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DOI: 10.1177/1474651413479981
2013 13: 2 British Journal of Diabetes & Vascular Disease
Caroline Day and Andrew V Bailey
Glucosuria: a counter intuitive treatment for diabesity

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The British Journal of
Diabetes & Vascular Disease
13(1) 2 6
The Author(s) 2013
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DOI: 10.1177/1474651413479981
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Introduction
Discourses on the treatment of long-term conditions
often refer to unmet needs, one such need is to improve
glycaemic control whilst facilitating weight loss in over-
weight and obese individuals with type 2 diabetes. It is
well known that weight loss is more difficult to achieve in
people with type 2 diabetes, despite energy intake and
output appearing to be the same as in weight-matched
non-diabetic subjects.
1,2
Efforts to improve glycaemic
control tend to be compromised by weight gain as fewer
calories are lost via glucosuria and compensatory dietary
reductions are not implemented.
Hypoglycaemic or antihyperglycaemic?
Hypoglycaemic agents, as monotherapy can cause hypo-
glycaemia to the point of neuroglycopenia, whereas
antihyperglycaemic agents as monotherapy will not
lower glycaemia beyond euglycaemia.
3
Thus exogenous
insulin and insulin secretagogues are hypoglycaemic
agents, although the rapid onset and short duration of
the meglitinides mean that these agents are rarely asso-
ciated with hypoglycaemia.
4,5
Although the DPP4 inhib-
itors (gliptins) and GLP-1 analogues exert glucose
lowering activity by facilitating increased insulin secre-
tion, the effects of these incretin agents are based on
potentiation of nutrient/glucose-induced insulin secre-
tion, rather than initiation and maintenance of insulin
secretion.
4,5
The other currently available agents, such as
the antihyperglycaemic drug metformin, do not have
glucose-lowering effects mediated via insulin secretion,
but they are not substitutes for insulin and require the
presence of insulin.
4,5
Established glucose lowering agents
Treatment with hypoglycaemic agents such as insulin or
sulphonylureas may increase appetite, but more particu-
larly stimulate increased consumption of uncounted
calories as patients snack to avoid a hypo or over con-
sume in response to hypo symptoms.
6
Indeed fear of
hypo may condition a preventive snacking habit.
Although these anti-hypo calories may be considered
medicinal they are nevertheless additions to the energy
quota of the daily diet: thus exacerbating the potential for
weight gain with lowering of hyperglycaemia.
The firstline pharmacological therapy in the treat-
ment of type 2 diabetes is the antihyperglycaemic met-
formin, which at worst is considered weight neutral and
at best is associated with a small weight loss. Its novel
mechanisms of action enhance sensitivity to endogenous
insulin, especially in the liver to decrease hepatic glucose
production, and to improve glucose uptake and utilisa-
tion by muscle; and as metformin passes through into
the blood there is also futile cycling of glucose in the
splanchnic bed
7
- it has been suggested that this action
contributes to the gastrointestinal incommode associ-
ated with metformin. Thus there is energy expenditure
and decreased energy consumption; at least in the early
days of treatment. Metformin has pleiotropic effects
which offer benefits beyond glycaemic control in type 2
diabetes. Indeed metformin is currently generating inter-
est as an anti-mitogenic agent, thought to operate via the
mTOR pathway.
8
The DPP4 inhibitors (gliptins) which facilitate an
increase in the half-life of incretin hormones, such as
GLP-1, also offer improved glycaemic control whilst
being weight neutral. The GLP-1 analogues, which are
administered via injection, potentiate nutrient/glu-
cose-induced insulin secretion, have a direct glucose-
dependent effect on the pancreatic alpha cells to
Glucosuria: a counter intuitive treatment
for diabesity
Caroline Day
1
and Andrew V Bailey
2
1
School of Life and Health Sciences, Aston University, Birmingham, UK
2
Queen Elizabeth Hospital Birmingham, Birmingham, UK
Corresponding author:
Dr Caroline Day School of Life and Health Sciences, Aston University,
Birmingham, B4 7ET, UK
Email: [email protected]
479981DVD13110.1177/1474651413479981EditorialEditorial
2013
Editorial
Abbreviations:
CHMP Committee for Medicinal Products for Human
Use
DPP dipeptidylpeptidase
GLP-1 glucagon-like peptide 1
PPAR peroxisome proliferator activated receptor
SGLT sodium glucose transporter
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Editorial 3
decrease glucagon secretion and additionally have
centrally mediated effects which enhance satiety and
reduce the rate of gastric emptying the latter can
cause the associated nausea and potentially decrease
food consumption . In consequence longer term
GLP-1 agonist treatment can reduce body weight by
2-4kg.
The PPARgamma agonist pioglitazone is associ-
ated with weight gain and a redistribution of body fat
from the viscera to the periphery. However much of
the weight gain with the insulin sensitising thiazo-
lidindiones (glitazones) can often be attributed to
fluid retention.
New class of glucose lowering agent
In November 2012 the European Commission granted
marketing authorisation to dapagliflozin (BMS-512148),
the first in a new class of glucose lowering agents the
SGLT2 inhibitors.
9
As reviewed previously in this
journal
10
(http://www.bjdvd.com/content/10/4/193.full.
pdf+html) inhibition of SGLT2 transporters, which are
located almost exclusively in the proximal renal tubule
reduce the amount of glucose reabsorbed back into the
circulation, thus excess glucose is eliminated in the urine
(Figure 1). This glucuretic effect results in improved gly-
caemic control and weight loss a happy coincidence for
the treatment of people with type 2 diabetes who are gen-
erally overweight or obese.
Dapagliflozin
In Europe dapagliflozin a selective, reversible SGLT2
inhibitor - has been approved for use in adults with type
2 diabetes in whom diet and exercise alone or in associa-
tion with other glucose lowering agents including
insulin - fail to provide adequate glycaemic control.
9,11

However there are no reported studies on dapagliflozin
in combination with DPP4 inhibitors or GLP-1 ana-
logues. Its monotherapy indication is only in patients for
whom metformin treatment is inappropriate. The results
of several randomised clinical trials with dapagliflozin as
monotherapy or in combination with other glucose-low-
ering agents in patients with type 2 diabetes are already
in the published literature.
1226
The recommended once daily dose of dapagliflozin
(Forxiga) is 10mg, although 5mg tablets are also avail-
able. Tablets can be taken at any time of day with or with-
out food. Dapagliflozin is 91% protein bound and is
metabolised via hepatic glucuronidation rather than via
CYP450, thus obviating drug interactions.
11,27,28
The
metabolite is inactive and is eliminated via the kidney.
Since dapagliflozin exposure is increased (12-67%) in
patients with hepatic impairment it is advisable to
Figure 1. Regulation of glucose excretion in the renal tubule.
10
Reproduced with permission from Bailey & Day, Br J Diabetes Vasc Dis 2010
10
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4 Editorial 13(1)
commence treatment with a 5mg dose in patients with
severe impairment (Child-Pugh class C) .
11
The efficacy of dapagliflozin is dependent upon
an adequate rate of renal perfusion, therefore it is not
recommended in patients with moderate or severe renal
impairment (eGFR <60 ml/min//1.73m
2
or creatinine
clearance <60 ml/min). Additionally these renally
impaired patients may also show increased creatinine,
phosphorous, parathyroid hormone and hypotension.
Thus renal monitoring is recommended prior to initia-
tion of therapy and at least yearly thereafter.
11
As an SGLT2 inhibitor dapagliflozin also exerts lim-
ited effects on sodium reabsorption which in associa-
tion with urinary glucose excretion results in a small
osmotic diuresis (~375 ml/day). Thus it may be addi-
tive to the diuretic effects of thiazide and loop diuretics.
However the mild diuresis is beneficial in reducing sys-
tolic (4.4 mmHg) and diastolic (2.1 mmgHg) blood
pressure.
11
In hyperglycaemic states dapagliflozin achieves a glu-
cosuria of about 70-80 g glucose/day. This equates to a
decrease in HbA1c of 0.5-1% and the caloric loss reduces
body weight by 2-3kg.
10,11
As monotherapy or in combi-
nation with metformin, glimepiride or insulin the glu-
cose lowering efficacy of dapagliflozin was maintained at
2yrs. The inhibition of SGLT2 carries glucose along the
nephron where there is increased glucose reabsorption
by SGLT1 in the third segment of the proximal tubule.
This represents a mechanism that blunts the fall in
glucose such that SGLT1 can almost completely reabsorb
all glucose at low plasma glucose concentrations there-
fore preventing severe hypoglycaemia.
The glucosuria is associated with increased reports of
genital tract infection (< 1in 100 subjects) and urinary
tract infection (< 1 in 10 subjects) although they were
generally self-managed in the clinical trials. These infec-
tions were also more frequent in females and in people
with a prior history of infections.
11
In July 2011 the FDA advisory committee voted 9 to
6 against recommending marketing authorisation for
dapagliflozin.
29
A major reason for concern was an
apparent increase in some malignancies; thus more data
were considered desirable. Interestingly media reports
of the incidence of malignancies generally failed to note
that in the trials there were almost twice as many sub-
jects in the treatment than placebo/comparator groups.
In July 2012, when the CHMP recommended EU mar-
keting authorisation
30
it was evident that the proportion
of malignant and unspecified tumours was similar
between the dapagliflozin (1.47%) and the placebo//
comparator (1.35%) groups. Although the relative risk
of ovarian, renal tract and other cancers was <1, the rel-
ative risk of prostate, breast and bladder cancer was >1,
prompting post authorisation studies. However a causal
relationship is considered unlikely due to the short time
between initial drug exposure and tumour diagnosis
and the ascertainment bias attached to these tumours in
clinical trials.
31
Figure 2. SGLT2 inhibitors to treat diabetes phase of development
3235
Note: 10th January 2013. US FDA advisory committee recommended approval of cangliflozin (http://www.nelm.nhs.uk/en/)
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Editorial 5
Glucuretics in development
Several SGLT2 inhibitors are in clinical development,
with the most advanced being canagliflozin (Figure 2).
3235

The main differences between these agents relate to their
specificity for SGLT2 and SGLT1 transporters, but stud-
ies to date suggest that these agents reduce hyperglycae-
mia and reduce body weight to similar extents.
Interestingly in the USA GSK has recently completed
a phase 2 study in a healthy, obese (BMI 30-40kg/m
2
)
non-diabetic population to ascertain change in body
weight over 12 weeks of thrice daily dosing treatment
with the SGLT2 inhibitor GW869682.
32
Conclusion
The glucuretic action of the SGLT2 inhibitors satisfies
unmet needs in the treatment of type 2 diabetes: most
notably reducing hyperglycaemia whilst facilitating
weight loss. Their action is independent of insulin and
not associated with hypoglycaemia.
Dapagliflozin offers once daily dosing, which should
aid adherence, and a new mode of action which is com-
plementary to that of other glucose lowering agents; but
it also brings a paradigm shift with a counter-intuitive
approach to glucosuria.
According to economic pundits there is good debt
and bad debt and in type 2 diabetes there is now good
glucosuria and bad glucosuria. Only time will tell.
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