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78
VOLUME 9 NUMBER 2 • JUNE 2012
CONFERENCE REPORT
SA JOURNAL OF DIABETES & VASCULAR DISEASE
There is still a dearth of evidence on the
cardiovascular effects of incretin therapy.
Research has found cardioprotective out-
comes in rats, which is most effective when
GLP-1 is accompanied by a DPP-4 inhibi-
tor. Also observed was increased functional
recovery of hearts in reperfusion after an
ischaemic event.
In this study, Dr Huisamen and colleagues
tested whether treatment with a DPP-4
inhibitor of obese, pre-diabetic rats with car-
diovascular pathology was cardioprotective.
Diet-induced obesity (animal feed supple-
mented with sucrose and condensed milk)
was effected in Wistar rats over a period
of 12 weeks, resulting in visceral obesity,
increased intraperitoneal fat levels and sig-
nificantly lower levels of GLP-1, exhibiting
insulin resistance. These animals had higher
blood glucose levels, dyslipidaemia and signs
of oxidative stress.
Following the initial 12-week period,
half of each of the control-fed and obesi-
ty-induced rats were treated orally for four
weeks with vildagliptin (DPP-4 inhibitor)
10 mg/kg/day in jelly blocks, in conjunc-
tion with the obesity-inducing diet. Upon
sacrifice, blood was collected and the body
weight and intraperitoneal fat weight was
recorded. Pancreases were also harvested.
Isolated hearts were perfused and the kinase
profile was determined in the reperfusion
phase. Ventricular myocytes were prepared
to determine insulin sensitivity.
Results indicated increased GLP-1 meas-
urement, a reduction in plasma insulin levels
and enhanced beta-cells (compared to base-
line beta-:alpha-cell ratio) upon treatment.
Dr Huisamen stated that similar to clinical
experience, vildagliptin therapy was found
to have no effect on weight and amount
of intraperitoneal fat, and insulin and non-
fasting glucose levels.
The area of infarct, as opposed to area
of infarct risk, was found to be larger in
the more obese animals. Those animals
with DPP-4 treatment had smaller infarcts.
The kinase pathway profile (associated with
cardioprotection) was used to measure car-
dioprotective effects. An increase in protein
kinase B levels and significantly reduced
phosphorylation of protein kinase B in obese
rats was found to be partially restored by the
use of DPP-4 inhibitors. Cardiomyocytes did
not show insulin sensitisation.
In summary, Dr Huisamen indicated that
vildagliptin therapy in obese, insulin-resist-
ant rat models was found to be cardiopro-
tective and alleviated insulin resistance.
Raising the bar: liraglutide
(GLP-1 analogues) and composite
endpoints
MAK Omar, Centre for Diabetes and
Endocrinology, Overport, Durban
Mortality in T2DM is most commonly a
result of cardiovascular disease. Obesity,
dyslipidaemia and hypertension co-exist
in up to 90% of T2DM patients. These are
all poorly controlled risk factors for cardi-
ovascular disease, with less than 10% of
diabetics having good control of all these
factors. However, optimal control with
existing treatments is counterbalanced by
the common side effects of weight gain and
increased hypoglycaemic events. Hypogly-
caemia is a very important risk factor of
cardiovascular disease.
Historically, the unmet needs of ideal
diabetes therapy include the issues of
weight gain, hypoglycaemia and increased
cardiovascular events. Prof Omar went on
to elaborate how the GLP-1 analogue,
liraglutide, can be effective in meeting the
needs of diabetes therapy, with a resultant
effect on cardiovascular risk factors.
Prof Omar referred to results of the LEAD
MT programme that compared liraglutide as
monotherapy and as combination therapy
with other agents (metformin, glimepiride,
rosiglitazone, insulin glargine and exenatide).
Liraglutide was shown to be the most effec-
tive at achieving the goal of improving HbA
1c
levels (78%) and weight loss. Liraglutide
was also found to have a modest effect on
hypertension, and in terms of dyslipidaemia,
there was a 10% reduction in total choles-
terol and an 18–20% reduction in LDL cho-
lesterol.
Two composite endpoints were exam-
ined. The first target group endpoint was
an HbA
1c
level < 7.0%, with no weight gain
and no confirmed hypoglycaemic episode.
The second target group endpoint differed
only in the third criterion, a systolic blood
pressure (SBP) < 130 mmHg.
Meta-analysis revealed that of those study
subjects taking liraglutide therapy, 40%
managed to achieve all three of the first
endpoints and 25% achieved all three of the
second endpoints. Two-thirds of liraglutide
patients achieved the HbA
1c
target and 70%
achieved the no weight-gain target. The
target SBP < 130 mmHg was achieved by
60% of the liraglutide patients. Liraglutide
was also found to have a more favourable
side-effects ratio than the comparator
agents in the LEAD study.
Prof Omar then pondered the question
of whether the above-established benefits
of liraglutide therapy favourably influence
cardiovascular events. Quite simply, there
is no answer yet. He referred to a number
of on-going intervention trials, with results
pending in 2015–2018, and concluded
by saying, ‘We are living in very exciting
times…’
Glenda Hardy
Campbell, RK. Clarifying the role of incretin-based
1.
therapies in the treatment of type 2 diabetes
mellitus.
Clin Therapeut
2011;
33
(5); 511–527.
Takiishi T,
2.
et al
. Vitamin D and diabetes.
Endocrinol
Metab Clin N Am
2010;
39
: 419–446.
Vitamin D is a secosteroid generated by
the skin under the influence of ultraviolet
light. Rather than a true vitamin, vitamin D
is a prohormone. Normal human diets are
Vitamin D and human health:
a magic bullet?
Roger Bouillon, professor of Medicine,
Laboratory for Experimental Medicine and
Endocrinology, Katholieke Universiteit,
Leuven, Belgium
usually poor in vitamin D, with fatty fish
being one of the few food sources rich in
vitamin D.
Regardless of the source of vitamin D,
it needs to be hydroxylated twice before
becoming biologically active. This occurs in
the liver and the kidney. Vitamin D and its
metabolites are bound to a carrier protein
(vitamin D-binding proteins: DBP) in the
circulation. Vitamin D receptors (VDRs) are
found in almost all nucleated cells present
in a range of tissues, with the highest VDR
concentrations being in the epithelial cells of
the gut.
The vitamin D endocrine system is essen-
tial for calcium and bone homeostasis. A
large number of genes exert direct and indi-
rect control of vitamin D receptor expres-
sion. Every tissue transports calcium, with
vitamin D required for calcium homeostasis.
In the absence of a functional VDR or cyto-
chrome P27B1 (CYP27B1), severely rachitic
bone occurs. Historically, ricketts was a fre-
quent cause of death. Enzymes and proteins