CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 6, July 2012
AFRICA
357
Drug Trends in Cardiology
ORIGIN trial shows safety and efficacy of insulin glargine
No adverse cardiovascular outcomes after a 6.2-year follow up of early insulin use
The ORIGIN trial, a large trial in
patients with high cardiovascular risk and
dysglycaemia, using an intervention of
initial basal insulin (glargine) in impaired
fasting glucose (IFG), impaired glucose
tolerance (IGT) or early-stage type 2
diabetes, has shown no cardiovascular
benefits or adverse cardiovascular
outcomes. However a reduction of
progression to diabetes did occur in
patients with IFG or IGT who were
treated with insulin, actively targeting
normoglycaemia of
<
5.3 mmol/l,
compared to those treated with standard
care and mainly oral agents.
1
Importantly,thelong-termuseofinsulin
glargine was shown to be efficacious in
lowering glucose levels safely over the
six-year period. There was no increase in
the incidence of cancer or cardiovascular
events in the more than 5 000 patients
treated over this extended period.
The trial showed that better glucose
control was achieved using a daily
injection of basal insulin (with or without
oral agents) in high-risk patients who
self-titrated their insulin dosage to a
fasting plasma glucose (FPG) level of
<
5.3 mmol/l compared to those offered
standard care. However, in both groups, a
mean HbA
1c
level of
≤
6.5% was achieved
over the duration of the study.
In those in the glargine arm of the
study, the median insulin dose rose from
0.31 U/kg by year one to 0.40 U/kg
by year six. Importantly, 83.6% (5 230
patients) were adherent to their insulin
glargine therapy at year six; 19% did
however permanently discontinue their
insulin therapy. In the standard-care
group, 11% of patients were using insulin
at the end of the study.
With regard to the co-primary
composite cardiovascular outcomes
of death from cardiovascular causes,
non-fatal myocardial infarction (MI) or
stroke, and secondly, the composite of
these events plus either a revascularisation
procedure or hospitalisation for heart
failure, there was no significant difference
between the two groups.
Compared to standard care,
insulin glargine, titrating towards
normoglycaemia, had a neutral outcome
with regard to cardiovascular outcomes.
There was also no significant difference
with regard to microvascular events. Of
particular importance was that there was
no significant difference in the incidence
of any cancer, death from cancer or cancer
at specific sites (Table 1).
The incidence of a first episode of
severe hypoglycaemia was a modest
1.00 per 100 person-years in the insulin
glargine-treated group, and 0.31 per 100
person-years in the standard-care group
(
p
<
0.001). Participants in the insulin
glargine group gained a median of 1.6 kg
whereas the standard-care group lost a
median of 0.5 kg.
Reduction in progression to
diabetes
In the sub-population of 1 456 partici-
pants without diabetes, but with IFG/IGT
and other cardiovascular risks at randomi-
sation, 737 were assigned to insulin glar-
gine and 719 to standard care. Those
assigned to insulin glargine were 28%
less likely to develop diabetes, as defined
by oral glucose tolerance tests performed
on 65% of this cohort.
Dr Landi Lombard, specialist
physician, diabetologist,
Kuilsriver, Cape Town and
editor of the
South African
Journal of Diabetes and Vascular
Disease
attended the American
Diabetes Association meeting and
commented
The ORIGIN trial had two main arms.
The first assessed the use of 1 g of
omega-3 fatty acid supplementation
in this cardiovascular high-risk group,
versus placebo. This was based on many
previous trials showing potential benefit,
and the GISSI trial showing statistically
significant benefit of this therapy in post-
myocardial infarction patients, with a
15% reduction in all-cause mortality.
A recent meta-analysis supported these
results and showed a 9% cardiovascular
mortality benefit. Unfortunately this
was not supported in the ORIGIN trial,
which showed no benefit. The absence
of benefit was found in both primary
and secondary outcomes and also in all
the subgroup analyses. This is obviously
very disappointing, with only a very
small reduction shown in triglyceride
levels. There is no positive take-home
message here and I cannot recommend
the use of omega-3 fatty acids in this
study population.
The second arm of the study assessed
insulin glargine versus standard care for
IFG, IGT or early diabetes in high-risk
cardiovascular patients. This arm of the
study was unfortunately also negative. No
cardiovascular benefits could be shown
for the primary or secondary endpoints
despite a 3% per year event rate.
These results were very disappointing
TABLE 1. CANCER INCIDENCE IN THE ORIGIN TRIAL
Cancer by site
Hazard ratio
Insulin glargine
n
(%)
Standard care
n
(%)
Breast
1.01
28 (0.4)
28 (0.4)
Lung
1.21
80 (1.3)
66 (1.1)
Colon
1.09
76 (1.2)
70 (1.1)
Prostate
0.94
88 (2.1)
89 (2.2)
Melanoma
0.88
15 (0.2)
17 (0.3)
Other
0.95
233 (3.7)
245 (3.9)
Amended from supplementary data, reference 1.
