Page 42 - The SA Journal Diabetes & Vascular Disease Volume 9 No 4 (November 2012)

184 VOLUME 9 NUMBER 4 • NOVEMBER 2012
REPORT SA JOURNAL OF DIABETES & VASCULAR DISEASE
cause erythropoietic stress. It’s important
to be aware of other abnormalities, as per-
sons with diabetes often have sub-clinical
cobalamin (vitamin B12) deficiency. This is
particularly common in the elderly.’
‘ Leucocytes also represent a veritable
minefield. Diabetic patients are at increased
risk of infection because their immune
system is dysfunctional.’ In addition, they
often have reduced platelet counts and
qualitative platelet dysfunction, accompa-
nied by comparable changes in the vascu-
lar endothelial cell. This aggravates platelet
aggregation, activating a coagulation cas-
cade that puts these individuals at high risk
of microvascular injury. Silent vasculopathy
causes substantial damage.
Plasma is the matrix for haemostatic
activation and is deranged in diabetes, so
the naturally occurring effects of anticoag-
ulants are slightly shifted. Diabetic keto-aci-
dosis is another danger that falls squarely in
the lap of the haematologist, as it is charac-
terised by hazardous thrombocytopenia.
Prof Jacobs emphasised that it needs to
be more widely appreciated what diabetes
does to the blood system and the haema-
tological changes that occur in diabetes.
‘ Because these changes aggravate the dia-
betic state, we need to pre-empt the pro-
gression of occult haematological injury.
Early screening and diagnosis will allow for
the identification of at-risk individuals and
enable us to better address the damage
diabetes does to all haematological param-
eters’, he concluded.
The concept and rationale for early
insulin therapy in type 2 diabetes
Prof David Owens, emeritus professor,
Cardiff University and chairman: Diabetic
Retinopathy Screening Programme of the
Diabetes Retinopathy Network, Wales
Introducing insulin therapy in type 2 diabe-
tes remains a controversial issue and there
are many barriers to its use. ‘It’s a challenge
to introduce it. When and how remain big
questions and it’s usually only introduced
10 years after diagnosis.’
Reviewing the chronology of clinical
studies dating back to the 1970s, Prof
Owens observed that there is a growing
body of evidence showing benefit from
early insulin use and that the focus is very
much on beta-cell responsiveness. ‘The use
of basal insulin has been associated with
improvements in beta-cell functioning as
well as improved insulin sensitivity, better
glycaemic control, enhanced insulin secre-
tion and near normalisation of hepatic
function and insulin resistance’, he said.
‘ Beta-cell deterioration is slower with insu-
lin than with oral agents, so early insulin
therapy can achieve better recovery and
maintenance of beta-cell function. It atten-
uates beta-cell overstimulation, allowing
the cells to rest.’
In addition, insulin has anti-inflamma-
tory and anti-oxidative properties that help
to regulate oxidative stress. ‘Metabolic
memory is important in oxidative stress.
Early metabolic control has long-term ben-
efits, which makes early glucose control an
investment in the future.’
It is important to achieve HbA1c targets
below 7% and therapy needs to be indi-
vidualised. ‘It’s more likely to be achieved
simply, safely and sustainably with the early
introduction of basal insulin. Pre-insulin
HbA1 c level is the greatest predictor of out-
comes. The ADA and EASD guidelines now
recommend the early addition of basal
insulin to metformin. It’s associated with a
dramatic improvement in preservation of
beta-cell function’, he continued.
Early insulinisation has quality-of-life
benefits, being associated with significant
improvements in general health, physi-
cal and social functioning, and mental
health. ‘Contrary to popular opinion, it’s
not a deterrent – patients find it easy to
accept and it is associated with good levels
of treatment satisfaction and a sense of
empowerment.’
The ADVANCE, ACCORD and VADT
trials raised cardiovascular concerns about
aggressive early insulinisation. Prof Owens
pointed out, however, it is important to
keep in mind that these trials involved
patient populations that already had poor
glucose control and existing cardiovascular
disease and it would have been unreason-
able to expect miraculous benefits in the
short term.
The recently published results of the
ORIGIN trial, 1 the largest ever study of a
single insulin (glargine), have allayed those
concerns. It differed from the other trials in
that it comprised patients with diabetes of
shorter duration (some were even pre-dia-
betic) who had lower baseline HbA 1c levels.
It set out to investigate whether insulin
replacement therapy with insulin glargine
reduced cardiovascular outcomes and pre-
vented progression of diabetes.
The first co-primary endpoint was a
composite of cardiovascular death and
non-fatal myocardial infarction/stroke. The
second added revascularisation and hospi-
talisation for heart failure to these criteria.
‘There was no increase in cardiovascular
death, and early introduction of insulin
achieved near-normal glycaemia at no risk
to the patients. There was also no increase
in cancer risk. This had previously been a
concern with insulin glargine, but it is no
longer supported by the evidence’, said
Prof Owens.
In those with pre-diabetes, there was
a 28% reduction in the risk of developing
new diabetes. There was also a significant
prevention of progression of diabetes, with
near normalisation of glucose levels, com-
pared with standard care. The durability of
this effect is still unclear, but an extension
of the trial will show whether the glycae-
mic benefit will affect future outcomes.
Summing up, Prof Owens underscored
that loss of beta-cell function is potentially
preventable and needs always to be kept in
mind. ‘Early insulin treatment may halt that
progressive decline because of its unique
physiological function. Basal glargine is a
flexible glucose-lowering drug in early dia-
betes and the ORIGIN trial showed no new
safety concerns to limit its use.’ He con-
cluded by stating that insulin should cer-
tainly be introduced earlier than is normally
done in current practice, but the debate
around how early continues.
Reference
1. The ORIGIN trial investigators. N Engl J Med 2012;
367: 319–328.
Managing difficult type 1 diabetes
Prof Colin Dayan, Clinical Diabetes and
Metabolism, Cardiff University School of
Medicine, Wales
Type 1 diabetes requires lifelong daily insu-
lin therapy.
The results of the Diabetes Control and
Complications trial (DCCT) showed that
lowering patients’ HbA1 c levels from 9.1 to
7.4% reduced microvascular complications
such as retinopathy, microalbuminuria and
cardiovascular disease. ‘But these effects
are not seen immediately, it can take a
number of years, a decade in the case of
cardiovascular disease, so it’s important
for patients to understand the time course
and that there is a legacy effect. Even 30
years later, the benefits are still apparent.
However, there is no free lunch as it comes
at the expense of increased hypoglycae-