Hong Kong Med J 2015 Oct;21(5):444–54 | Epub 5 Jun 2015
DOI: 10.12809/hkmj144494
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
REVIEW ARTICLE CME
Avoiding hypoglycaemia: a new target of care for elderly diabetic patients
CW Wong, FHKCP, FHKAM (Medicine)
Department of Medicine and Geriatrics, Caritas Medical Centre, Shamshuipo, Hong Kong
Corresponding author: Dr CW Wong (chitwaiwong@hotmail.com)
Abstract
Optimising glycaemic control to prevent diabetes-associated
complications has received much
attention. The associated risk of iatrogenic
hypoglycaemia, however, is inevitable and can have
a significant impact on health. The prevalence of
iatrogenic hypoglycaemia tends to increase with
advancing age. Elderly people are intrinsically prone
to hypoglycaemia. Ageing attenuates the glucose
counter-regulatory and symptomatic response to
hypoglycaemia, particularly in the presence of a
longer duration of diabetes. Multiple co-morbidities
and polypharmacy correlated with advancing age
also increase the hypoglycaemic risk. In addition
to the acute adverse effects of hypoglycaemia,
such as fall with injury, cardiovascular events and
mortality, a hypoglycaemic episode can have long-term
consequences. Repeated episodes may have a
significant psychological impact and are also a risk
factor for dementia. Because of the heterogeneous
health status of the elderly, not all will benefit from
optimal glycaemic control. Setting an individual
glycaemic target and formulating a management
plan that takes account of the patient’s circumstances
combined with balancing the benefit and risk of
diabetes intervention to avoid hypoglycaemia is
a more practical approach to the management of
elderly diabetic patients.
Introduction
Diabetes mellitus is a prevalent health problem in
the elderly and contributes to significant morbidity
and mortality due to its acute and long-term
complications. Optimising diabetic control to
prevent or delay microvascular complications is
well-established and it may also reduce macrovascular
events. However, it takes time for good diabetic
control to come into effect. Given the heterogeneous
health status of elderly people, diabetes intervention
strategies designed for long-term benefit may not be
appropriate for all elderly patients, especially those
who are frail or who have a limited life expectancy.
Furthermore, hypoglycaemia is an inevitable
complication of good diabetic control and elderly
people are particularly vulnerable, with both acute
and long-term detrimental effects. Thus, avoidance
of hypoglycaemia is important. This review will
discuss the risk factors for hypoglycaemia in the
elderly, the impact of hypoglycaemia, and whether
the elderly can benefit from stringent glycaemic
control. The recently promoted patient-centred
approach to diabetes management in older people
will also be reviewed.
In this article, hypoglycaemia refers to
treatment-induced or iatrogenic hypoglycaemia in
patients with diabetes. It is defined as any episode of
an abnormally low plasma glucose level that exposes
the individual to potential harm,1 2 confirmed by the documentation of Whipple’s triad: symptoms
and signs consistent with hypoglycaemia, a low
blood glucose level, and resolution of symptoms
and signs after blood glucose concentration is
raised.3 There is no definitive blood glucose level to
define hypoglycaemia as the glycaemic threshold
for activation of the physiological defences against
hypoglycaemia and the hypoglycaemic symptom
response are dynamic. It may be shifted to a higher
or lower value depending on the degree of diabetic
control and the prior hypoglycaemic episode.1 The
American Diabetes Association recommends that
diabetic patients with a plasma glucose level of
3.9 mmol/L (70 mg/dL) should be alert to the
possibility of developing hypoglycaemia.1 2 4 5 This
value (3.9 mmol/L, 70 mg/dL) approximates the
glycaemic threshold for activation of physiological
glucose counter-regulatory mechanisms6 7 and is the upper limit of plasma glucose level to blunt
the counter-regulatory response to subsequent
hypoglycaemia8; it is also suggested as the cutoff
value in the classification of hypoglycaemia in
diabetes.1 Severe hypoglycaemia is usually defined as
episode requiring external assistance, while a mild
episode can be self-treated.
Prevalence of hypoglycaemia in type 2 diabetes
The prevalence of diabetes mellitus increases
with age. A local large-scale population-based
epidemiological study using 1985 World Health
Organization (WHO) diagnostic criteria showed
that the prevalence of type 2 diabetes was 26%
in people aged 65 to 74 years, compared with
approximately 10% in those aged 35 to 64 years.9 10 Another local study of 1467 elderly subjects using a
fasting plasma glucose (FPG) level of >7.8 mmol/L
for diabetes screening showed a prevalence of 15%
in people aged 60 to 80 years and 17% in those older
than 80 years.11 These figures would be higher if an
oral glucose tolerance test was performed. Likewise,
the prevalence of diabetes in these studies would
be further increased if the 1999 WHO diagnostic
criteria for diabetes mellitus were used, in which the
cutoff value of FPG is 7 mmol/L.
A high prevalence of diabetes in the elderly
and a corresponding increased consumption of
anti-diabetic therapies implies that the incidence
of iatrogenic hypoglycaemia increases with age.
Nonetheless, the prevalence of hypoglycaemia
is difficult to estimate because it is often under-recognised
and under-reported in clinical practice.
Severe hypoglycaemia is a dramatic event that is
more likely to be reported but the recall of mild
hypoglycaemia is unreliable. The wide variation in
reporting of hypoglycaemia prevalence is due to the
absence of a standardised definition among studies.
In general, the frequency of hypoglycaemia
is substantially lower in type 2 than in type 1
diabetes.12 Event rates for severe hypoglycaemia in
type 2 diabetes range from 3 to 73 episodes per 100
patient-years compared with 62 to 320 episodes per
100 patient-years in type 1 diabetes.4 A number of
variables correlate with hypoglycaemic episodes.
Risk of hypoglycaemia appears to increase with
advancing age even when glycaemic control is
comparable. A prospective observational registry of
3810 patients with type 2 diabetes prescribed oral
anti-diabetic therapy and with comparable glycated
haemoglobin (HbA1c) level (7.3%-7.6%) showed
that 12.8% of those aged ≥70 years, 10.1% aged 60
to 69 years, and 9% aged <60 years experienced
hypoglycaemia, of any severity, in a year.13 Data from
interventional trials showed that the incidence of
hypoglycaemia was higher in the intensive treatment
group. In the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, 2.7% and 52% of patients in the intensive treatment
group experienced severe or minor hypoglycaemic
episodes, respectively during 5 years of follow-up,
compared with 1.5% and 37.3% of patients in the
standard treatment group.14 In the ACCORD (Action
to Control Cardiovascular Risk in Diabetes) trial, the
annual rate of hypoglycaemic episodes requiring
medical assistance was 3.1% in the intensive
treatment group and 1% in the standard treatment
group.15 The prevalence of hypoglycaemia also varies
with different treatment regimens. In the UKPDS
(UK Prospective Diabetes Study), 2.4% of patients
using metformin, 3.3% using sulfonylurea, and 11.2%
using insulin experienced hypoglycaemia requiring
medical attention or hospital admission over 6 years
of follow-up.16 The incidence of hypoglycaemia
also increases with longer duration of diabetes and
insulin treatment.17 It has been reported that the
frequency of severe hypoglycaemia is comparable
in type 1 and 2 diabetes matched for duration of
insulin therapy.18 These findings indicate that as
type 2 diabetic patients become insulin-deficient,
hypoglycaemia becomes more frequent as in type 1
diabetes.
In a local study, drug-induced hypoglycaemia
accounted for approximately 0.5% of admissions
to a local hospital.19 The most vulnerable group
was elderly people with co-morbidities including
macrovascular complications, renal insufficiency,
and concurrent infection, and those living in an
institution or with high dependency.
Elderly people are at risk of hypoglycaemia
Risk factors for hypoglycaemia in type 2 diabetes
are excessive exogenous insulin or insulin
secretagogue, exercise, erratic meal intake with
respect to anti-diabetic therapy intake, treatment
with insulin for more than 10 years, prior
hypoglycaemia, renal insufficiency, alcohol intake,
and polypharmacy.4 18 20 21 22 Advanced age is an independent risk factor for serious hypoglycaemia.
In the Tennessee Medicaid study, diabetic patients
aged ≥80 years treated with insulin or sulfonylureas
had a 1.8-times increased risk of developing serious
hypoglycaemia when compared with those aged 65
to 70 years.23 In a survey of emergency department
visits for hypoglycaemia, diabetic patients aged ≥75
years had twice the number of visits as the general
diabetic population.24 Why are elderly diabetic
patients prone to hypoglycaemia?
Defective glucose counter-regulation and lack of awareness of hypoglycaemia
A fall in blood glucose level initiates a sequence of
hierarchical counter-regulatory responses to limit
the hypoglycaemia.6 7 25 Prior to a blood glucose
level fall below the physiological range (ie 4.7-4.4 mmol/L), insulin secretion from pancreatic islet β-cells is decreased. A further fall in blood glucose level
below the physiological range (ie 3.9-3.6 mmol/L)
precipitates increased glucagon secretion from
pancreatic islet α-cells and epinephrine secretion
from the adrenal medulla. These counter-regulatory
hormones are important to protect against acute
hypoglycaemia. With prolonged hypoglycaemia,
growth hormone and cortisol secretion are
increased to restore the normal blood glucose
level. With a further fall in blood glucose level to 3.1-2.8
mmol/L, hypoglycaemic warning symptoms develop
to prompt a behavioural defence of food ingestion.
Neurogenic or autonomic symptoms—such as
palpitations, tremor, and sweating—that enable a
subjective awareness of hypoglycaemia, are the result
of autonomic activation (both sympathoadrenal
and parasympathetic) and begin at 3.2-3 mmol/L.
Neuroglycopenic symptoms—such as confusion,
seizure, and loss of consciousness—are the result of
brain glucose deprivation and begin at 2.8 mmol/L.
The higher blood glucose level for initiation of
neurogenic warning symptoms than that of onset
of neuroglycopenic symptoms allows time to take
measures to avoid neuroglycopenia and severe
hypoglycaemia.
Glucose counter-regulatory mechanisms are
intact in the early stage of type 2 diabetes and can
effectively protect against hypoglycaemia, thus the
frequency of hypoglycaemic episodes is low. With progression
to insulin deficiency in type 2 diabetes and
in insulin-deficient type 1 diabetes, however, all three
physiological defences of glucose counter-regulation
(decreased insulin secretion, increased glucagon and epinephrine secretion) are compromised.12 26
In the absence of endogenous insulin, the insulin
level is unregulated and depends on the interplay
of absorption and clearance of exogenous insulin.
In the absence of an intra-islet insulin signal, the
glucagon response to hypoglycaemia is lost. In the
absence of both endogenous insulin and glucagon
response, epinephrine is the main defence against
hypoglycaemia in patients with type 1 and advanced
type 2 diabetes requiring insulin. Nonetheless,
the epinephrine response is often attenuated with
the glycaemic threshold for response shifts to
a lower blood glucose level.12 26 This attenuated
epinephrine response is the result of an attenuated
sympathoadrenal response to the falling blood
glucose level that also causes a decrease or loss
of neurogenic warning symptoms, and leads to
hypoglycaemia unawareness.12 26 Compromised glucose counter-regulation and hypoglycaemia
unawareness increase the risk of severe iatrogenic
hypoglycaemia by 25-fold and 6-fold, respectively.27 28
In addition, recent hypoglycaemia induces
hypoglycaemia-associated autonomic failure in
type 1 and advanced type 2 diabetes.12 20 26 29 It
causes further defective glucose counter-regulation
and hypoglycaemia unawareness by reducing
the epinephrine and symptomatic response to
subsequent hypoglycaemia, and thus, a vicious cycle
of recurrent hypoglycaemia ensues.
Since a longer duration of diabetes with
endogenous insulin deficiency often correlates
with advancing age, elderly people are at risk of
compromised glucose counter-regulation and
hypoglycaemia.
Ageing and the physiological response to hypoglycaemia
With increasing age, hypoglycaemic warning
symptoms are less intense and reduced
hypoglycaemic awareness becomes more common,
even with intact counter-regulatory responses.30 31 32 33
This is reflected by the lower autonomic symptom
scores in older people compared with younger
people in the hypoglycaemic clamp studies,30 31 32 33
and that is independent of the presence or absence
of diabetes.34 In addition, half of the middle-aged
(39-64 years) diabetic patients but only one of 13
older (≥65 years) diabetic patients were aware that
their blood glucose level was low during a hypoglycaemic
episode.30 This diminished hypoglycaemia symptom
intensity may be the consequence of the impaired
counter-regulatory response,32 or the impaired end-organ
response to counter-regulatory hormones
(catecholamine) that occurs with advancing age.31
Impaired perception of the warning symptoms of
hypoglycaemia put elderly diabetic patients at a high
risk of severe hypoglycaemic episodes.
The glycaemic threshold gap between the
development of neurogenic and neuroglycopenic
symptoms becomes narrower or even lost in older
people. In a study that compared the response of
healthy younger diabetic men (aged 22-36 years) with
older men (aged 60-70 years) to stepped reduction in
the blood glucose level, neurogenic symptoms began
at a lower blood glucose level in older men than in
younger men (3 ± 0.2 mmol/L vs 3.6 ± 0.1 mmol/L)
and their symptoms were less intense.33 Furthermore,
the difference between the blood glucose level
for subjective awareness of hypoglycaemia and
the onset of cognitive dysfunction was lost in the
older men but retained in the younger men (0 ±
0.2 mmol/L vs 0.8 ± 0.1 mmol/L). This narrower or
absent glycaemic threshold gap between the onset
of neurogenic and neuroglycopenic symptoms
may limit the time available for self-treatment and
increase the risk of evolving into neuroglycopenia
and severe hypoglycaemia in the elderly.
Older people have an increased susceptibility
to cognitive impairment during a hypoglycaemic
episode. In normal situations, they tend to have
a longer reaction time for cognitive performance
(a measure of cognitive function) than younger
people and this reaction time is further prolonged
by hypoglycaemia.30 Psychomotor incoordination
is also more marked and occurs earlier during the
course of hypoglycaemia in older people.33 Thus,
the earlier onset and greater degree of cognitive
dysfunction in the elderly during an episode of
hypoglycaemia may impair their ability to perceive
the warning symptoms to prompt corrective action.
The effect of ageing on the physiological
response to hypoglycaemia indicates that
elderly people are intrinsically at greater risk for
asymptomatic serious hypoglycaemia even before
the start of anti-diabetic therapy.
Co-morbidities and polypharmacy
The prevalence of multiple chronic conditions
increases with advancing age: as many as 40% of
elderly people with diabetes have four or more chronic
conditions.35 In a population-based study, advanced
age and multiple co-morbidities, especially renal
impairment, were the most frequent contributing
factors to severe hypoglycaemia in type 2 diabetic
patients.36 In another study of hypoglycaemia-associated
mortality in patients admitted to general
wards, those who developed hypoglycaemia were
older and had more co-morbidities, regardless of
whether they had diabetes.37 Renal insufficiency
and hepatic disease affecting glucose homeostasis
and drug metabolism increase the hypoglycaemic
risk. Cognitive dysfunction and depression affecting
self-care ability and functionality may cause erratic
timing of medication intake, irregular eating,
inability to self-monitor blood glucose, and failure
to recognise hypoglycaemic symptoms to enable
prompt management, and thus increase the risk of
hypoglycaemia.38 39 40 Elderly people with multiple
co-morbidities are also likely to be admitted to
hospital for worsening or developing complications
of underlying medical illness, which is another
risk factor for subsequent hypoglycaemia. Recent
hospitalisation (first 30 days after discharge)
was associated with a 4.5-times increased risk of
developing serious hypoglycaemia compared with
the risk of ≥366 days after discharge.23 The risk was
further increased with advancing age when patients
aged ≥80 years were compared with those aged
65 to 69 years.
Medications prescribed for co-morbidities
make patients prone to the impact of polypharmacy
and increase the risk of drug side-effects and drug-to-drug interactions. Adverse effects are further
exacerbated in the elderly because of the age-related
changes in pharmacokinetics and pharmacodynamics
that affect drug deposition. Elderly diabetic
patients using four or more concomitant medications
have been found to be at increased risk of developing
serious hypoglycaemia.23 36 In addition to the insulin and insulin secretagogues, a number of drugs (beta-blockers,
angiotensin-converting enzyme inhibitors,
quinine, indomethacin, lithium, levofloxacin) have
been reported to cause hypoglycaemia although
evidence for the associated hypoglycaemia is
poor.4 41 Non-selective beta-blockers exert a potential hypoglycaemic effect by blunting the signs
and symptoms of hypoglycaemia, diminishing the
physiological response to hypoglycaemia and direct
potentiation of the effect of insulin. However, the
evidence to support the increased hypoglycaemic risk
among those prescribed non-selective beta-blockers
is weak despite a 2-fold increased risk reported in
patients on insulin.42 Selective beta-blockers appear
to be safe.42 43 Angiotensin-converting enzyme inhibitors may increase insulin sensitivity in diabetic
patients. They have been found to increase the risk of
hypoglycaemia by nearly 3-fold in patients prescribed
insulin or oral antidiabetic drugs44 although other
studies have failed to show any effect.42 43 Overall, the combination of these commonly used drugs with
insulin and insulin secretagogues in daily practice
may potentiate the hypoglycaemic risk in the elderly
diabetic patients.
Impact of hypoglycaemia
Patients with a hypoglycaemic attack are at risk of
adverse outcomes. The immediate adverse effects
range from unpleasant symptoms, to significant
morbidities such as fall and accident with fracture
and injury,45 46 47 cardiovascular events,48 49 transient
cognitive impairment,50 51 seizure, coma and death. Some of these adverse effects can endure
for a period of time after the hypoglycaemic
episode or have long-term sequelae. In addition to
physical morbidity, hypoglycaemia has a long-term
psychological impact. It is associated with lower
health-related quality of life and greater burden of
depression and fear of hypoglycaemia.52 53 These may preclude patients from adherence to treatment in
order to prevent hypoglycaemic attacks.
Fall and fracture
Elderly people with diabetes are at risk of fall even
in the absence of hypoglycaemic episodes. Diabetes
complications (such as autonomic dysfunction with
orthostatic hypotension, peripheral neuropathy with
gait disorder, and diabetes retinopathy with poor
vision54) and the treatment complications (such as
metformin-associated vitamin B12 deficiency with
resultant neuropathy55) increase the susceptibility of
diabetic patients to fall. Diabetes is itself a factor for
increased fracture risk and elderly diabetic patients
are at even higher risk.56 The underlying mechanisms
are complex.57 Nevertheless, the frail elderly with
multiple co-morbidities including osteoporosis
are vulnerable to bone fracture after fall; both
thiazolidinediones and insulin administration
are found to be associated with increased risk of
fracture.47 56 57 58 In this way, a hypoglycaemic episode
precipitates the pre-existing increased fall and
fracture risk in the elderly diabetic patients.
Cardiovascular complications
Severe hypoglycaemia is a potential risk factor
for cardiovascular disease in people with type 2
diabetes. A meta-analysis of six studies with 903 510
participants and mean age of 60 to 67 years revealed
that severe hypoglycaemia was associated with approximately
twice the risk of cardiovascular disease,
including myocardial infarction, congestive heart
failure, stroke, and cardiovascular death.48 A study of
21 type 2 diabetic patients treated with insulin with
good glycaemic control but concomitant coronary
artery disease showed that significantly more patients
experienced chest pain and demonstrated ischaemic
electrocardiogram changes when blood glucose level was
<3.8 mmol/L compared with blood glucose level
of normal range during 72 hours of continuous
glucose monitoring.59 Hypoglycaemia can also
cause alteration of ventricular repolarisation with
prolongation of the QT interval that can precipitate
ventricular arrhythmia and result in sudden death.49 60 Although the causal link between hypoglycaemia and
cardiovascular disease is unknown, hypoglycaemia
can trigger a series of responses with detrimental
effects on the cardiovascular system. The responses
include sympathoadrenal activation, inflammation,
endothelial dysfunction, and increased platelet
activation and coagulability.61 62 63 These pose an
adverse effect on the myocardium and vascular
system, and may induce a cardiovascular event. Thus,
elderly diabetic patients at risk of cardiovascular
disease are particularly prone to hypoglycaemia-associated
cardiovascular events.
Dementia
Many epidemiological studies have demonstrated
that patients with diabetes are at increased risk of
dementia. The underlying pathophysiology linking
diabetes to cognitive impairment is potentially
complex and is not well understood. Diabetes
is known to cause cerebrovascular disease that
can in turn cause vascular cognitive impairment.
Hyperglycaemia with hyperinsulinaemia, and
increased formation of advanced glycation end
products and reactive oxygen species may play a role
in causing cognitive impairment.50 51
Recently, hypoglycaemia has been increasingly
recognised to be associated with subsequent
dementia in elderly patients. During an acute
hypoglycaemic episode, numerous aspects of
cognition—such as immediate verbal and visual
memory, working memory, delayed memory, visual-motor
skills, visual-spatial skills, and global cognitive
function—are impaired.50 51 These transient deficits might translate into long-term cognitive deficits,
especially if the hypoglycaemic episode is severe or
recurrent. The exact mechanism is not completely
understood although it has been proposed that
hypoglycaemia reduces the brain’s supply of sugar
causing neuronal damage or death that in turn
accelerates the development of dementia.64 The
elderly patients are particularly vulnerable because
of less brain reserve.
A large-scale longitudinal cohort study
from 1980 to 2007 in the United States, based on the electronic hospital
records of 16 667 type 2 diabetic patients with a mean
age of 65 years, showed that severe hypoglycaemic
episodes (requiring hospitalisation or an emergency
department visit) were associated with increased
risk of dementia.65 Patients with a history of
hypoglycaemia had a 2.4% increase in absolute risk
of dementia per year when compared with patients
without a hypoglycaemic history. There was also
a graded increase in the dementia risk according
to the number of severe hypoglycaemia episodes
experienced, such that the risk was almost double
with three or more episodes. Another similar study
in Taiwan involved 15 404 type 2 diabetic patients
with a mean age of 64 years and over 7 years of
follow-up found that prior hypoglycaemia had a
significant increased risk of dementia with a risk
ratio of 1.6 after adjustment for age and sex.66 In a
cross-sectional study of 1066 type 2 diabetic patients
aged 60 to 75 years, self-reported history of severe
hypoglycaemia was associated with poorer late-life
cognitive ability after adjustment for the estimated
prior cognitive ability.67
A recently published prospective study
gives further support to the association between
hypoglycaemia and dementia in elderly patients
with diabetes. Since 1997, a total of 783 diabetic
patients without dementia and with a mean age of 74
years have been followed up for at least 12 years.39
In contrast to previous studies, this study showed
a bidirectional association of hypoglycaemia with
dementia; patients who experienced at least one
episode of significant hypoglycaemia were twice
as likely to develop dementia compared with those
who did not have a hypoglycaemic event. Furthermore,
demented patients were 2.2 times more likely
than those diabetic patients without dementia to
become hypoglycaemic. The results suggest that
hypoglycaemia and dementia can create a vicious
cycle in which hypoglycaemia damages the brain
that in turn decreases the ability to manage diabetes
or recognise hypoglycaemic symptoms, and thus
leads to increased risk for hypoglycaemia.
The association of hypoglycaemia with
cognitive dysfunction has implications for clinical
practice. Detecting and avoiding hypoglycaemia is
important to prevent or delay cognitive impairment.
Cognitive function should be taken into account in
the clinical management of elderly diabetic patients
to minimise the risk of hypoglycaemic complications.
Management of hypoglycaemia
The primary aim of diabetes management is
optimisation of glycaemic control to avoid acute
hyperglycaemia complications and prevent long-term
diabetes complications, both microvascular
and macrovascular, and at the same time to minimise
the treatment side-effect of hypoglycaemia. In
younger people with new-onset diabetes, stringent
glycaemic control before the establishment of long-term
complications is of paramount importance.
On the other hand, in those with advanced age and
limited life expectancy or with longer duration of
diabetes and established complications and multiple
co-morbidities, the benefit of stringent glycaemic
control is dubious. Diabetes management guidelines,
mainly based on studies of a younger population,
may not be appropriate for the older population
with heterogeneous health status. A more patient-centred
approach for type 2 diabetes management
that takes account of the potential benefits and
risks of treatment, health and functional state, and
social background for an individual patient has been
emphasised recently.
Does stringent glycaemic control benefit the elderly diabetic patients?
The long-term benefit of good glycaemic control
seems to be affected by the duration of type 2 diabetes
and the presence or absence of the established
macrovascular and microvascular complications.
In the UKPDS, newly diagnosed type 2 diabetic
patients (mean age, 53 years) who received intensive
therapy (HbA1c achieved, 7%) with a median follow-up
of 11 years showed borderline significance for
reduction in risk of myocardial infarction but a
25% risk reduction in microvascular complications,
mainly due to fewer cases of retinal photocoagulation.68 During 10 years of post-trial follow-up, the previous intensive therapy group continued to
show fewer microvascular complications and had
emergent macrovascular benefit in terms of a 15%
risk reduction for myocardial infarction.69
In three more recent large-scale trials,
ACCORD, ADVANCE and VADT (Veterans Affairs
Diabetes Trial) that recruited older people (mean
age, 60-66 years) with longer type 2 diabetes duration
(8-11.5 years) and of whom 32% to 40% had a history
of cardiovascular events, the intensive therapy
group (HbA1c achieved, 6.4%-6.9%) showed no
benefit in reduction of overall major cardiovascular
events and death over 5 years of follow-up,15 70 71 but only a lower rate of non-fatal myocardial
infarction in the ACCORD trial.72 Instead, there
was a higher mortality rate in the intensive therapy
group of the ACCORD trial that led to premature
discontinuation of intensive therapy after 3.5 years
of follow-up. In the VADT subtype analysis of the
effect of calcified coronary atherosclerosis on the
cardiovascular outcomes of intensive therapy,
patients with a higher coronary calcium score (>100;
associated with more advanced vascular disease or
atherosclerosis) on intensive therapy showed no
reduction in cardiovascular events.73 On the other
hand, those with lower scores (≤100) showed benefit
from intensive therapy but the benefit diminished
progressively with increasing coronary calcium
score. For microvascular renal outcomes, most
renal benefits derived from reduced development of
macroalbuminuria. Both ADVANCE and ACCORD
trials showed that the intensive therapy group had
30% lower macroalbuminuria development whilst
VADT showed only borderline significant reduction
in any worsening of albumin excretion in the
intensive therapy group.70 71 74 None of them showed
any effect on the progression of renal impairment.
The ACCORD trial showed that intensive therapy
was associated with decreased progression of
retinopathy by 33%75 and modest risk reduction
in development of peripheral neuropathy.74 The
ADVANCE trial and VADT showed no such effect.
Treatment benefit is also affected by underlying
co-morbidity. In a 5-year observational study of
Italian patients with type 2 diabetes and baseline
HbA1c of ≤6.5% to 7%, those with low-to-moderate
co-morbidity (mean age, 61.7 years) had a lower
incidence of cardiovascular events than those with
high co-morbidity (mean age, 64.3 years).76
Targeting HbA1c to a low level may increase
mortality. A retrospective study from the UK
General Practice Research Database showed a
U-shaped relationship between HbA1c level and
mortality in type 2 diabetic patients (mean age, 64 years) who received
intensified treatment, with the lowest hazard ratio
for mortality at HbA1c level of 7.5%.77 An HbA1c level
higher or lower than 7.5% was associated with higher
all-cause mortality and cardiac events, which was
independent of treatment regimen.
These findings imply that good glycaemic
control does not always have a positive effect:
most benefit appears to be derived if such control
commences earlier, before the establishment of
long-term complications. It is important to note,
deduced from the studies, that it takes over 5 years
of intensive glycaemic control to reap microvascular
benefit68 70 71 74 75 and over 10 to 20 years for macrovascular benefit.69 For those with a limited life
expectancy and multiple co-morbidities, the adverse
effects are likely to outweigh the benefit.
Individualised glycaemic targets
There are various frameworks or guidelines based
on patient characteristics and health status to assist
in determining glycaemic treatment goals in elderly
patients with type 2 diabetes.78 79 80 81 82 In generally healthy young and active elderly people without significant co-morbidities,
the same glycaemic target as for young
adults may be worthwhile to prevent long-term
complications. For the frail elderly with multiple
illnesses and limited life expectancy, the aim of
glycaemic control is to prevent acute hyperglycaemic
complications (polyuria, dehydration, hyperglycaemic
hyperosmolar syndrome, infection, and
poor wound healing) and to avoid treatment adverse
effects, but not to gain long-term benefit. Thus
glycaemic control can be less stringent.
The suggested target HbA1c level varies from
<7.5% for healthy young elderly people to 8%-9% for
those with very poor health and limited life expectancy.
The Table79 shows a framework for considering
treatment goals in elderly patients with diabetes
produced by the American Diabetes Association
and American Geriatrics Society. It classifies elderly
patients into three groups: (1) relatively healthy
with longer life expectancy; (2) multiple co-morbidities
and decreased self-care ability; (3) very poor health
with significant co-morbidities and functional
impairment and limited life expectancy. Although
the framework may not address the health status of
all elderly patients, it gives an idea of individualised
treatment decisions. Further studies are needed to
guide the glycaemic target and clinical care plan for
heterogeneous elderly patients.
Table. American Diabetes Association/American Geriatrics Society consensus guideline for glycaemia goal in elderly people with diabetes79
Pharmacotherapy
Metformin, which is associated with a low risk for
hypoglycaemia, is the preferred initial therapy in
the elderly with type 2 diabetes.79 80 The dosage must be reduced in chronic kidney disease and
should be avoided in patients with an estimated
glomerular filtration rate of <30 mL/min per 1.73 m2
or in patients at risk of lactic acidosis. Long-acting
sulfonylurea, such as chlorpropamide and
glibenclamide, is associated with a high risk of
hypoglycaemia83 84 and is not recommended for the elderly.85 It should be replaced by a short-acting
sulfonylurea such as glipizide as it is less associated
with hypoglycaemia.84 An α-glucosidase inhibitor
for postprandial hyperglycaemia has a low risk
of hypoglycaemia and can be considered for the
elderly.79 Thiazolidinedione—with side-effects of
weight gain, water retention with oedema and
heart failure, bone fractures, and possible bladder
cancer—may not be suitable for elderly people.58 86 87
More recently approved therapy, the incretin-based
therapies such as glucagon-like peptide receptor
agonists and dipeptidyl peptidase-IV inhibitors, are
useful for postprandial hyperglycaemia. They have a
low risk of hypoglycaemia, are well tolerated without
weight gain, and may be beneficial for the elderly
people.88
In those treated with insulin, substitution of
long-acting basal insulin analogue (glargine and
detemir) for intermediate-acting insulin and
substitution of preprandial rapid-acting insulin
analogue (lispro and aspart) for short-acting
(regular) insulin are associated with lower overall
and nocturnal hypoglycaemia, less weight gain, and
greater reduction in postprandial blood glucose
level.89 90 91 The higher cost, however, may limit their
popularity in the elderly.
Properties of anti-diabetic medications, their
adverse effects, and patient’s tolerability should be
considered when planning treatment. Management
of other cardiovascular risk factors (eg smoking,
hypertension, and hypercholesterolaemia) is also
important. Patients should be assessed for glycaemic
control and any hypoglycaemic events during follow-up
with the treatment regimen adjusted accordingly.
Adequate diabetes education should be offered to
patients or their caregiver. It includes goal setting,
self-monitoring of blood glucose level, regular meal intake in
relation to drug intake, recognising risk factors and
symptoms of hypoglycaemia and self-management.
Recent hypoglycaemia
Patients with recent episodes of hypoglycaemia are
at risk of a blunted counter-regulatory response to
subsequent hypoglycaemia within a short period of
time. This may lead to recurrent hypoglycaemia of
a severe degree and hypoglycaemia unawareness.8
Patients with episodic severe hypoglycaemia or
hypoglycaemia unawareness, which indicates
underlying defective glucose counter-regulation, are
particularly at risk. A 2-to-3-week period of scrupulous
avoidance of hypoglycaemia with loose glycaemic
control for restoring the glucose counter-regulatory
response and hypoglycaemia awareness is advised in
order to prevent the recurrent hypoglycaemia.4
Conclusion
Elderly people are potentially at risk of hypoglycaemia.
Longer duration of diabetes with endogenous insulin
deficiency, which is often linked with advancing
age, compromises the glucose counter-regulation.
Together with the decreased hypoglycaemia
symptomatic response with ageing, elderly people
are prone to hypoglycaemia unawareness and
severe hypoglycaemic episodes. Multiple co-morbidities
and polypharmacy further exacerbate
this hypoglycaemic risk. Hypoglycaemia can have a
significant acute and long-term impact on the elderly.
Accident, fall with injuries, or a cardiovascular event
following hypoglycaemia can all be life-threatening.
Dementia risk in the long term can compromise
self-management of diabetes and further increase
the hypoglycaemic risk. More importantly, stringent
glycaemic control offers only modest benefit to
the elderly; it takes over 5 years for microvascular
and over 10 to 20 years for macrovascular benefits
to appear; and in patients with established
complications and multiple co-morbidities, the
additional benefit of stringent control is in doubt. An
individualised treatment target that takes account of
the heterogeneous health status with the intention of
avoiding hypoglycaemia and acute hyperglycaemic
complications should be emphasised, especially in
the frail elderly. Multifactorial and multidisciplinary
approaches to integrate a patient’s needs, preference,
and social supportive network should be considered;
management of other cardiovascular risk factors,
nutritional assessment and nutritional plan and
serving meal strategies, physical activity and exercise
advice, and education are all useful. Finally, studies
on elderly diabetic patients, especially the older old,
are limited. Further studies are needed to reach a
clear consensus on the management of the elderly
diabetic patients.
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