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John PH Wilding
worlie, more tan alf te eole it tye 2 iabetes ave bloo
gucose concentrations that are too high, eading to a greater
risk
o comications. This is arty because many existing treatments
have liitatios. metfori, for exaple, usually the first drug
recommene if lifestyle canges are not sufficient to control
bloo
glucose, may cause nausea an stomac uset, an cannot be given
to eole it kiney failure; sulonylureas may cause eigt gainan
yoglycaemia; an ioglitazone as been associate it eigt
gain, flui retention, eart failure, bone fractures an blaer
cancer.
new drugs have becoe available i the last few years iclude
dpp-4 inibitors, suc as sitaglitin, saxaglitin an linaglitin.
Te
injectabe Glp-1 anaogues, such as exenatide and iragutide,
are
a signiicant advance as they have a ower risk o hyogycaemia
an eigt gain. hoever, bloo glucose concentrations ten to
rise
over time in tye 2 iabetes, esite rug teraies, so eole nee
aitional treatments te longer tey ave a te conition many
eventuay needing insuin.
Therefore, ew treatets that ight help to overcoe soe of
tese roblems, articularly eigt gain an yoglycaemia, bot of
which aso are a robem with insuin treatment and oss o insuin
secretion over time, are esirable. here, Jon wiling revies
some
of te latest researc into ne meicines for tye 2 iabetes,
focusing
on drugs that might become avaiabe in the next ew years.
health Delivery
Activators of the gut and pancreas
G-protein coupled-receptors
Normal control of insulin release and
food intake
When we eat, the intestines produce
a cocktail of hormones that travel in
the blood to the pancreas, giving ad-
vanced warning that food is on its way.
Normally, this stimulates the release of
insulin to ensure that sugar, fats and
proteins are correctly stored and used
by the body. Some of the hormones (of
which the most familiar is GLP-1, ma-
nipulation of which is already used to
treat diabetes) also travel to the brain,
where they help transmit the message
that we are full and that it is time to stop
eating. Recent research has found some
of the sensor molecules in the intestinesthat recognize when the
intestines con-
tain food and control the release of those
hormones. Two of these sensor mol-
ecules are known as G-protein-coupled
receptor (GPR) 40 and GPR 119.
Potential to lower glucose and reduce
weight
Interestingly, these receptors are also
found in the pancreas, where they are
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health Delivery
thought to be involved in the control of insulin release. So
drugs that activate this system might assist the pancreas to
produce more insulin in response to food (helping to keep
blood glucose down after meals), while at the same time
allowing people to feel fuller sooner after a meal which
might help to control body weight.
Drugs in development
A number of companies have developed drugs that work
by activating either GPR 40 or GPR 119, and some of these
are now starting clinical trials in people with diabetes. It
will be a few years before we know for sure whether this
interesting new idea really is effective to help treat
diabetes
and perhaps a little longer before such treatments become
available, assuming the preliminary studies show that this
approach works in people with diabetes.
Sodium glucose transporter 2 inhibitors
The normal role of the kidney in controlling blood glucose
Glucose is often found in the urine in people with diabe-
tes - especially if their blood glucose is high. Most people
without diabetes do not have glucose in their urine. This is
because the kidney has a very efficient mechanism to catch
all the glucose very early in the process of urine formation
and pump it back into the bloodstream so that none of this
precious body fuel is wasted. If blood glucose is high
(above
approximately 11 mmol/l, as can often be the case in diabe-
tes), the capacity of this pumping system is exceeded and
some glucose remains in the urine. The main pump return-
ing glucose to the circulation from the urine is called the
sodium glucose co-transporter 2 (SGLT2). A similar pump,
called SGLT1, transports any leftover glucose. Importantly,
SGLT2 is only found in the kidney, whereas SGLT1 is also
found in the intestines where it is responsible for helping
absorb sugars from the diet.
A prototype drug from the apple tree
It has been known for more than 100 years that a chemicalcalled
phlorizin, originally purified from the bark of the apple
tree, could cause glucose to appear in the urine
(glucosuria).
In the 1970s, it was shown that phlorizin could lower blood
glucose in rats and mice with diabetes. However, it is not
practical to use phlorizin to treat people with diabetes for
a number of reasons: it has a weak effect, blocks SGLT1 in
the intestines (causing severe diarrhoea) and has to be
given
by injection. Although the structure of phlorizin is similar
to that of glucose, phlorizin jams up the glucose pumping
mechanism. Pharmaceutical companies have now developed
drugs that, while they are similar to phlorizin in
structure,
are selective: they only block SGLT2 in the kidney and can
be given as tablets once a day.
Clinical data on SGLT2 inhibitors in development
Several SGLT2 inhibitors are being tested in people with
dia-betes. All of them provoke the loss in the urine of about 50 g
of
glucose each day (about the same amount as in a standard can
of fizzy drink) and have been shown to lower blood glucose
(and HbA1c
, which indicates longer term glucose control). The
SGLT2 inhibitors seem to work irrespective of whatever other
therapy the person is taking, demonstrating their
effectiveness
when used as the only drug treatment in combination with
metformin, sulfonylureas, pioglitazone or insulin.
Because some glucose is lost in the urine, the SGLT2 inhibi-
tors also help a little with weight people lose about 2.5 kgon
average over 6 months. The drugs also appear slightly to
lower blood pressure (probably because some sodium is lost
with the glucose). The main side effects relate to an excess
of glucose in the urine people might expect to empty their
bladder once more per day than usual. There is also a
slightly
higher risk of developing yeast infections (thrush) and
water
infections (cystitis) but these tend to be mild and respond
to
standard treatments. The risk of hypoglycaemia is low
because
SGLT2 inhibitors do not provoke insulin to be secreted from
the pancreas.
Who might benefit?
These drugs are not yet available for healthcare
professionals
to prescribe. However, they might be particularly helpful
for
people who are struggling to control their weight and some
people who are already on insulin, where they have been
shown to improve blood glucose control without having to
increase the insulin dose.
Jon ph wiling
John PH Wilding is Professor of Medicine and HonoraryConsultant
Physician at the University of Liverpool, UK. Heis Head of the
Department of Obesity and Endocrinologyat the Clinical Sciences
Centre, University Hospital Aintree,Liverpool, UK
([email protected])further reading
Nair S, Wilding JPH. Sodium glucose co-transporter 2 inhibitors
as a new
treatment for diabetes mellitus. J Clin Endocrinol Metab 2010;
95: 34-42.
Telvekar VN, HS Kundaikar. GPR40 Carboxylic Acid Receptor Family
and
Diabetes: A New Drug Target. Curr Drug Targets 2008; 9:
899-910.
Aprl 2012Volume 57issue 1
