CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 3, April 2012
AFRICA
175
Getting to the root of diabetes and the effect of GLP-1 on the cardiovascular system
Prof Wolfgang Schmidt
The need to initiate tight glycaemic
control immediately after a diagnosis of
diabetes is essential for cardiovascular
benefits in the years to come, achieving
significant reductions in myocardial
infarctions and all-cause mortality. Prof
Schmidt stressed that even patients with
no cardiovascular history and those with
HbA
1c
levels
≤
8.0% will benefit from
tight glycaemic control.
Limitations of diabetes treatment
The traditional classes of oral anti-diabetic
agents and human insulin formulations
are limited in their ability to help patients
achieve their targets of glycaemic
control. These agents are associated
with adverse events that relate to their
mode of action, and pharmacokinetic and
pharmacodynamic properties.
Prof Schmidt examined a variety of
problems and limitations of diabetes
treatment, referring to outcomes of the
ACCORD, VADT and ADVANCE trials.
His first concern was therapy-induced
hypoglycaemia, found to increase in the
intensive-treatment arms, with severe
hypoglycaemia being directly related
to cardiovascular events and possibly
associated with dementia.
A second concern was treatment-
related weight gain, of which insulin
was found to be the most potent inducer.
Apoptosis and loss of beta-cell function
was a third concern that arose from
these trials. It emerged that progressive
beta-cell loss is already occurring in the
pre-diabetic stage of insulin resistance,
with as much as 50% of beta-cell function
lost by the time of diagnosis. Beta-cell
apoptosis increases with the use of
sulfonyl urea in the treatment of diabetes.
Prof Schmidt’s final concern was
that reduction of HbA
1c
level is efficient
for the first year or two, regardless of
therapeutic agent utilised, but then begins
to slip and diabetes disease progresses.
Considering the above limitations, there
is a need for new, effective agents that
can attain targets of glycaemic control
and weight reduction without inducing
hypoglycaemia, while addressing other
comorbidities commonly associated with
type 2 diabetes.
Incretin therapy
Prof Schmidt elaborated on the need
for long, outcome-directed studies to
finally determine the place for incretin
mimetic therapy in diabetes management.
The basis of incretin mimetic therapy is
two-fold. Incretin mimetics inhibit gastric
emptying through direct action on the
ileum and stomach, and indirect effects
on the endocrine pancreas; as well as
decreasing appetite and increasing satiety
through brain action.
Early use of incretin therapy in
the diabetic patient has the benefits
of glycaemic control without induced
hypoglycaemia (it only occurs in
combination with other agents), weight
loss (average loss of 7.7 kg within 26
weeks), a decrease in systolic blood
pressure, and improved beta-cell function.
Liraglutide
Liraglutide, the first human GLP-1
analogue, acts on multiple physiological
systems and demonstrates beneficial
effects on several aspects of glycaemic
control. The protracted half-life of
liraglutide allows for once-daily, meal-
independent dosing.
Prof Schmidt stated that liraglutide
also has anti-hypertensive effects,
evidenced in all instances and in all
trials. The beneficial weight loss seen
with liraglutide is accompanied by
improvements in other cardiovascular
risk factors, including blood pressure,
triglyceride levels and cardiovascular
risk biomarkers. In a 14-week trial of
liraglutide monotherapy, systolic blood
pressure decreased by 7.9 mmHg vs
placebo (
p
= 0.002) and triglyceride levels
demonstrated a 22% reduction vs placebo
(
p
= 0.01).
There are currently liraglutide trials
at every stage of the type 2 diabetes
continuum. Liraglutide has been shown
to improve biomarkers for cardiovascular
risk. Relief from the side effect of nausea
is faster with liraglutide than with any
other incretin mimetics and liraglutide has
been shown to be superior to sitagliptin
in improving HbA
1c
levels and weight
reduction. When compared to once-
weekly exenatide, once-daily liraglutide
had benefit for HbA
1c
levels, weight loss
and hypoglycaemic events.
Liraglutide has a good safety and
tolerability profile. Nausea is found in
up to 15% of patients but it appears to
be transient and the rate of reporting
decreases over the first few weeks.
The risk of pancreatitis is similar to
that of other agents. In general, there
is no strong evidence for increased risk
of pancreatitis when considering the
incidence of pancreatitis in this population,
and the combination of multiple risk
factors for pancreatitis (including obesity)
in the diabetic patient.
In summary, Professor Schmidt
recommended individualising treatment
according to patient need to attain
targets of glycaemic control as soon after
diagnosis as possible, in order to avoid
hypoglycaemic episodes and weight gain.
Attention should also be directed towards
the lowering of other cardiac risks such as
blood pressure.
G Hardy
Source: Schmidt WE. Early clinical studies with
liraglutide.
Int J Clin Pract
2010;
64
(suppl 167):
12–20.
Prof Wolfgang Schmidt
Chair and professor of Internal
Medicine, Ruhr University, Bochum
School of Medicine, Germany
Major research areas include the
entero-insular axis, incretins, regula-
tory gut–brain peptides, type 2 diabetes
(pathophysiology and novel therapeutic
strategies), pancreatitis and gastrointes-
tinal malignancies.
