
PhD, BM Frier
a
MD
a
Diabetes, Royal Infirmary of Edinburgh,
b
Psychology, University of Edinburgh,
Edinburgh, United Kingdom.
Correspondence to:
Professor Brian M Frier
Consultant Physician and Honorary Professor of Diabetes
The Royal Infirmary of Edinburgh
51 Little France Crescent
Edinburgh. EH16 4SA
Scotland
United Kingdom
Email: brian.frier@luht.scot.nhs.uk
Short running title: Evaluation of hypoglycemia awareness
1
Diabetes Care In Press, published online April 6, 2007
Copyright American Diabetes Association, Inc., 2007
Diabetes Care In Press, published online April 6, 2007
Copyright American Diabetes Association, Inc., 2007
INTRODUCTION
Subjective recognition of the warning
symptoms of hypoglycemia is
fundamental to allow self-treatment and
prevent progression to severe
hypoglycemia (SH)
1,2
. Recognition of
the onset of these premonitory
symptoms constitutes “awareness” of
hypoglycemia
3
. With increasing
duration of insulin therapy, many
people
with type 1 diabetes experience a change
in their hypoglycemia awareness
associated with either a reduction in
symptom intensity or a change in
symptom profile, or both
3-6
. Impaired
awareness of hypoglycemia (IAH) is
associated with a six-fold greater
frequency of SH and is a recognised risk
factor for this problem
7,8
.
Accurate identification of individuals
with IAH is important to allow
modification of their glycemic targets
and to adjust insulin therapy to minimise
hypoglycemia risk. Three methods have
been proposed to assess awareness of
hypoglycemia for clinical application
7-9
,
but to date have not been compared
directly. The present study was
performed in a randomly selected cohort
of people with type 1 diabetes to assess
the concordance between these methods
in ascertaining the prevalence of IAH
and whether the methods have
equivalent sensitivity in identifying
affected individuals.
SUBJECTS AND METHODS
Subjects
One hundred and forty participants were
recruited; 80 completed the study. Those
who completed the study (n = 80) were
significantly older than those who did
not (n = 60), (47.6 (12.7) vs 41.1 (12.6)
years, p = 0.04). No differences in
duration of diabetes (p = 0.7) or in
glycemic control (p = 0.35) were
observed between these two groups. All
completed a questionnaire to assess
awareness of hypoglycemia using each
of the three methods (Gold
7
, Clarke
8
,
Pedersen-Bjergaard
9
). The participants
were then asked to perform capillary
blood glucose measurements (using their
own blood glucose meters) four times
daily, prospectively over a four-week
period. When any blood glucose value
was recorded < 3 mmol/L (54mg/dl), the
subjects were asked to complete a
validated symptom questionnaire (the
Edinburgh Hypoglycemia Score
10
) to
document the nature (autonomic,
neuroglycopenic and malaise) and the
intensity of the hypoglycemic symptoms
that were experienced. Completed
diaries and information sheets (n=80)
were returned at the conclusion of the
monitoring period.Methods of assessing
awareness of hypoglycemia
The Gold method
7
poses the question:
“do you know when your hypos are
commencing?” The respondent then
completes a 7-point Likert scale with 1
representing “always aware” and 7
representing “never aware”. A score of 4
or more implies impaired awareness of
hypoglycemia.
The Clarke method
8
comprises eight
questions characterising the participant’s
exposure to episodes of moderate and
severe hypoglycemia. It also examines
the glycemic threshold for, and
symptomatic responses to,
hypoglycemia. A score of 4 or more
implies impaired awareness of
hypoglycemia.
The Pedersen-Bjergaard method
9
requires the patient to respond to the
question: “do you have symptoms when
you have a hypo?” requiring the
selection of one response from
“always”, “sometimes” or “never”.
Only patients who answer “always” are
considered to have normal symptomatic
awareness of hypoglycemia, the others
are designated as having impaired or
absent awareness”.
2
Differences between groups (normal
awareness versus IAH) were analyzed
using the two-sample t test/Mann-
Whitney-U test or the χ
2
/Fishers exact
test. To assess the linear relationship
between two variables a Spearman rank
correlation coefficient was calculated.
All analyses were performed using
SPSS version 12.0 for Microsoft
Windows.
RESULTS
Prevalence of impaired awareness of
hypoglycemia
The prevalences of IAH as identified by
the Gold , Clarke and Pedersen-
Bjergaard methods were 24%, 26% and
62.5% respectively. A strong
association, using Spearman’s test was
found between the Gold and Clarke
methods for identifying impaired
awareness (r
s
= 0.868, p = 0.001). If the
Pedersen-Bjergaard method was revised
to include “always and usually”
representing normal awareness and
“occasionally and never” representing
IAH in response to the question “do you
have symptoms when you have a hypo?”
the percentage of IAH fell substantially
to 15.4%. A poorer correlation was also
demonstrated between this revised
method and with the other methods of
assessment (Gold r = 0.531, Clarke r =
0.536).
Those patients with IAH identified by
the Gold method (p = 0.001) and the
Clarke method (p = 0.007) were
significantly older than those with
normal awareness. No such age
difference was observed using the
Pedersen-Bjergaard method (p = 0.10).
The duration of diabetes was
significantly longer in the IAH group of
patients using all three methods but no
statistical difference was observed in
HbA1c between the two groups,
subdivided by state of awareness.
Frequency of biochemical hypoglycemia
(Table 1)
The patients designated as having IAH
using the Gold and Clarke methods
reported a significantly higher number
of episodes of biochemical
hypoglycemia over the four-week
monitoring period than those patients
considered to have normal awareness.
No statistical differences were observed
between the two sub-groups using the
Pedersen-Bjergaard method (p = 0.06).
During this period the reported intensity
of autonomic symptoms was lower
during biochemical hypoglycemia in
those in whom IAH had been identified
using the Clarke and Gold methods,
compared to patients designated as
having normal awareness. No
symptomatic differences were observed
between the groups identified using the
Pedersen-Bjergaard method (p = 0.22).
Using all three methods no statistical
differences were observed between the
groups in either self-reported
neuroglycopenic symptoms or mean
incidence of severe hypoglycemia in the
year preceding the study.
DISCUSSION
In the present study the three methods
currently available to assess
symptomatic awareness of
hypoglycemia were evaluated for their
concordance in identifying impaired
awareness of hypoglycaemia. In the
present randomly selected cohort of
adults with type 1 diabetes, equivalent
prevalences of impaired awareness (24%
and 26%), with a strong correlation (r
s
=
0.868,) were obtained with two of the
methods (Gold and Clarke). This is
consistent with previous population
surveys, which have suggested that,
based on clinical history; approximately
25% of unselected adults with type 1
diabetes have some form of this
acquired syndrome
4,11,12
. A much
higher (62.5%) prevalence was observed
3
using the method of Pedersen-
Bjergaard. Differences between the
methods were also apparent with respect
to patients considered to be at high risk
of impaired awareness. With the Clarke
and Gold methods, the patients
identified as having IAH were older, had
a longer duration of diabetes, had
experienced more episodes of severe
hypoglycemia during the preceding year
and recorded frequent mild biochemical
hypoglycaemia during the monitoring
period. Those with IAH according to the
Gold and Clarke methods had
significantly lower autonomic and non-
significantly higher neuroglycopenic
symptom scores during hypoglycemia
compared to those with intact
awareness, which are recognised
characteristics of this syndrome
7
. The
Pedersen-Bjergaard method appears to
over-estimate the prevalence of IAH and
identified only those people who had a
long duration of diabetes and a history
of previous SH as characteristics
relevant to those who had impaired
symptomatic awareness.
When methods that utilise
questionnaires are used to ascertain
awareness of
hypoglycemia, some overlap may occur.
No currently available method can be
considered to be fully reliable and valid.
However, the Pedersen-Bjergaard
method to identify patients with
impaired awareness of hypoglycemia
offers too simplified an approach to this
complex clinical condition and appears
to be insensitive and undiscriminating,
so over-estimating its prevalence. It
cannot therefore be endorsed for routine
clinical use.
In conclusion, for clinical and research
use, the Clarke and Gold methods
should be used preferentially, either
separately or in combination, to identify
people with type 1 diabetes who have
impaired awareness of hypoglycemia.
Acknowledgements
Dr Jacqueline Geddes was supported by
a research grant from the Chief Scientist
Office of Health of the Scottish
Executive.
4
REFERENCES
1. Deary IJ: Symptoms of hypoglycaemia and effects on mental performance
and emotions. In: Hypoglycaemia in Clinical Diabetes. Eds. Frier BM, Fisher
BM. John Wiley and Sons, Chichester; p29-54, 1999.
2. McAulay V, Deary IJ, Frier BM: Symptoms of hypoglycaemia in people with
diabetes. Diabet Med 2001; 18: 690-705.
3. Frier B.M, Fisher B.M Impaired hypoglycaemia awareness. In:
Hypoglycaemia in Clinical Diabetes. Eds. Frier BM, Fisher BM. John Wiley
and Sons, Chichester; p111-146, 1999.
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hypoglycaemia in 411 Type 1 diabetic patients. Diabet Med 1991; 8: 217-
222.
5. Cryer P, Binder C, Bolli G, Cherrington A, Gale E, Gerich J, Sherwin R.
Hypoglycemia in IDDM. Diabetes 1989; 38:1193-1199.
6. Gerich JE, Mokan M, Veneman T, Korytkowski M, Mitrakou A.
Hypoglycemia unawareness. Endocrine Reviews 1991; 12: 164-179.
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patients with type 1 diabetes and impaired awareness of hypoglycemia.
Diabetes Care 1994; 17: 697-703.
8. Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky
W. Reduced awareness of hypoglycemia in adults with IDDM: A prospective
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1995; 18: 517-522.
9. Pedersen-Bjergaard U, Agerholm-Larsen B, Pramming S, Hougaard P,
Thorsteinsson B. Activity of angiotensin-converting enzyme and risk of
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Diabetologia 1993; 36: 771-777.
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745-9.
5
Table 1 The frequency of episodes of biochemical hypoglycemia over the 4 week
period and recollected total number of episodes of severe hypoglycemia (SH) during
the preceeding year.
Method of
assessment
Gold
7
Clarke
8
Pedersen-Bjergaard
9
Awareness
Normal Impaired p Normal Impaired p Normal Impaired p
From record
sheets (%)
Total
biochemical
glucose values
< 3.0mmol/L
3.49
(3.64)
7.62 (5.35) 0.003 3.40
(2.65)
7.86 (5.10) 0.001 3.31
(3.51)
5.37 (4.90) 0.06
Biochemical
glucose values
2.5-2.9 mmol/
2.38
(2.64)
4.14 (2.92) 0.02 2.33
(2.65)
4.29 (2.81) 0.006 2.26
(2.55)
3.24 (2.91) 0.11
Biochemical
glucose values
<2.5mmol/l
1.11
(1.71)
3.47 (3.81) 0.01 1.02
(1.67)
3.57 (3.80) 0.005 1.05
(1.51)
2.08 (3.11) 0.11
Severe
hypoglycemic
reactions
0 (0) 0.1 (0.7) 0.10 0.05
(0.47)
0 (0) 0.55
0 (0) 0.05 (0.43) 0.44
Autonomic
symptoms
2.88
(1.06)
2.09 (0.99) 0.005 2.96
(1.05)
1.89 (0.79) 0.001 2.87
(1.08)
2.54 (1.09) 0.22
Neuro-
glycopenic
symptoms
2.25
(1.02)
2.45 (1.14) 0.47 2.29
(1.06)
2.35 (1.06) 0.83 2.12
(1.00)
2.41 (1.08) 0.27
From
questionnaire
Incidence of SH
(episodes per
patient year)
0.07
(0.32)
1.57 (2.82) 0.001 0.05 (0.29 1.62 (2.80) 0.001 0 (0) 0.76 (1.98) 0.04
Prevalence of
SH
5% 53% - 5% 57% - 0% 26% -
6
... The primary finding of our study is a confirmation of the usefulness of HypoA-Q, a new selfreport questionnaire designed to assess awareness of hypoglycemia. Traditionally used scales, such as Clarke, Gold, and Pedersen-Bjergaard, have limitations [25]. There are no clear guidelines on the most accurate non-invasive tool for assessing hypoglycemia awareness status, and none of the methods widely used to date are entirely reliable. ...
... In our study, we observed a comparable occurrence of IAH diagnosed by the Clarke and the Gold scales in patients with T1D, consistent with findings from other studies [25,27]. ...
... Patients with IAH reported more lifetime episodes of severe hypoglycemia, which is understandable given that recurrent exposure to hypoglycemia can lead to the development of IAH. Our observations align with those previously announced [25,31]. Additionally, we identified that episodes of severe hypoglycemia were associated with a 31% increased risk of the diagnosis of IAH. ...
Efficacy of selected scales in the assessment of impaired awareness of hypoglycemia in adults with type 1 diabetes
Article
Full-text available
  • Feb 2025
  • Pol Arch Med Wewn
Introduction: Impaired awareness of hypoglycemia (IAH) increases the risk of severe hypoglycemia. Questionnaires may allow for easy identification of patients with IAH and facilitate appropriate intervention. Objectives: This study aims to assess the clinical utility of commonly used questionnaires for diagnosing IAH, providing practical insight for medical professionals. Additionally, we seek to identify clinical factors associated with IAH in adults with type 1 diabetes (T1D), enhancing understanding of this condition in a real-world context. Patients and methods: The study included 252 adults with T1D (135 men) aged 41 years (IQR: 30-52). Awareness of hypoglycemia using the validated questionnaires [Clarke scale, Gold scale, and Hypoglycemia Awareness Questionnaire (HypoA-Q)], anthropometric data, and metabolic control were evaluated. To estimate the optimal cut-off point for the diagnosis of IAH using HypoA-Q, the Receiver Operating Characteristic (ROC) curve analysis was used. IAH was diagnosed by at least one abnormal questionnaire score. Results: We found a cut-off point of 9 points for diagnosing IAH on HypoA-Q (sensitivity of 79%, specificity of 82%, AUC = 0.898). IAH in any abnormal test was found in 98 patients (39%). In the univariable logistic regression models, the diagnosis of IAH was associated with lifetime episodes of severe hypoglycemia, hypertension, glycated hemoglobin (A1c) value, mean glycemia, standard deviation (SD), total, LDL and non-HDL cholesterol levels, and daily dose of insulin. Conclusions: The HypoA-Q, with a 9-point cut-off, demonstrated the highest sensitivity for diagnosing IAH, and may be considered the most valuable screening tool for IAH detection.
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... This result from the current study is consistent with previous studies that used the Pedersen-Bjergaard method (9), in which the prevalence of HU was between 52% and 63% in T1DM and 52% and 56.5% in T2DM patients (15)(16)(17)(18)(19). The Pedersen-Bjergaard method tends to overestimate the prevalence of HU as documented previously by Geddes et al. (12) That study evaluated the concordance between the three methods for assessing awareness of hypoglycemia-the Gold (7), the Clarke (8), and the Pedersen-Bjergaard (9) methodsin patients with T1DM and found a strong correlation between the Clarke and Gold methods but poor correlation between the Pedersen-Bjergaard method and the other two methods. The prevalence of HU was 24%, 26%, and 62.5%, as observed by the Gold, Clarke, and Pedersen-Bjergaard methods, respectively (7). ...
... The factors reported to affect HU are not consistent among different studies, and some factors that were demonstrated to increase the risk for HU in some studies were not confirmed in others. However, long diabetes duration and strict blood sugar control are the most commonly reported factors that raise the risk of HU (12). Nevertheless, in the present study, patients with HU had disease durations and HbA1c levels similar to those of aware subjects, findings that were also documented in other studies (14). ...
Hypoglycemia unawareness among insulin-treated diabetic patients in Madinah, Saudi Arabia: prevalence and risk factors
Article
Full-text available
  • Oct 2023
Background Hypoglycemia unawareness (HU) is associated with significant risks. Screening for impaired awareness of hypoglycemia in patients with diabetes is important to minimize those risks. There are limited data on the prevalence of HU in patients with diabetes in Saudi Arabia (KSA). In the current study, we investigated the frequency of HU and its risk factors among insulin treated diabetic patients in Madinah, KSA. Methods A cross-sectional study was conducted in a diabetes center and four primary healthcare centers at Madinha, KSA. Patients ≥14 years old with type 1 or type 2 diabetes treated with insulin for more than a year were included. HU was assessed by Clarke’s and modified Pedersen-Bjergaard’s scores. The risk factors for HU were determined. Results Of the 413 included patients, 60.3% were women, and 60.8% were on insulin alone. One-third of the participants had T1DM, while 68.5% had T2DM, with median ages of 25 and 56 years, diabetes durations of 10 and 15 years, and durations of insulin use of 10 and 5 years, respectively. The prevalence of HU was 25.2% by Clarke’s survey. The risk factors for HU were poor knowledge of the patient’s latest HbA1c, type of insulin, and dose of insulin. Poor medical follow-up, previous stroke, and ischemic heart disease were the other risk factors for HU. When the modified Pedersen-Bjergaard method was used, the prevalence of HU was 48.9%. Conclusion Despite the advances in diabetes management, HU continues to be prevalent among diabetic patients on insulin, and poor diabetes knowledge is a major risk factor. Diabetes education on self-management is of utmost importance to reduce hypoglycemia and HU.
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... The first part of the questionnaire included a Gold [9] and Clarke [22] Score. Both are validated methods for assessing hypoglycaemia awareness in people with T1D [23]. In brief, for the Gold Score the participant is asked 'Do you know when your hypos are commencing?'. ...
A cross-sectional questionnaire study: Impaired awareness of hypoglycaemia remains prevalent in adults with type 1 diabetes and is associated with the risk of severe hypoglycaemia
Article
Full-text available
Objective Impaired awareness of hypoglycaemia (IAH) is a risk factor for severe hypoglycaemia (SH) in type 1 diabetes (T1D). Much of the IAH prevalence data comes from older studies where participants did not have the benefit of the latest insulins and technologies. This study surveyed the prevalence of IAH and SH in a tertiary adult clinic population and investigated the associated factors. Methods Adults (≥18 years) attending a tertiary T1D clinic completed a questionnaire, including a Gold and Clarke score. Background information was collected from health records. Results 189 people (56.1% female) with T1D (median [IQR] disease duration 19.3 [11.5, 29.1] years and age of 41.0 [29.0, 52.0] years) participated. 17.5% had IAH and 16.0% reported ≥1 episode of SH in the previous 12 months. Those with IAH were more likely to report SH (37.5% versus 11.7%, p = 0.001) a greater number of SH episodes per person (median [IQR] 0 [0,2] versus 0 [0,0] P<0.001) and be female (72.7% versus 52.6%, p = 0.036). Socio-economic deprivation was associated with IAH (p = 0.032) and SH (p = 0.005). Use of technology was the same between IAH vs aware groups, however, participants reporting SH were more likely to use multiple daily injections (p = 0.026). Higher detectable C-peptide concentrations were associated with a reduced risk of SH (p = 0.04). Conclusion Insulin pump and continuous glucose monitor use was comparable in IAH versus aware groups. Despite this, IAH remains a risk factor for SH and is prevalent in females and in older people. Socioeconomic deprivation was associated with IAH and SH, making this an important population to target for interventions.
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Hipoglucemia desapercibida e hipoglucemia severa en población con Diabetes Mellitus
Article
  • Mar 2025
Introducción: El buen control glucémico es fundamental para retrasar o disminuir las complicaciones de la Diabetes Mellitus (DM). La hipoglucemia secundaria al tratamiento insulínico, se cataloga según su severidad. La presentación clínica es variada y su reiteración conduce a bajos umbrales sintomáticos, pudiendo ocasionar hipoglucemia desapercibida; esta última se asocia a su vez con hipoglucemia severa. El objetivo del trabajo fue conocer la prevalencia de hipoglucemia desapercibida y/o severa en pacientes con DM tipo 1 y DM tipo 2 tratados con insulina, así como su asociación con las variables: edad, sexo, tipo de DM, duración de la misma y tipo de insulina utilizada. Metodología: Se realizó un estudio descriptivo observacional, de 4 meses. Se evaluó hipoglucemia desapercibida con el cuestionario validado de Clarke y se utilizó la definición de hipoglucemia severa según el mismo instrumento. Resultados: Se captaron 116 pacientes, 52% sexo masculino, edad promedio 42 años. 60% con DM1, con 13 años promedio de evolución de la DM. La insulina basal más utilizada fue NPH (58.6%). La hipoglucemia desapercibida se registró en 32.8 % (66% para DM 1 y 34 % para DM2) y se asoció significativamente con tiempo de evolución de la DM. En la subpoblación con DM1 (p < 0.001). La hipoglucemia severa se registró en 41.4 % (65 % para DM1 y 35% para DM2). Se demostró la asociación significativa entre hipoglucemia desapercibida y severa (p < 0.001). Conclusiones: Se plantea que las nuevas tecnologías en diabetes puedan ser una herramienta que permita descender estas cifras.
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Electrocardiograpic responses during spontaneous hypoglycaemia in people with type 1 diabetes and impaired awareness of hypoglycaemia
Article
  • Feb 2025
  • DIABETIC MED
Aims Hypoglycaemia causes abnormal cardiac repolarisation, which has been related to sympathoadrenal activation. We examined whether individuals with type 1 diabetes (T1D) and impaired awareness of hypoglycaemia (IAH) were protected against proarrhythmogenic alterations on their electrocardiogram during clinical episodes of hypoglycaemia. Methods Adults with T1D and IAH underwent 96 h of simultaneous ambulatory electrocardiogram and blinded continuous interstitial glucose (IG) monitoring. Measures of cardiac repolarisation and heart rate variability (HRV) were compared during hypoglycaemia versus time and person‐matched euglycaemia. We compared these data to a historical control group of individuals with T1D and no IAH. Results Fourteen individuals (10/14 female) with a mean (SD) age of 39 (10) years and T1D duration of 24 (9) years were examined. Fourteen daytime and 12 nocturnal hypoglycaemic episodes were analysed. During daytime hypoglycaemia versus euglycaemia, the mean (SD) QT c interval was prolonged to 443 (38) versus 422 (27) ms, p = 0.027; the Tpeak‐to‐Tend interval was prolonged to 93 (18) versus 77 (9) ms, p = 0.002; and the T wave area symmetry decreased to 1.19 (0.37) versus 1.39 (0.23), p = 0.014. High‐frequency power decreased during daytime hypoglycaemia versus euglycaemia to 1.66 (0.41) versus 1.92 (0.52), p = 0.038. At daytime, the Tpeak‐to‐Tend interval decreased significantly more (hypoglycaemia vs. euglycaemia) in the IAH group in comparison to the decrease observed in the historical control group of T1D individuals without IAH ( p for interaction 0.005). Cardiac arrhythmias were infrequent and of no clinical significance. Conclusions Hypoglycaemia can still lead to proarrhythmogenic electrocardiographic changes in individuals with T1D and IAH. We observed diurnal, inter‐ and intraindividual variability in responses to hypoglycaemia.
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The challenge of assessing impaired awareness of hypoglycaemia in diabetes in the era of continuous glucose monitoring: A narrative review of evidence and translation into clinical practice
Article
  • Feb 2025
  • DIABETES OBES METAB
Iatrogenic hypoglycaemia remains a major barrier in diabetes care. Over time, and with repeated hypoglycaemic episodes, the physiological responses to hypoglycaemia can become blunted, resulting in impaired awareness of hypoglycaemia (IAH). In IAH, the onset of cognitive dysfunction precedes the onset of autonomic symptoms, often preventing appropriate self‐treatment, thus increasing the frequency of severe hypoglycaemia (SH). Historically, IAH has been assessed with questionnaires, such as the Gold and Clarke scores, which were developed in the 1990s. A stepwise change in diabetes management in the last few decades has been the deployment of continuous glucose monitoring (CGM). CGM allows people with diabetes to set alarms that can warn them of hypoglycaemia or even impending hypoglycaemia, thus providing a degree of ‘technological’ awareness. This creates a challenge in assessing awareness status, as people may be alerted to low‐sensor glucose events before they experience any symptoms. CGM also allows the introduction of new measures of hypoglycaemia exposure such as time below range, which might complement traditional methods of risk assessment. These changes in the field prompt a need for reassessment of the measures of IAH. This narrative review evaluates the current epidemiology of SH and IAH, explores different measures of IAH, and evaluates the relationship between CGM metrics, IAH and SH. We conclude that a clinical approach involving traditional questionnaires, or newer updated alternatives such as the Hypo A‐Q awareness scale, combined with CGM metrics and clinical assessment of human factors is recommended in the absence of a clearly superior measure.
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A cross-sectional questionnaire study: impaired awareness of hypoglycaemia remains prevalent in adults with type 1 diabetes and is associated with the risk of severe hypoglycaemia
Preprint
Full-text available
  • Jan 2024
Objective Impaired awareness of hypoglycaemia (IAH) is a risk factor for severe hypoglycaemia (SH) in type 1 diabetes (T1D). Much of the IAH prevalence data comes from older studies where participants did not have the benefit of the latest insulins and technologies. This study surveyed the prevalence of IAH and SH in a tertiary adult clinic population and investigated the associated factors. Methods Adults (≥18 years) attending a tertiary T1D clinic completed a questionnaire, including a Gold and Clarke score. Background information was collected from health records. Results 189 people (56.1% female) with T1D (median [IQR] disease duration 19.3 [11.5, 29.1] years and age of 41.0 [29.0, 52.0] years) participated. 17.5% had IAH and 16.0% reported ≥1 episode of SH in the previous 12 months. Those with IAH were more likely to report SH (37.5% versus 11.7%, p=0.001) a greater number of SH episodes per person (median [IQR] 0 [0,2] versus 0 [0,0] P<0.001) and be female (72.7% versus 52.6%, p=0.036). Socio-economic deprivation was associated with IAH (p=0.032) and SH (p=0.005). Use of technology was the same between IAH vs aware groups, however, participants reporting SH were more likely to use multiple daily injections (p=0.026). Higher detectable C-peptide concentrations were associated with a reduced risk of SH (p=0.04). Conclusion IAH remains a risk factor for SH and is prevalent in females. Insulin pump and continuous glucose monitor use was comparable in IAH vs aware groups. Socioeconomic deprivation was associated with IAH and SH, making this an important population to target for interventions.
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Forensic Law in Hypoglycaemia-3
Article
  • Sep 2023
“Environmental Enrichment” (EE) is a proven alternative therapy for Type 2 diabetes related complications. EE preserves the Purkinje cells in the brain. The latter is a promising therapy for prevention of diabetes related mental disorders. Sensory nerves are at higher risk of damage in the hyperglycemic milieu leading to diabetic neuropathy. Patients lose sensation in their lower extremities making them vulnerable to injury because they do not feel the pain, which is a warning sign of tissue damage. That can lead to catastrophic outcomes because with high blood glucose, wounds get difficult to heal. Gas gangrene and tissue necrosis develop, leading to the only resort being amputation and life change challenge. Early diagnosis of diabetes is nevertheless crucial in prolonging the onset of diabetes and its complication. To date many candidate early biomolecules have been reported which are promising early indicators for diabetes. However, advancement in this field of research has not been reported. Holistically diet, lifestyle, mental health and clinical treatment of Diabetes and Thyroid Disease, including Addison’s Disease, plays an important role in patient welfare. Tragically many patients die young or go through life suffering from the old Victorian Stigma of being tainted by having to treat an uncurable illness. This is not a joke as suggested in September 2006 in ignorance by a Hertfordshire Insurance Broker describing Diabetes with Neuroglycopenia as a Joke and Nonsense. This caused Obstructed Justice in Law of a critical life-threatening complication of Diabetes and Endocrinology Disease in Hypoglycaemia Unawareness and now in 2023 Otitis Externa and Osteomyelitis as disclosed in a tragic young law student death with likely clinically undiagnosed Otitis Externa and Osteomyelitis. A patient requiring clinician prescribed Insulin justifies clinical respect and understanding in English Law which has been misunderstood since 1994 with sad consequences in this investigation. Today in recovering and managing the COVID-19 Pandemic of 2020 we move forward with new welfare ideas. It is a delight to be able to share some latest work for future research based on 44 years T1 Diabetes experience complimented by Purkinje Cell environmental welfare.
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Hypoglycemic Symptoms and Frequency of Severe Hypoglycemia in Patients Treated With Human and Animal Insulin Preparations
Article
Full-text available
  • Sep 1991
  • DIABETES CARE
To compare hypoglycemic warning symptoms (main objective) and incidence of severe hypoglycemia (secondary objective) between patients treated with animal and human insulin preparations. Two hundred forty-seven patients on treatment with animal insulin preparations and 276 patients on human insulins, matched for duration of diabetes (16 +/- 11 vs. 15 +/- 10 yr), were recruited for the study. Patients were interviewed with a standardized questionnaire. When asked which symptom usually occurs first during hypoglycemia, 19% of the animal insulin group and 22% of the human insulin group answered "sweating," 19 and 17%, respectively, answered "trembling," and 15 and 11%, respectively, answered "unrest." According to the patients' perception, in both groups, their most reliable hypoglycemic warning symptoms were "trembling" (26 and 22%) and "sweating" (15 and 18%). Six and eight percent of patients, respectively, reported hypoglycemia unawareness and 17 and 18%, respectively, impaired awareness of hypoglycemia. The incidence of severe hypoglycemia was 0.45 cases/patient-yr in patients treated with animal insulins and 0.46 cases/patient-yr in patients treated with human insulin preparations. The differences were not statistically significant. This study shows that hypoglycemic warning symptoms and the incidence of severe hypoglycemia are comparable between patients on treatment with human and animal insulin preparations.
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Reduced Awareness of Hypoglycemia in Adults With IDDM: A prospective study of hypoglycemic frequency and associated symptoms
Article
Full-text available
  • Apr 1995
  • DIABETES CARE
To prospectively evaluate the frequency and severity of hypoglycemic episodes in IDDM subjects who declare themselves to have reduced awareness of hypoglycemia, to validate their self-designations in their natural environment, and to determine objectively the presence or absence of autonomic and neuroglycopenic symptoms associated with their low blood glucose (BG) levels. A total of 78 insulin-dependent diabetes mellitus (IDDM) subjects (mean age 38.3 +/- 9.2 years; duration of diabetes 19.3 +/- 10.4 years) completed two sets of assessments separated by 6 months. The assessments included reports of frequency and severity of low BG, symptoms associated with low BG, and a BG symptom/estimation trial using a hand-held computer (HHC). Diaries of hypoglycemic episodes were kept for the intervening 6 months. HbA1 levels were determined at each assessment. Of the subjects, 39 declared themselves as having reduced awareness of hypoglycemia (reduced-awareness subjects). There were no differences between these reduced-awareness subjects and aware subjects with regard to age, sex, disease duration, insulin dose, or HbA1. During the HHC trials, reduced-awareness subjects were significantly less accurate in detecting BG < 3.9 mmol/l (33.2 +/- 47 vs. 47.6 +/- 50% detection, P = 0.001) and had significantly fewer autonomic (0.41 +/- 0.82 vs. 1.08 +/- 1.22, P = 0.006, reduced-awareness vs. aware) and neuroglycopenic (0.44 +/- 0.85 vs. 1.18 +/- 1.32, P = 0.004, reduced-awareness vs. aware) symptoms per subject. Prospective diary records revealed that reduced-awareness subjects experienced more moderate (351 vs. 238, P = 0.026) and severe (50 vs. 17, P = 0.0062) hypoglycemic events. The second assessment results were similar to the first and verified the reliability of the data. IDDM subjects who believe they have reduced awareness of hypoglycemia are generally correct. They have a history of more moderate and severe hypoglycemia, are less accurate at detecting BG < 3.9 mmol/l, and prospectively experience more moderate and severe hypoglycemia than do aware subjects. Neither disease duration nor level of glucose control explains their reduced awareness of hypoglycemia. Reduced-awareness individuals may benefit from interventions designed to teach them to recognize all of their potential early warning symptoms.
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Frequency of Severe Hypoglycemia in Patients With Type I Diabetes With Impaired Awareness of Hypoglycemia
Article
Full-text available
  • Aug 1994
  • DIABETES CARE
To determine the frequency of hypoglycemia in patients with type I diabetes and impaired awareness of hypoglycemia by prospective assessment. A prospective study was undertaken for 12 months in 60 patients with type I diabetes: 29 had impaired awareness of hypoglycemia and 31 retained normal awareness of hypoglycemia. The two groups of patients were matched for age, age at onset of diabetes, duration of diabetes, and glycemic control. Episodes of severe hypoglycemia were recorded within 24 h of the event and verified where possible by witnesses. During the 12 months, 19 (66%) of the patients with impaired awareness had one or more episodes of severe hypoglycemia with an overall incidence of 2.8 episodes.patient-1.year-1. By comparison, 8 (26%) of the patients with normal awareness experienced severe hypoglycemia (P < 0.01) with an annual incidence of 0.5 episode.patient-1.year-1 (P < 0.001). Severe hypoglycemia occurred at different times of the day in the two groups: patients with impaired awareness experienced a greater proportion of episodes during the evening (P = 0.03), and patients with normal awareness experienced a greater proportion in the early morning (P = 0.05). An assessment of fear of hypoglycemia revealed that patients with impaired awareness of hypoglycemia worried more about hypoglycemia than did patients with normal awareness (P = 0.008), but did not modify their behavior accordingly. This prospective evaluation demonstrated that impaired awareness of hypoglycemia predisposes to a sixfold increase in the frequency of severe hypoglycemia, much of which occurred at home during waking hours.
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Impaired Awareness of Hypoglycaemia
Chapter
  • Jan 2014
Impaired awareness of hypoglycaemia (IAH) is the inability to perceive the onset of the warning symptoms of hypoglycaemia, which diminish in intensity and number over time; loss of autonomic symptoms allows neuroglycopenic symptoms to predominate. This acquired syndrome is a consequence of exposure to recurrent hypoglycaemia, which promotes cerebral adaptation to reset the glycaemic threshold for the generation of symptoms to a lower blood glucose level. Cognitive function is preserved at much lower blood glucose levels than usual but severe neuroglycopenia can then rapidly supervene without warning. IAH coexists with deficient counterregulatory responses to hypoglycaemia and affects 20-25% of adults with type 1 diabetes and <10% with insulin-treated type 2 diabetes. A spectrum of abnormality is present, and prevalence increases with duration of diabetes. IAH is associated with a 3 to 6-fold higher risk of severe hypoglycaemia with significant morbidity. It may be reversible if hypoglycaemia is completely eradicated, but affected patients require appropriate insulin regimens, with frequent blood glucose monitoring and regular meals.
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Hypoglycaemia in Clinical Diabetes, Second Edition
Chapter
  • Oct 2007
IntroductionSymptoms of HypoglycaemiaAcute Hypoglycaemia and Cognitive FunctioningAcute Hypoglycaemia and EmotionsConclusions References
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Hypoglycemia Unawareness
Article
  • Dec 1991
Hypoglycemia unawareness can occur in diabetic as well as nondiabetic individuals. A single causative mechanism for its occurrence is not yet apparent. It is likely to be multifactorial but current evidence favors a major role for some type of CNS adaptation. Certainly in some instances, classic autonomic neuropathy could be a contributory factor in patients with longstanding diabetes. Most, if not all, individuals with this condition have reduced plasma epinephrine and/or norepinephrine responses during mild hypoglycemia. Although it may be difficult to distinguish between mere reductions in the magnitude of a response and a true alteration in the threshold to initiate that response, four studies (44, 59, 65, 86) have provided evidence for an increase in the threshold (greater hypoglycemia required) for activation of counterregulatory hormone secretion associated with reduced awareness of hypoglycemia; in one study (44), diabetic patients had developed abnormalities with improved glycemic control after intensive insulin therapy; in another study (59), diabetic patients had recurrent hypoglycemia but did not differ in glycemic control (as assessed by glycosylated hemoglobin values) from subjects aware of hypoglycemia. In the two other studies, patients with impaired counterregulatory hormone responses and hypoglycemia unawareness had lower glycosylated hemoglobin levels than the other patients (65, 86). Altered tissue sensitivity to catecholamines seems unlikely to provide a primary explanation since not all symptoms are adrenergic and since, as mentioned earlier, most patients with this condition have reduced or delayed catecholamine responses to hypoglycemia, which in themselves could explain reduced awareness of hypoglycemia. Furthermore, patients with diabetic autonomic neuropathy have been reported to have increased sensitivity to catecholamines (143). One frequent observation, dating back to the early descriptions of hypoglycemia unawareness (17-19), is that patients with this condition have had frequent episodes of hypoglycemia. Although it is easy to envision how reduced warning symptoms could result in development of severe hypoglycemia, it is quite possible that frequent episodes of hypoglycemia themselves might initiate the process. For example, as depicted in Fig. 4, episodes of mild hypoglycemia occurring in insulinoma patients, diabetic patients undergoing intensive insulin therapy, or patients with longstanding diabetes complicated by autonomic neuropathy and impaired glucagon secretion could lead to CNS adaptation.(ABSTRACT TRUNCATED AT 400 WORDS)
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Symptomatic Hypoglycaemia in 411 Type 1 Diabetic Patients
Article
  • May 1991
The frequency of symptomatic hypoglycaemic episodes was studied in 411 randomly selected conventionally treated Type 1 diabetic out-patients. Between two consecutive visits to the out-patient clinic each patient filled in a questionnaire at home. The number of hypoglycaemic episodes was then recorded prospectively in a diary for 1 week. From the questionnaires, the (retrospective) frequencies of mild and severe symptomatic hypoglycaemia were 1.6 and 0.029 episodes patient-1 week-1. From the diaries, the (prospective) frequencies of mild and severe hypoglycaemic episodes were 1.8 and 0.027 patient-1 week-1. Symptomatic hypoglycaemia was more frequent on working days than during weekends (1.8:1) and more frequent in the morning than during the afternoon, evening, and night (4.5:2.2:1.4:1). The symptoms of hypoglycaemia were non-specific, heterogeneous, and weakened with increasing duration of diabetes. During their diabetic life, 36% of the patients had experienced hypoglycaemic coma. The frequency of hypoglycaemia was positively, but only weakly, correlated with insulin dose, number of injections, percentage unmodified insulin of the total dose, and HbA1c (mild hypoglycaemia only). The frequency was also negatively, but weakly, correlated with age and HbA1c (episodes with coma only), but not correlated with sex, duration of diabetes, or patients' ratings of worries about mild and severe hypoglycaemia.
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Unawareness of Hypoglycaemia in Insulin-treated Diabetic Patients: Prevalence and Relationship to Autonomic Neuropathy
Article
  • Sep 1990
Three-hundred and two insulin-treated diabetic patients were questioned about hypoglycaemia using a structured questionnaire interview. Two-hundred and twenty-six patients (75%) had normal symptomatic awareness, 48 (16%) had partial awareness, 21 (7%) had absent awareness of hypoglycaemia, and 7 (2%) denied ever experiencing hypoglycaemia. Patients with complete loss of awareness of hypoglycaemia had diabetes of longer duration; none had a HbA1 concentration within the non-diabetic range. Loss of awareness of hypoglycaemia was associated with an increased incidence of severe hypoglycaemia, 19 (91%) of the patients with absent awareness, and 33 (69%) with partial awareness of hypoglycaemia experiencing severe hypoglycaemia over 1 year compared with only 41 (18%) of patients with normal awareness of hypoglycaemia (p less than 0.001). Cardiovascular autonomic function tests were performed in 226 (75% of the whole group). Of the patients who had diabetes for more than 15 years, 54% (n = 39) with normal awareness of hypoglycaemia, compared with 59% (n = 10) with absent awareness of hypoglycaemia, had evidence of cardiovascular autonomic impairment (NS). Seven (41%) of the 17 patients with absent awareness of hypoglycaemia and diabetes of greater than 15 years duration had no evidence of autonomic dysfunction. Loss of hypoglycaemia awareness is a common problem in patients with insulin-treated diabetes of long duration, is associated with an increased incidence of severe hypoglycaemia, but is not invariably associated with abnormal cardiovascular autonomic function tests.
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Hypoglycaemia in IDDM
Article
  • Oct 1989
  • DIABETES
Hypoglycemia causes substantial morbidity and some mortality in insulin-dependent diabetes mellitus (IDDM). It is often the limiting factor in attempts to achieve euglycemia. The prevention or correction of hypoglycemia normally involves both dissipation of insulin and activation of glucose counterregulatory systems. Among the latter, glucagon plays a primary role initially, whereas epinephrine is not critical, although it becomes critical when glucagon is deficient. Growth hormone and cortisol play demonstrable roles in recovery from prolonged hypoglycemia. Glucose autoregulation may be involved in defense against severe hypoglycemia. With respect to pathophysiology, counterregulatory systems are involved in at least five clinical glucoregulatory syndromes. Defective glucose counterregulation is associated with, and best attributed to, combined deficiencies of the glucagon and epinephrine responses to plasma glucose decrements. Almost assuredly in concert with hypoglycemia unawareness, it results in a markedly increased frequency of severe hypoglycemia, at least during intensive therapy of IDDM. Defined as a night to morning increase in plasma glucose concentration, the dawn phenomenon is thought to result from dissipation of insulin plus the effects of nocturnal growth hormone secretion. Despite a sound rationale, the clinical relevance of the Somogyi phenomenon has been recently questioned. The clinical impression of altered glycemic thresholds for symptoms, i.e., patients with poorly controlled IDDM suffer symptoms of hypoglycemia at relatively high plasma glucose levels, whereas those with very well-controlled IDDM often tolerate subnormal glucose levels, has received experimental support. Clearly, hypoglycemia in IDDM is a problem that needs to be solved. Numerous issues need to be addressed through both basic and clinical research.(ABSTRACT TRUNCATED AT 250 WORDS)
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