Safety and Efficacy of SGLT2 Inhibitors in the Treatment ofType 2 Diabetes Mellitus

Review Article

Safety and efficacy of SGLT2 inhibitors in the treatment oftype 2 diabetes mellitus

Tirthankar Chaudhury

Senior Consultant, Diabetes and Endocrinology, Apollo Gleneagles Hospital, Kolkata, India

a r t i c l e i n f o

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 glyce-

mic 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 ca-

pacity (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.

Available online at www.sciencedirect.com

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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-gluco-

sides entered phase 3 trials. These are showing dose depen-

dent glucosuria, increased IGF1 levels, HbA1c reduction

equivalent to Metformin and better with higher baseline

HbA1c. Causes weight loss due to loss of calories. Dapagli-

flozin 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). Sig-

nificant 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 absorptionwith SGLT2

inhibitors would lead to more sodium to the juxtaglomerular

apparatus and this may inhibit renineangiotensin system

leading to less glomerular pressure and decreased hyper-

filtration. So some renoprotection is expected.12

3. Nonglycemic benefits observed

Weight loss.

Reduction in BP due to more sodium filtering out and

decreased activity of RAS due to more sodium at juxtaglo-

merular 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.

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 ani-

mals do not reflect carcinogenic potential.

5. 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.

Conflicts of interest

The author has none to declare.

r e f e r e n c e s

1. DCCT Research Group. N Engl J Med. 1993;329:977e986.2. UKPDS. Lancet. 1998;352:837e853.3. DeFranzo RA. Banting lecture. Diabetes. 2009;58:773e795.4. Rosseti L, Giacarri A, DeFranzo RA. Glucose toxicity. Diabetes

Care. 1990;13:610e630.5. Li A, Zhang J, Greenberg J, Lee T, Liu J. Discovery of non-

glucoside SGLT2 inhibitors. Bioorg Med Chem Lett.2011;21:2472e2475.

6. Valtin H. Tubular Reabsorption. Boston: Little Brown andCompany; 1983.

7. Vick HD, Deidrich DF. Reevaluation of renal tubular glucosetransport inhibition by phlorizin analogs. Am J Physiol.1973;224:552e557.

8. Ehrenkranz JR, Lewis NG, Khan CR, Roth J. Phlorizin: a review.Diabetes Metab Res Rev. 2005;21:31e38.

9. Rosseti L, Shulman GI, Zawalich W, DeFranzo RA. Effect ofchronic hyperglycemia on in vivo insulin secretion inpartially pancreatectomized rat. J Clin Invest.1987;80:1037e1044.

10. Hussey E, Clark R, Amin D, et al. Early clinical studies toassess safety, tolerability, pharmacokinetics andpharmacodynamics of single dose of sergliflozin, a novelinhibitor of renal glucose reabsorption in healthy volunteersand subjects with type 2 diabetes mellitus. Diabetes.2007;56(suppl):A189.

11. Hussey E, Dobbins R, Stolz R, et al. A double blind randomizedrepeat dose study to assess safety, tolerability,pharmacokinetics and pharmacodynamics of three timesdaily dosing of sergliflozin, a novel inhibitor of renal glucosereabsorption in healthy overweight and obese subjects.Diabetes. 2007;56(suppl):A491.

12. Arakawa K, Ishihara T, Oku A, et al. Improved diabeticsyndrome in C57BL/KsJ-db/db mice by oral administration ofthe Naþ glucose cotransporter inhibitor T-1095. Br JPharmacol. 2001;132:578e586.

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