Hyperglycemia leads to microvascular complications and glucotoxicity, which results in metabolic abnormalities and progression of the disease. Inspite of many drugs available, managing hyperglycemia remains a challenge. We are still far from a molecule that will not cause hypoglycemia and weight gain and at the same time offer durable and optimum glycemic control. Inhibitors of renal sodiumeglucose cotransporter have recently been developed and this acts independent of beta cell and insulin resistance. This also causes weight loss and improves glycemic control without causing hypoglycemia.

1. Safety and Efficacy of SGLT2 Inhibitors in the Treatment of
Type 2 Diabetes Mellitus

2. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 1 6 e1 1 7
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
Review Article
Safety and efficacy of SGLT2 inhibitors in the treatment of
type 2 diabetes mellitus
Tirthankar Chaudhury
Senior Consultant, Diabetes and Endocrinology, Apollo Gleneagles Hospital, Kolkata, India
article info
Article history:
Received 30 April 2013
Accepted 15 May 2013
Available online 6 June 2013
Keywords:
Phlorizin
Empagliflozin
Glucosuria
Hyperglycemia leads to microvascular complications and
glucotoxicity, which results in metabolic abnormalities and
progression of the disease. Inspite of many drugs available,
managing hyperglycemia remains a challenge. We are still far
from a molecule that will not cause hypoglycemia and weight
gain and at the same time offer durable and optimum glycemic control. Inhibitors of renal sodiumeglucose cotransporter
have recently been developed and this acts independent of
beta cell and insulin resistance. This also causes weight
loss and improves glycemic control without causing
hypoglycemia.
Many studies have shown that 1% reduction in HbA1c
leads to 35% risk reduction in microvascular complications.1,2
Managing glucotoxicity leads to decreased insulin resistance
and rate of beta cell failure.3,4 Hypoglycemia, weight gain and
beta cell failure are the bigger obstacles in achieving HbA1c
below 7%. A new molecule has been developed to reduce
hyperglycemia by increasing glucosuria.
1.
Physiology of glucose transport in kidney
The maximum glucose transport capacity of the proximal
tubule is 375 mg/min5 and almost all the glucose is absorbed
in the S1 and S3 segment of proximal tubule by SGLT2
(sodiumeglucose transporter) and SGLT1 respectively. SGLT2
has low affinity and high capacity for glucose absorption
responsible for 80e90% of the glucose absorption in the S1
segment of proximal tubule. SGLT1 has high affinity and low
capacity for glucose absorption.6
Normally 180 L of plasma is filtered through the kidney and
contains 162 g of glucose and all of which is reabsorbed. In
diabetes the threshold of maximum glucose transport capacity (Tm) is increased. This is a maladaptive process
happening due to excess glucose filtration and inherent
function of the kidney to preserve glucose needed by the brain
for neuronal nutrition. In diabetes, it is desired that the excess
glucose is discarded to help achieve normoglycemia. SGLT2
E-mail address: tchaudhury67@yahoo.co.uk.
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http://dx.doi.org/10.1016/j.apme.2013.05.011

3. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 1 6 e1 1 7
inhibitor is desired over SGLT1 inhibitor as the receptors of the
later are also present in intestine.
2.
SGLT2 inhibitors
Dapagliflozin
Canagliflozin
Ipragliflozin
Empagliflozin
LX4211
PF04971729
TS-071
Phlorizin was the first SGLT2 inhibitor but with very poor
bioavailability.5,7,8
Phlorizin administration in 90% pancreatectomized rats
caused reversal of hyperglycemia, reversed insulin resistance
and caused glucosuria and provided proof of concept.9
Initial studies started with O-glucosides but later C-glucosides entered phase 3 trials. These are showing dose dependent glucosuria, increased IGF1 levels, HbA1c reduction
equivalent to Metformin and better with higher baseline
HbA1c. Causes weight loss due to loss of calories. Dapagliflozin is the most ahead among SGLT2 inhibitors in studies.
Initial studies demonstrated Dapagliflozin in doses (5,
25,100 mg/day) produced glucosuria (37, 62, 80 g/24 h). Significant decrease in fasting and postprandial glucose levels.
Highly protein bound and minimal renal excretion. Major
metabolite is an inert glucuronide (M15).10,11 In a head to head
comparison between Metformin þ Sulphonylurea and
Metformin þ Dapagliflozin, the results of reduction in HbA1c
were comparable but the subjects in the study had relatively
low HbA1c at the baseline. (11) Other SGLT2 inhibitors are also
in various stages of development with similar encouraging
results. Decreased glucose and sodium absorption with SGLT2
inhibitors would lead to more sodium to the juxtaglomerular
apparatus and this may inhibit renineangiotensin system
leading to less glomerular pressure and decreased hyperfiltration. So some renoprotection is expected.12
Increased rate of urinary tract infection has been noted.
Also the incidence of vulvovaginitis and balanitis was slightly
higher.
Some reports of breast and bladder cancer but these tissues
do not express SGLT2 receptors and intensive study in animals do not reflect carcinogenic potential.
5.
Conflicts of interest
The author has none to declare.
references
1.
2.
3.
4.
5.
6.
7.
8.
9.
Nonglycemic benefits observed
Weight loss.
Reduction in BP due to more sodium filtering out and
decreased activity of RAS due to more sodium at juxtaglomerular junction.
Some reduction in uric acid.
4.
Safety
Since ‘Familial renal glucosuria’ is a benign condition without
any problem, SGLT2 inhibitors should not pose a problem.
Conclusion
This is a new molecule with potential to decrease HbA1c by
0.8% and is not affected by progressive beta cell failure. Author
is presently engaged in the phase 3 trial of one of the SGLT2
inhibitors.
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