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VOLUME 7 NUMBER 4 • NOVEMBER 2010
EASD WATCH
SA JOURNAL OF DIABETES & VASCULAR DISEASE
vascular outcomes. This arm of the NAVI-
GATOR trial was largely negative, showing
that there was no decrease in the incidence
of diabetes and no cardiovascular benefit
from treatment with nateglinide in early
diabetes.
The second part of the NAVIGATOR trial
looked at valsartan use. There was a sig-
nificant decrease in systolic blood pressure
and incidence of diabetes in the valsartan-
treated patients but no significant change
in the primary outcome of cardiovascular
events.
The next trial was the LEAD 1860 study
analysing the use of liraglutide, a GLP I
analogue, compared to sitagliptin, a DPP IV
inhibitor, in diabetes. This was a 26-week
study with patients randomised to receive
either 1.2 or 1.8 mg liraglutide once daily
or 100 mg sitagliptin once daily.
Liraglutide reduced the HbA
1c
level
from baseline more than sitagliptin, and
body weight was also reduced to a greater
extent with liraglutide. Interestingly, sitag-
liptin also resulted in a small but modest
reduction in weight, which was clinically
significant. Previously, DPP IV inhibitors had
been thought to be weight neutral.
In a 52-week extension in which patients
remained on their randomised therapy,
reductions in HbA
1c
levels and weight were
maintained in all treatment groups. Patient
satisfaction was higher in patients treated
with liraglutide. Antibody titre levels to
liraglutide were small and not thought to
be clinically significant, and not associated
with a reduction in efficacy.
This shows that liraglutide is both an
effective and safe therapy for once-daily
treatment in patients with type 2 diabe-
tes who are not controlled on metformin
mono-therapy. Compared to DPP IV inhibi-
tors, liraglutide resulted in significantly
greater HbA
1c
and weight reduction.
DIABETIC NEPHROPATHY: CLINI-
CAL TRIALS
Intensive glucose control is reno-
protective in type 2 diabetes: new
analyses from ADVANCE
Intensive glucose control with a target
HbA
1c
level
≤
6.5% in known patients with
type 2 diabetes mellitus provided renal
benefits, including the regression and nor-
malisation of micro-albuminuria.
In the Action in Diabetes and Vascular
disease: preterAx and diamicroN-MR Con-
trolled Evaluation (ADVANCE) study, the
effects of intensive glucose lowering (HbA
1c
≤
6.5%) on renal outcomes were investi-
gated.
More than 11 000 participants were
enrolled and were either randomised to
the intensive glucose control group, which
included the use of gliclazide MR, or to
the standard glucose control group. The
median follow up was 5.0 years with a
mean HbA
1c
of 6.5% in the intensively con-
trolled group versus 7.3% in the normally
controlled group.
The intensively controlled group out-
performed the normal-control group in
reducing total renal events by 11% (
p
<
0.001) and new or worsening nephropathy
by 21% (
p
<
0.006).
New-onset micro-albuminuria was
reduced by 9% (
p
<
0.018) and new-onset
macro-albuminuria by 30% (
p
<
0.001).
Progression of albuminuria was reduced by
15% (
p
<
0.001).
It was also shown that there was a direct
correlation between the degree of albumi-
nuria and cardiovascular complications. A
question was raised whether this correla-
tion was maintained over time.
Aldosterone reduction during 24
weeks of treatment with aliskiren
or placebo added to losartan in
patients with type 2 diabetes and
nephropathy; an AVOID sub-study
Adding aliskiren to losartan and optimal
hypertensive therapy provided superior
reductions in urinary aldosterone when
compared to losartan and optimal hyper-
tensive therapy alone.
Aliskiren is a direct renin inhibitor. It has
been shown that aldosterone suppression
reduces albuminuria in normal as well as
diabetic patients. This has been shown to
have positive effects on cardio-renal out-
comes.
The Aliskiren in the eValuation of
prOteinuria In Diabetes (AVOID) study
evaluated the effects of aliskiren in com-
bination with losartan on urinary aldoster-
one, plasma renin activity and plasma renin
concentration; 599 patients suffering from
diabetic nephropathy were included and
were either assigned to the aliskiren–losar-
tan group or the placebo–losartan group.
In the aliskiren–losartan group there
was a 24% reduction in urinary aldoster-
one. There was no correlation between the
reduction in urinary aldosterone and the
change in urinary albumin:creatinine ratio
or the change in systolic blood pressure.
Plasma renin concentration increased by
228% in the aliskiren-treated group.
DIABETES AND BONE DISEASE
This was a series of a fascinating talks
expanding on what for many people has
been a new relationship between diabetes
and bone disease, highlighted mainly by
the effects of the thiozolidinediones and
their effect on bones, particularly causing
osteoporosis, with fractures in unusual
places.
It was pointed out that a high glucose
level affects bones in two different ways:
first, directly by increasing calcium excre-
tion in the urine, impairing the function
of osteoblasts, resulting in glycosylation of
collagen and impaired cross-links.
Indirectly, high glucose levels affect
bone by decreasing renal function, which
has an effect on reducing the amount of
active 125 hydroxy vitamin D produced.
The neuropathy results in immobilisation,
which increases bone loss. Micro-angiopa-
thy affects nutrient supply.
As a whole, diabetes is considered to
be a disease of low bone turnover with
decreased resorption and formation. The
hypercalciuria seen in early diabetes tends
to normalise later and this is mimicked by
the risk of facture and bone density, which
are more affected earlier in the course of
diabetes and return to near-normal levels
later in the disease.
A second talk outlined the effect of bone
on glucose metabolism and this focused on
the hormone osteocalcin, which seems to
increase insulin secretion and insulin sensi-
tivity and also stimulate
b
-cell mass. It was
hypothesised in this talk that osteocalcin
is released from the bone matrix during
turnover and the low bone turnover seen
in diabetes decreases osteocalcin levels and
hence insulin secretion, insulin sensitivity
and
b
-cell mass.
DIABETES AND PREGNANCY
Screening and prevention of gesta-
tional diabetes
During the session on screening and pre-
vention of gestational diabetes, much
attention was given to the new IADPSG
criteria for the diagnosis of gestational dia-
betes mellitus.
