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Key Words: Glycaemic control, Insulin analogues, Basal insulin, Insulin glargine
Received: 31.12.2007 Accept: 1.2.2008
Introduction
The 2005 Annual Meeting of the European
Association for the Study of Diabetes
(EASD) reignited the debate regarding what
constitutes good glycaemic control. While
the American Diabetes Association (ADA)
recommend that people with diabetes aim for
a HbA1c level <7.0%1, a global guideline for
Type 2 diabetes compiled by the International Diabetes Federation (IDF), recommends a target level of <6.5%.2 This move
mirrors the recommendations of the UKbased National Institute of Clinical Excellence (NICE), which set an HbA1c target for
those with Type 2 diabetes of between 6.5%
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MJ Davies et al.
munity setting,22 a burden which can only increase as the prevalence of Type 2 diabetes
continues to rise.
There is clearly a need to refine the way insulin is used in the management of Type 2
diabetes and this review examines the potential of the first available basal insulin analogue, insulin glargine, to address some of
these issues and increase the probability of
achieving the elusive glycaemic control targets. Insulin glargine has now been available
for 5 years. Over this time much evidence
has accumulated of its role, particularly in the
management of Type 2 diabetes.
Role of insulin versus oral antidiabetes
therapy
Perceived patient barriers, such as needle
phobia or, as discussed above, the sense of
self-blame, have led researchers to look for
alternatives to the initiation of insulin. One of
these alternatives is use of a combination of
three oral agents (metformin plus sulphonylurea plus glitazone). Schwartz et al reported
that a combination of insulin 70/30 mix plus
metformin was as effective as, and better tolerated than, triple oral therapy.23 Furthermore, a study by Rosenstock et al compared
the addition of rosiglitazone or insulin
glargine in patients inadequately controlled
on a combination of sulphonylurea and metformin.24 This randomised trial, which included 217 patients, found that HbA1c levels
were lowered by similar amounts in both
groups ( 1.70.1% vs 1.50.1 for insulin
glargine and rosiglitazone, respectively).
However, insulin glargine was associated
with a greater reduction in FPG ( 3.60.2
mmol/l vs 2.50.2 mmol/l; p0.001) and a
much lower drop-out rate (8% vs 19%;
p=0.005) compared with rosiglitazone. Additionally, rosiglitazone was associated with a
less favourable lipid profile, more adverse
events (including oedema), and significantly
more weight gain compared with the insulin
glargine group (+1.60.4 kg vs 3.00.4 kg,
p=0.02).24
41
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MJ Davies et al.
The final two years of this study will examine complex insulin regimens in this group of
patients and the 3 year results are planned to
report in 2009.
Basal only insulin regimens have become
more popular since the introduction of basal
insulin analogues. Evidence suggests that
fasting, rather than postprandial glycaemia,
plays the major role on overall glycaemia
when glucose control is poor.37 Therefore,
while postprandial glycaemia is an important
consideration in all patients with diabetes, the
use of basal insulin to address fasting glucose
levels is likely to be a valuable tool for many
of the diabetes patients encountered in primary care. The attributes of insulin glargine
that make it an attractive option for basal insulin therapy include a duration of action that
allows once-daily injection for most patients,
and a peakless time activity profile38,39 and a
lower risk of hypoglycaemia than NPH insulin.40
Janka et al compared the addition of insulin
glargine to metformin and sulphonylurea
therapy with discontinuation of oral agents
and the initiation of twice-daily pre-mix
70/30 insulin, in a 24-week trial of 742 insulin-nave people with Type 2 diabetes.41 At
study end, HbA1c had reduced more substantially ( 1.64 vs 1.31; p=0.0003) and more
patients reached a HbA1c of M7.0% without
confirmed nocturnal hypoglycaemia (4.5.5 vs
28.6%; p=0.0013) with oral agents and insulin glargine, compared with the pre-mix
regimen one. A second 28-week study compared the addition of twice-daily pre-mix
70/30 insulin or once-daily insulin glargine to
metformin in 209 insulin-nave patients. In
this study, unlike the previous one, MF was
compared in the premix arm and the premix
included short-acting insulin analogue. Significant HbA1c reductions were seen in both
arms, but were greater in the pre-mix than the
insulin glargine arm ( 2.790.11 vs 2.360.11%,
p<0.01). However, weight gain was significantly
greater in the pre-mix versus insulin glargine
group (5.44.8 vs 3.54.5 kg, p<0.01) as was
43
Fig. 1. Percentage of patients treated with insulin glargine or NPH insulin with symptomatic
hyperglycaemia34
44
MJ Davies et al.
Table 1. Percentage of patients reporting one or more hypoglycaemic episodes and degree of risk reduction achieved with insulin glargine versus NPH insulin40
Type of documented
Insulin glargine
NPH insulin (%
% risk reduction
P value
symptomatic hypogly(% of patients)
of patients)
(where significant)
caemia
Overall
54.2
61.2
11
0.0006
Nocturnal
28.4
38.2
26
<0.0001
Non-nocturnal
49.6
51.7
Severe
1.4
2.6
46
0.0442
Severe nocturnal
0.7
1.7
59
0.0231
Severe non-nocturnal
0.8
0.9
45
Target FPG 5.5 mmol/l. Insulin glargine was administered once daily at bedtime. The starting dose for insulin-nave
subjects was 10 IU/day for algorithm 1. For algorithm 2, the dose was numerically equivalent to the highest FPG value in
millimols per litre over the previous 7 days. In those switching from once-daily intermediate- or long-acting insulin to insulin glargine, an equivalent dose was recommended. For those switching from twice-daily NPH, a reduction by 2030%
from the total NPH dose was recommended.
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MJ Davies et al.
Although this study was limited by the absence of a control group, the results indicate
that patients with Type 2 diabetes can safely
and effectively be involved in the management of their disease. Not only does this increase patient empowerment, but also has the
potential to reduce the burden on healthcare
professionals.
Ensuring optimal control adding prandial to basal insulin
While a single dose of insulin glargine will
effectively control glycaemia in some patients, evidence suggests that in others basal
insulin alone will not be sufficient to improve
or maintain glycaemia to acceptable levels.
Monnier pooled evidence from six studies to
show that for people below a baseline HbA1c
of 9%, good glycaemic control (HbA1c <7%)
can be achieved by titrating basal insulin up
to 0.5U/kg body weight/day.52 However, for
those above the HbA1c 9% threshold, further
Conclusions
The quest for effective pharmacotherapy to
achieve tight glycaemic control continues
and the stricter glycaemic goals recommended by the IDF emphasie the need to
achieve these. Evidence suggests that fasting
glucose levels play a primary role in overall
glycaemia when glucose control is poor. The
ability of basal insulin therapy to effectively
address fasting glucose levels means that this
therapy is likely to occupy an increasingly
important role as a tool to improve and maintain tight glycaemic control in people with
Type 2 diabetes. Insulin glargine fulfils much
of the requirements for a once-daily, peakless
basal insulin and clinical trials have demonstrated that insulin glargine achieves the
same degree of glycaemic control as NPH in-
47
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