DISCUSSION
Hypoglycaemia, severe hypoglycaemia and IAH are important clinical
problems. Hypoglycaemia is the major limiting factor in achieving
optimal glycaemic control2, while IAH is one of the
most important risk factors for severe hypoglycaemia, increasing the
risk up to six-fold5,9,14. Severe hypoglycaemia can
lead to permanent cognitive impairment, cardiac arrhythmias, seizures
and coma3,5,6,15,16. Other consequences of IAH include
fear of hypoglycaemia, which leads to increased anxiety, decreased
satisfaction and poor treatment compliance, reduced work productivity,
strain in interpersonal relationships and decreased quality of
life5. To compound this problem,
IAH is common in people with T1D.
In prior studies, depending on the study population and method of
assessment, the frequency of IAH can range from 19.5% to
62.5%7,10,14,17. Therefore, assessment for both
symptomatic and asymptomatic hypoglycaemia should be part of routine
diabetes care in patients at risk for
hypoglycaemia3,16. However,
objective
methods to screen for IAH are not in routine clinical use.
Based on Gold score >= 4 and Clarke score >=
4, the frequency of IAH in our study population was
28.3% and 24.6% respectively,
which was similar to previous studies. In a study of 140 T1D subjects in
Edinburgh by Geddes et al, using a Gold score of >=4 and
Clarke score of >=4, the frequency of IAH was 24% and 26%
respectively7. In a subsequent study by the same
author of 518 subjects, 19.5% of subjects had IAH, based on a Gold
score of >=414. A study by Choudhary et
al found a similar IAH frequency of 22.1%, based on a Gold score of
>=415. That said, these studies were all
done in Western populations – as far as we are aware, the Gold and
Clarke scores have only been studied in one prior local study, which had
looked at patients with Type 2 Diabetes (rather than
T1D)18.
Despite fairly similar frequency of IAH, the frequency of severe
hypoglycaemia was lower in our study (32.4% and 41.4% in subjects with
Gold score >= 4 and Clarke score >= 4
respectively) compared to the aforementioned studies by Geddes et al and
Choudhary et al, in which the frequency of severe hypoglycaemia was 50.5
– 57.1% (in subjects with Gold score >= 4) and 57% (in
subjects with Clarke score >= 4)7,14,15.
Increasing age and longer duration of diabetes are well-recognized risk
factors for severe hypoglycaemia1,10,19–21. In our
study, the subjects had a younger age (median age 35 years) and shorter
duration of diabetes (14 years) compared to the subjects in these
studies (mean age 45 – 52 years, mean duration of diabetes 23 – 34
years)5,7,14,15, which might account for the
observation of lower frequency of severe hypoglycaemia.
The Gold and Clarke scores are
simple clinical tools which can be used to screen for IAH. The
underlying basis of these scores is that T1D patients who believe they
have reduced awareness of hypoglycaemia are generally
correct8. Based on the literature, both Gold and
Clarke scores have been validated to be associated with increased
frequency of severe hypoglycaemia over the preceding one year and
increased frequency of biochemical hypoglycaemia over a prospective 4
week period of SMBG5,7,8,14,15. The Clarke score also
correlated with hypoglycaemic events on CGM, defined by glucose
< 3.9 mmol/L and < 3 mmol/L22,
which is not surprising as recurrent hypoglycaemic events leads to
blunted counterregulatory hormonal responses23,24.
Both Gold and Clarke scores were associated with increasing age and
longer duration of diabetes – aforementioned risk factors for severe
hypoglycaemia5,7,14,15, and correlated well with each
other (r2 = 0.868)7,14.
In our study, IAH as defined by Clarke score >= 4 was
associated with increased frequency of hypoglycaemia during the
prospective 4 week period of SMBG and increased frequency of severe
hypoglycaemia over the preceding one year, which was consistent with the
literature. However, no significant association between the Gold score
and these outcomes was found in our study. There was also no observed
association between both scores and age, duration of diabetes or
glycaemic control. A positive, albeit weaker correlation
(r2 = 0.415) between the Gold and Clarke scores was
observed.
There are several possibilities to explain the discrepancies between our
study findings compared to the literature. Firstly, there is an inherent
difference between the Gold and Clarke scores. The Clarke score involves
eight questions while the Gold score requires just a single question.
Therefore, the Gold score might be more susceptible to day-to-day
variation, lower specificity and lower test-retest and inter-rater
reliability25. When added to the fairly small sample
size in our study, this might account for the lack of association
between the Gold score and hypoglycaemic events, as well as the modest
correlation with the Clarke score. Relevant to our findings, Hatle et al
had found that the Clarke score was superior to the Gold score in
identifying subjects at risk of severe hypoglycaemia and clinically
significant hypoglycaemia25.
The HYPO score is a composite
hypoglycaemia score designed by Ryan et al based on the frequency,
severity and degree of unawareness of hypoglycaemia11.
Its primary utility is to provide an objective discriminator of the
severity of problems that occur with hypoglycaemia, in subjects who were
being considered for islet transplantation11. Based on
a cohort of T1D patients in Edmonton, a score of < 423
indicated that hypoglycaemia was unlikely to be a major clinical
concern, a score of 423 – 1046 indicated moderate problems with
hypoglycaemia while a score of >= 1047 (representing
90th percentile) indicated severe problems with
hypoglycaemia11. For comparison, in our study, the
median HYPO score was 6 while the 90th percentile
score was 80. However, the drawback of the HYPO score is that it is
labour and resource intensive, requiring subjects to perform 4 weeks of
SMBG followed by data collection and calculation of the scores, and is
therefore less suitable for routine clinical use. We observed an
association between the HYPO and Clarke score in our study – as far as
we are aware, this is the first study to directly compare the utility of
the HYPO and Clarke score.
On the basis of the relatively high rates of IAH, serious consequences
of severe hypoglycaemia and negligible cost of test administration, we
propose the routine use of the Clarke score in all patients with T1D to
identify IAH7. As described, the Clarke score is
associated with the important clinical outcome of severe hypoglycaemia
as well as diabetes self-management practices, which justifies its use
despite its more time-consuming format. If there are limitations with
its use, for instance due to time constraints in a busy outpatient
clinic, we suggest that physicians obtain the Gold score despite its
lower specificity25. As previously demonstrated by
Pedersen et al, the distribution of severe hypoglycaemia is highly
skewed, with 5% of subjects accounting for 54% of all episodes of
severe hypoglycaemia17. Therefore, the benefit-risk
ratio remains in favour of using these scores, which can allow the
timely diagnosis of this subset of patients at high risk of severe
hypoglycaemia and introduction of specific interventions to prevent
serious complications.
For patients with IAH, the previous main recommendation was strict
avoidance of hypoglycaemia by relaxation of glycaemic targets until
restoration of glycaemic awareness3,9,26. However,
this process might take several weeks to three months, lead to
deterioration in glycaemic control and is difficult to achieve and
sustain in clinical practice9,26. Thus, specific
interventions can be taken to restore glycaemic awareness. These can
broadly be divided into three groups: education, use of technology such
as continuous glucose monitoring (CGM) and continuous subcutaneous
insulin infusion (CSII), and pharmacological methods such as switching
to insulin analogs9,24. For patients who are
refractory to all other measures, islet cell transplantation can be
considered24.
Our study confirms the central
role of education in the potential reduction of IAH, which was
previously demonstrated by the Dose Adjustment For Normal
Eating-Hypoglycaemia Awareness Restoration Training (DAFNE-HART), HyPOS
and HAATT trials27–30. These studies showed that in
subjects with IAH, a psychobehavioural education program led to improved
hypoglycaemic awareness with reductions in severe
hypoglycaemia27–30.
In addition, our study clarified the content and delivery of education
which is most efficacious. In our study, lower rates of IAH (based on
the Clarke score) were seen in patients who had received
group education, dietary
education, education on self-adjustment of insulin doses and education
on blood glucose targets. This is consistent with the findings by Yeoh
et al that group education can improve hypoglycaemia awareness and
reduce severe hypoglycaemia in up to 45% of people with
IAH9. Thus, we suggest that T1D patients who have high
Gold and/or Clarke scores be referred for structured diabetes education,
in a group format if possible, to decrease the risk of IAH and its
complications.
Our study is not without its limitations. This was a single centre study
and the sample size is fairly small, which might account for the lack of
association between the scores and established risk factors for IAH, as
well as the modest correlation between the Gold and Clarke scores. In
this study, capillary glucose testing was used, with about one-third of
patients performing at least 3 blood glucose tests daily. At the time of
this study, flash glucose monitoring was not available in Singapore,
while continuous glucose monitoring was costly and not widely available.
We acknowledge that episodes of hypoglycaemia may be missed during SMBG
due to the limited frequency of testing. However, even today, capillary
blood glucose testing (rather than continuous or flash glucose
monitoring) remains the mainstay of home glucose monitoring for most of
our patients. The continued utility of SMBG even today was well
illustrated by the HypoCOMPaSS study, which showed that when subjects
with IAH were provided with hypoglycaemia-focused structured education,
glucose monitoring and optimised insulin replacement, there was no
difference in hypoglycaemic awareness and treatment satisfaction between
the different methods of glucose monitoring (SMBG vs real-time
CGM)31.
Thus, as our study reflects the “real world” situation in actual
clinical practice, we believe it remains relevant and provides important
information for the management of T1D patients. In addition, the
retrospective nature of the study in the form of a questionnaire
precludes drawing conclusions about causation, for which an
interventional study is required. Despite these limitations, we believe
that based on this study, important recommendations which impact
clinical practice can be drawn.
In conclusion, this is the first available study assessing IAH and its
complications in a cohort of Singapore T1D subjects. Our study
demonstrates that IAH is common and is associated with increased risk of
serious complications, particularly severe hypoglycaemia. Simple
questionnaires such as the Gold and Clarke scores should be routinely
administered to identify patients with IAH who might benefit from
specific interventions, particularly structured diabetes education, to
decrease IAH and its complications.