DRUG TRENDS
SA JOURNAL OF DIABETES & VASCULAR DISEASE
40
VOLUME 10 NUMBER 1 • MARCH 2013
and other adverse events, the duration of
diabetes and life expectancy, and the presence
of microvascular disease, cardiovascular
disease and other co-morbidities. Targets for
HbA
1c
levels will differ accordingly.
Lifestyle intervention is effective; however
the willpower required for lifestyle changes
is often short lived. Because of this, many
protocols recommend initiation of first-line
therapy (usually metformin as monotherapy)
on diagnosis of diabetes. This is based
largely on the United Kingdom Prospective
Diabetes Study (UKPDS) sub-group analysis
of 342 obese patients reflecting an improved
relative risk of myocardial infarction, all-cause
mortality and diabetes-related deaths and
end-points with earlier metformin initiation.
The side effects of metformin include
gastrointestinal disturbances, vitamin B
12
deficiency, and in rare cases (1:100 000) lactic
acidosis. In the context of renal impairment,
dose reduction or cessation of the drug is
indicated.
Prof Distiller added that sulphonylureas
(SU) have a small but significant benefit in
terms of heart disease, although this risk–
benefit in conjunctionwith insulin use remains
uncertain. Although relatively cheap, SU have
the disadvantage of increased hypoglycaemic
events and weight gain. Use of glibenclamide
is no longer recommended due to the risk
of hypoglycaemia and the International
Diabetes Federation (IDF) recommends slow-
release gliclazide as the SU of choice. Prof
Distiller recommended glimepiride as another
reasonable alternative.
Acarbose has seen limited use in South
Africa. Its cost versus its relatively weak blood
glucose-lowering effect and unpleasant
gastrointestinal side effects have not made
it popular in this region. In terms of the
thiazolidinediones, rosiglitazone has been
withdrawn due to fears of increased risk
of cardiovascular disease. Pioglitazone has
been withdrawn from French and German
markets and has a ‘black-box warning’ in the
USA due to concerns surrounding increased
risk of fractures and bladder cancer.
Incretin-based therapies are relatively
recent additions to the treatment options
available for T2DM. The dipeptidyl peptidase
(DPP-4) inhibitors are all equivalent in
reducing HbA
1c
levels (0.5–1%). They have
the advantage of no hypoglycaemia, and
possibly, preservation of
β
-cell function. The
glucagon-like peptide-1 (GLP-1) agonists
exhibit a 0.8 to 1.5% reduction in HbA
1c
level, promote weight loss and demonstrate
a reduced risk of hypoglycaemia. GLP-1
agonists may also reduce cardiovascular
risk, and early outcome studies indicate
preservation of
β
-cell function and possibly
β
-cell regeneration.
Within the GLP-1 class, liraglutide has
slight advantages over exenatide, which
requires twice-daily dosing, whereas
liraglutide has the benefits of once-daily
dosing and slightly greater reductions in
HbA
1c
level and body weight. Prof Distiller
did question whether the benefits of
small weight loss (average of 3 kg) and a
slightly reduced risk of hypoglycaemia were
sufficient to justify the relative cost of the
use of these agents.
Insulin therapy is a vital tool in the
management of T2DM, especially with the
inevitable decline in
β
-cell function seen
with the condition. All other therapies
targeting insulin deficiency rely on the
presence of functioning
β
-cells. Weight
gain associated with insulin use is mostly
due to achieving better glycaemic control,
resulting in decreased glycosuria, as well
as increased fat storage. The earlier insulin
is used, the less weight gain is evident,
although insulin resistance remains an issue.
It is for this reason that metformin therapy
is maintained.
A dose of intermediate- or long-
acting insulin at bedtime to provide basal
supplementation of insulin is appropriate
for early initiation in the patient with some
β
-cell function, and may be effective for
months or years. As
β
-cell loss progresses,
boluses of short- or rapid-acting insulin prior
to meals will also be required (the so-called
incremental basal-plus or full basal-bolus
approaches). The patient should be prepared
to expect insulin therapy as inevitable at
some stage of the management of his/her
diabetes.
Talking about bariatric surgery, Prof
Distiller pointed out that this does not
represent a cure for diabetes and is not free
of complications. Bariatric surgery is most
effective in recently diagnosed T2DM and
can be considered in those where lifestyle
interventions (nutrition and activity levels)
have not been effective. There is, however,
an 80% redevelopment of diabetes post-
surgery.
In summary, Prof Distiller concluded
that doctors should be using guidelines to
facilitate decision making and that these
recommendations should never replace
clinical judgment. Lifestyle modification
is highly effective and is the essential
foundation for drug therapy. There is no
best therapeutic algorithm, with each of the
diabetes agents having their own merits. No
drug will work as well without appropriate
behavioural modification.
Dyslipidaemia in diabetes = LDL-C
lowering + X (?)
Dr Dirk Blom, head of Lipidology, Groote
Schuur Hospital Lipid Unit, Cape Heart
Centre, UCT
Dr Blom began by emphasising that
atherosclerosis appears to be an almost
inevitable complication of long-standing
T2DM. Atherosclerosis manifests clinically
with cardiovascular events and it is therefore
not surprising that 50 to 75% of deaths
in those with T2DM are secondary to
cardiovascular disease. Atherosclerosis in
T2DM is often diffuse with a higher plaque
burden, smaller arteries and inadequate
compensatory heart remodelling. Very high
rates of peripheral vascular disease are also
observed in patients with diabetes. Dr Blom
added that the younger the patient when
diagnosed with diabetes, the greater the
number of life years lost, predominantly due
to vascular disease.
The pathogenesis of vascular disease is
complex, with manifold interactions between
factors such as dyslipidaemia, hypergly-
caemia and insulin resistance, hypertension,
inflammation, oxidation and smoking. Two
major mechanisms in the pathogenesis of
atherosclerosis are endothelial dysfunction
or the response-to-injury reaction, and sub-
endothelial retention and accumulation of
lipids, leading to what is often called the
response-to-retention reaction. Thinking of
T2DM as a vascular disorder with increased
glucose levels rather than as a pure disorder of
glucose metabolism helps to focus attention
on the fact that treatment of T2DM involves
much more than just controlling glucose
levels.
Dr Blom is of the opinion that targeting
dyslipidaemia in T2DM is a highly effective
and worthwhile intervention. Lipids should
be considered the ‘low-hanging fruit’ in the
management of T2DM, as it is often easier to
control lipids well than, for instance, achieve
tight glycaemic control.
In terms of low-density lipoprotein (LDL)
cholesterol, lower is better (LDL-C < 1.8
mmol/l; apoB < 0.80 g/l). LDL and remnant
lipoproteins are the two most atherogenic
lipoproteins and are central to the
pathogenesis of atherosclerosis. The CARDS
study enrolled patients with T2DM with one
added vascular risk factor who were free of
