VOLUME 10 NUMBER 1 • MARCH 2013
13
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
Early initiation of insulin
In patients who do not achieve or maintain their HbA
1c
target
with oral hypoglycaemic monotherapy, guidelines recommend the
addition of a second oral medication or early initiation of insulin.
3,4
In
contrast to oral hypoglycaemic agents, insulin is the most effective
treatment to lower glycaemia and there is no maximum dose of
insulin beyond which a therapeutic effect will not occur. When
used in adequate doses, insulin will decrease any level of elevated
HbA
1c
to, or close to, target values.
8
Indeed, delaying insulin initiation in patients who progressively
fail stepwise treatment and progress through lifestyle modification
to oral monotherapy to combination oral therapy is associated
with further deterioration in HbA
1c
values and exposes patients to
prolonged periods of uncontrolled glycaemia, which increases the
risk of diabetes-related complications.
7,9
Conversely, early initiation
of insulin reduces the risk of diabetes-related complications
and potentially helps to preserve beta-cell function, without
compromising quality of life or treatment satisfaction.
7
However, both physicians and patients demonstrate reluctance
to initiate insulin, resulting in delay of treatment until late into
the progression of the disease when the opportunity for optimal
micro- and macrovascular protection has been missed. Patients’
concerns regarding insulin include anxiety about injections, fear of
hypoglycaemia and other adverse health effects, a belief that their
disease has progressed because they have managed their condition
poorly (feelings of failure), social stigma of having to inject in
public, and fear of weight gain. Concerns about insulin-related
hypoglycaemia and weight gain may also underlie physicians’
reluctance to commence insulin earlier.
10,11
Overweight and diabetes
Weight gain is a specific concern among patients with diabetes.
Obesity, particularly abdominal obesity, plays a pivotal role in the
development of type 2 diabetes and more than 80% of patients
with type 2 diabetes are overweight or obese, many at the time of
diagnosis. Both diabetes and obesity are independently associated
with additional cardiovascular risk factors, including hypertension
and an atherogenic lipid profile and, compared to individuals
without diabetes, diabetics have a significantly higher risk of
cardiovascular events and death from cardiovascular causes.
12
Even in combination with metformin, most treatments for type
2 diabetes, including sulphonylureas, glinides, thiazolidinediones,
and basal and biphasic insulins are associated with modest
weight gain.
13
Compared to alternative treatments, intensive
glucose control with insulin is associated with the greatest gain
in body weight, with an average increase of 4.3 ± 2.74 kg (mean
± SD, range –2.76 to 14.7 kg, 95% CI: 4.32–4.38) during the
first year of treatment.
14-16
Most of the weight gain occurs during
this first year after insulin initiation, but it is progressive after
that.
In the UKPDS, insulin-treated patients had gained an average
of 6.5 kg during 10 years of follow up.
15
Higher doses of insulin,
lower HbA
1c
targets and lower achieved levels of HbA
1c
were
associated with greater increases in body weight. Possibly as
a consequence of the lower doses that are used, basal insulin
regimens are associated with less weight gain than prandial or
twice-daily regimens.
16
Although, in general, all types of insulins
are associated with weight gain, an exception appears to be
detemir, which is associated with significantly less or no weight
gain compared with alternatives. Its weight-sparing benefits are
especially evident in patients with a higher body mass index.
16,17
Although the exact mechanisms underlying this weight-sparing
effect are uncertain, a number of theories have been proposed. It
has been suggested that because detemir is associated with sig-
nificantly less hypoglycaemia than isophane insulin (NPH), patients
may be less prone to defensive snacking.
17
However, while hypogly-
caemia is predictive of weight gain with NPH insulin, no such asso-
ciation could be demonstrated with detemir, so it seems likely that
less hypoglycaemia does not fully explain less weight gain.
18
Because it is highly bound to albumin, detemir may have limited
access to peripheral compartments and therefore may influence
hepatic glucose to a greater extent than in adipose tissue and
muscle. Decreased peripheral glucose uptake in comparison
with NPH may contribute to lower weight gain. Detemir may
also cross the blood–brain barrier more efficiently. Therefore it
may be more effective at communicating satiety signals in the
central nervous system than other insulins. Lastly, detemir may
be less adipogenic than human insulin and may have direct
effects on adipocytes, influencing the expression of adiponectin.
Adiponectin and leptin are derived from adipose tissue and
influence food intake, insulin resistance and lipolysis.
19
Mechanisms of insulin-related weight gain
Various mechanisms have been proposed to account for weight gain
associated with insulin therapy:
Improved glycaemic control may lower blood glucose levels
•
to below the renal threshold, thereby reducing or eliminating
glycosuria and improving conservation of ingested calories.
Insulin itself is an anabolic hormone that inhibits lipolysis and
•
protein catabolism and stimulates lipogenesis and fatty acid
conversion into triglycerides in adipose tissue, favouring an
increase in adipose mass.
Improved glycaemic control is also associated with reduced
•
resting energy expenditure per lean body mass, which suggests
a role for increased efficiency of fuel usage.
Fear of insulin-related hypoglycaemia may result in ‘defensive
•
snacking’, contributing to increased carbohydrate intake and
increasing total calorie intake. In addition, ‘new’ low glucose
levels may also be associated with an involuntary adaptive
increase in appetite.
‘Central insulin resistance’ associated with a defect in insulin
•
and leptin signalling pathways in the hypothalamus may disrupt
normal catabolic and anorectic signalling pathways in the
central nervous system that promote satiety and balance the
anabolic actions of circulating insulin.
Exogenous insulin administration is unphysiological in that
•
dosing schedules create an unpredictable imbalance between
insulin supply and insulin need, leading to periods of over-
and undersupply and consequently hyper- and hypoglycaemia
interspersed throughout the day. Furthermore, unlike physio-
logically secreted insulin, subcutaneous insulin circulates
systemically before passing through the liver, so it exerts a
disproportionate influence on muscle and adipose tissue.
20,21
Does weight gain associated with intensive glucose
control matter?
While obesity is undoubtedly a factor that increases the risk
of cardiovascular events, the role of weight gain consequent to
