SA JOURNAL OF DIABETES & VASCULAR DISEASE
DRUG TRENDS
VOLUME 7 NUMBER 2 • JUNE 2010
85
Diabetes myth-busters
A Novo Nordisk-sponsored education symposium
Insulin resistance, pre-diabetes and met-
formin: much ado about nothing?
Dr Aslam Amod, Durban
Plasma glucose levels are used to predict the
risk of microvascular complications, of devel-
oping diabetes in the future and of cardiovas-
cular morbidity and mortality. ‘If we’re using
plasma glucose for three different purposes,
we cannot expect one value to give us the
same prediction rate’, said Durban-based
endocrinologist, Dr Aslam Amod, speaking at
the annual pre-SEMDSA Novo Nordisk Diabe-
tes Update symposium this year, titled ‘Diabe-
tes myth-busters’.
For example, the curves for retinopathy are
different from those for mortality. There is no
discrete cut-off point. The same is true for pre-
dicting diabetes risk. The higher up one goes
in the so-called normal range, the greater the
risk. ‘For all three tests, the risk is continuous,
extending below the lower limits of the range
and becoming disproportionately greater at
the higher ends’, observed Dr Amod.
Any value chosen is therefore by defini-
tion arbitrary, balancing sensitivity against cost
effectiveness. Currently the cut-off for fasting
plasma glucose is 6–6.9 mmol/l or 5.6–6.9
mmol/l (depending on which definition is fol-
lowed), for two-hour plasma glucose it is
7.8–11 mmol/l, and for HbA
1c
5.7–6.4 mmol/l.
‘Pre-diabetes’ is an umbrella term applied
to impaired fasting glucose (IFG) and impaired
glucose tolerance (IGT). Dr Amod pointed out
that IFG and IGT are not equivalent conditions,
however, and that IGT carries the higher rela-
tive risk for progression to diabetes, cardiovas-
cular risk and cardiovascular mortality.
In patients with pre-diabetes (whether IGT
or IFG), 50% progress to diabetes, 25% revert
to normal and 25% remain in the pre-diabetic
state. ‘The rationale for prevention is therefore
clear, and we need to change the natural his-
tory of the disease to prevent micro- and mac-
rovascular complications.’
Regarding pharmacological interventions in
pre-diabetes, Dr Amod referred to various trials
that supported the use of drugs in pre-diabetic
patients, and showed the glitazones to be
more powerful than metformin. However, he
questioned their findings, asking, ‘Is this true
prevention? These medications lowered the
endpoint being measured. In all cases, the
patients involved were still taking the drug at
the end of the study. After a washout period,
most of the efficacy was lost. In reality, these
medications were not preventing diabetes, but
rather masking it by lowering the endpoints
the studies were measuring.’
By contrast, studies evaluating intensive
diet and lifestyle modification showed a much
more enduring effect in respect of delaying the
onset of diabetes. ‘The chances of developing
diabetes, as well as developing complications
and dying, are lower with intensive lifestyle
measures, calling into question whether it’s
cost effective to try to prevent progression
pharmacologically. It’s probably more cost
effective to intervene with metformin at the
onset of overt diabetes.’
Dr Amod raised a number of other questions
that need to be considered. If the target HbA
1c
in diabetes is 7 mmol/l, what target should be
set for pre-diabetes? Should the same inter-
ventions be applied in respect of pre-diabetes
diagnosed by HbA
1c
as in instances diagnosed
by the glucose tolerance test? There are no
studies to show what measures are effective
and no evidence that lowering glucose in pre-
diabetes lowers cardiovascular mortality.
The metabolic syndrome adds little value,
either. Dr Amod pointed out that it involves
five different variables, all with arbitrary cut-
off points. ‘It’s resulted in a huge amount of
confusion’, he said. ‘A recent change in mind-
set has seen the IDF introduce a new world-
wide definition that makes central obesity
rather than insulin resistance the variable at
the centre of the syndrome, and the condi-
tion is now diagnosed based on the presence
of central obesity plus two other risk factors.
But all the cut-off points remain arbitrary and
there is no hard science behind any of them.
Criteria are ambiguous and ill defined and the
so-called syndrome’s clinical utility remains
questionable. Cardiovascular risk with the syn-
drome is no different from that relative to the
syndrome’s individual components. Likewise,
treatment of the syndrome is no different from
the treatment of its individual components.’
Dr Amod underscored that all these fac-
tors point to type 2 diabetes and the meta-
bolic syndrome not being a single disorder,
and that one cannot treat all diabetes as one
and the same thing. ‘You get obese individu-
als who are metabolically normal, and young,
thin people can develop diabetes. Insulin resist-
ance is therefore not a cause of obesity, rather
a result – an adaptation to increasing weight.
The majority of patients with insulin resistance
have it because they’re fat – they’re not fat
because they’re insulin resistant.’
Bringing it all together, Dr Amod high-
lighted again that neither type 2 diabetes nor
the metabolic syndrome should be viewed as a
single disease and that obesity affects different
people differently. ‘We therefore need to stop
looking for a single cause and panacea. Pre-
vention needs to start with children and society
in general’, he concluded.
Beyond glycaemia – ‘a sum of the parts’
Dr Hoosen Randeree, Durban
There are problems with the ‘glucocentric’
approach to the treatment of type 2 diabetes.
Targets are not achieved globally and even in
the presence of seemingly adequate control,
the risk for macrovascular disease remains.
Dr Hoosen Randeree, an endocrinologist/
diabetologist in private practice in Durban, said
that reducing HbA
1c
through intensive therapy
shows only a trend towards improvement. He
feels that the holistic treatment of diabetes
requires a greater focus on the other modifi-
able risk factors associated with the condition,
notably hypertension, hyperlipidaemia, obesity
and smoking.
‘Diabetic dyslipidaemia is associated with
both quantitative and qualitative abnormali-
ties. Where the latter is concerned, one is deal-
ing with highly atherogenic LDL cholesterol
made of small dense particles. In addition,
thyroid disease is often present in diabetic dys-
lipidaemia and is often overlooked. An annual
lipogram should be taken and, if the condition
is diagnosed, lifestyle modification and possibly
pharmacological treatment should be initiated.’
When it comes to lifestyle, Dr Randeree rec-
ommends a diet in which ‘fish, foul and fibre’
predominate, along with 30 to 45 minutes of
exercise most days of the week. Pharmacologi-
cal treatment should be guided by the nature
of the abnormality, with statins the first choice
for pure hypercholesterolaemia and fibrates
for hypertriglyceridaemia.
Dr Randeree observed that diabetes should
be viewed as a coronary risk equivalent and
that the following targets should be aimed for
in respect of addressing diabetic dyslipidaemia:
total cholesterol
•
<
4 mmol/l
LDL cholesterol
•
<
2.6 mmol/l
HDL cholesterol
•
>
1.0 mmol/l in men;
>
1.2 mmol/l in women
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