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VOLUME 10 NUMBER 3 • SEPTEMBER 2013
EASD WATCH
SA JOURNAL OF DIABETES & VASCULAR DISEASE
patients receiving sulfonylureas than those
receiving metformin.
Data from the Clinical Practice Research
Datalink (CPRD) was used to evaluate the
comparative risk of all-cause mortality
for patients exposed to first-line diabetes
monotherapy with either sulfonylureas or
metformin. Each arm of the direct-matched
cohort included 2 048 patients, with 8 836
patients in each propensity-matched arm.
Those patients prescribed sulfonylureas
were 58% more likely to die from any
cause than those prescribed metformin.
Additional research presented by Dr
Currie indicated that a combination of
metformin and a sulfonylurea significantly
increased risk for death when compared
with combination therapy of metformin
and a DPP-4 inhibitor. Important to note,
however, is that not all sulfonylureas are
the same. Long-term outcomes from the
ADVANCE study indicate that modified-
release gliclazide is safe.
Obesity is associated with lower
mortality in older patients with
type 2 diabetes
The role of obesity in the development of
insulin resistance and type 2 diabetes (T2DM)
is well recognised. Contrary to what may be
expected, recent evidence has suggested
that obese patients with type 2 diabetes may
have lower morbidity and mortality rates
compared to patients of normal weight.
Research by Dr Pierluigi Costanzo and
colleagues from the Universities of Hull
and York sought to establish the relation-
ship between body mass index (BMI),
mortality and cardiovascular morbidity in
patients with diabetes. In total, 12 025
patients attending the diabetes service
at Hull and East Yorkshire hospitals, NHS
Trust, UK were followed for a mean of 10
years. Age, gender, height, weight, blood
pressure and information on co-morbidities
were recorded, as well as total mortality
and hospital admissions for acute coronary
syndrome, cerebrovascular accidents and
heart failure.
Of the study population (54% men,
mean age 60 ± 15 years, 15% T1DM,
remainder T2DM), acute coronary syn-
drome occurred in 9%, cerebrovascular
accident in 7% and a heart failure hos-
pitalisation in 6%. Risk of acute coronary
syndrome progressively increased with
BMI, being 49% higher in obese (BMI >
30 kg/m
2
) patients. Obese patients also
faced a 53% higher risk of heart failure.
However, risk of cerebro-vascular acci-
dent was 25% higher in overweight (BMI
25–28 kg/m
2
) patients. Despite increased
risk of cardiovascular events with increas-
ing BMI, all-cause mortality showed an
inverse relationship with BMI, being 25%
lower in obese subjects compared to those
of normal weight in older (> 67 years)
patients with type 2 diabetes.
Dr Costanzo explains, ‘…diabetes
induced by the metabolic stress of obesity
may be a fundamentally different problem
from diabetes that develops in the absence
of the stress of obesity. Alternatively, obes-
ity may provide a protective metabolic
reserve in older diabetic patients.’
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aspx?id=10968&topic=mc-topic::JJY7WSLM
DPP-4 inhibitor trial data
Trial data on both saxagliptin and aloglip-
tin were presented at the meeting. Neither
agent showed an increased risk for pan-
creatitis or pancreatic cancer. Both drugs
showed a modest reduction in HbA
1c
levels,
reduced progression to use of insulin, both
had a neutral effect on weight gain and low
rates of hypoglycaemia (with the exception
of the combination of saxagliptin in combi-
nation with sulfonylureas).
SAVOR TIMI 53 study
The positive effect of blood glucose lower-
ing on macrovascular complications is still
controversial. In most cases, maintaining a
target of near normal HbA
1c
levels requires a
combination of several drugs. Recent retro-
spective analyses of several hypoglycaemic
drugs have raised the possibility that they
may have a negative effect on the heart.
The SAVOR (Saxagliptin Assessment of
Vascular Outcomes Recorded in Patients
with Diabetes Mellitus) TIMI 53 study was
designed to assess the cardiovascular safety
of saxagliptin, along with the possibility of
beneficial cardiovascular effect. Cases of
pancreatitis were also adjudicated.
Approximately 16 500 type 2 diabetes
patients on any therapy except incretin ther-
apy were randomised to either saxagliptin or
placebo. Of those older than 40 years, 80%
had known cardiovascular disease and the
remainder were at high risk of developing
cardiovascular disease.
The primary end-point of a combination of
acute myocardial infarction, ischaemic stroke
and death was equal in the saxagliptin and
placebo arms. Hospitalisation for heart failure
was significantly increased in the saxagliptin
arm. No increase in death related to heart
failure was associated with saxagliptin.
Other study results indicated that treat-
ment with saxagliptin nearly doubled the
percentage of patients attaining HbA
1c
target levels. Attaining target without
hypoglycaemia was approximately double
in the saxagliptin versus placebo arms in
combination with any other agents except
sulfonylureas. Major hypoglycaemic events
were rare, the most at-risk patient being
treated with saxagliptin and sulfonylurea,
with HbA
1c
< 7% at baseline. No significant
difference in reports of pancreatitis were
evident between the saxagliptin and
placebo arms.
EXAMINE Cardiovascular Safety
Outcomes trial
Data from the global EXAMINE (Examina-
tion of Cardiovascular Outcomes: Alogliptin
vs Standard of Care in Patients with Type 2
Diabetes Mellitus and Acute Coronary Syn-
drome) cardiovascular safety outcomes trial
indicated that alogliptin did not increase
cardiovascular ischaemic events including
all-cause mortality, non-fatal myocardial
infarction, non-fatal stroke and urgent
revascularisation due to unstable angina.
Exploratory data also showed that rates
of hospitalisation for heart failure were
comparable across alogliptin and placebo
groups.
The EXAMINE trial did not have heart
failure as a specific pre-specified endpoint
on its own. It was included in a compos-
ite endpoint with death included, which
showed no difference (HR = 1.07;
p
=
0.657). When a
post hoc
analysis was done
on heart failure admissions only, it showed
a clear increased trend, although not sig-
nificant, with HR = 1.19 and
p
= 0.222.
The EXAMINE trial evaluated a total of
5 380 patients with type 2 diabetes and a
recent acute coronary syndrome (within 15
to 90 days prior to randomisation). Aloglip-
tin doses were adjusted according to
renal function, and the median duration of
alogliptin exposure was 533 days. At study
end, mean HbA
1c
change from baseline was
–0.33% and 0.03% in the alogliptin and
placebo groups, respectively.
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results-foronglyza.cfm
