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SODIUMGLUCOSE CO-TRANSPORTERS (SGLTS) INHIBITORS

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INTRODUCTION

T2DM progressive -cell dysfunction & peripheral insulin resistance

Persisting hyperglycemia -cell dysfunction & worsens insulin resistance

T2DM obese, HTN and dyslipidemia

Need arises for new, well tolerated in all stages of disease7/13/20152

MOA OF OHAS

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HISTORY

Phlorizin, a bitter white glycoside isolated from apple tree bark by French chemists in 1835, is a naturally occurring inhibitor of both SGLT1 and SGLT2 and was used for the treatment of diabetes in the pre-insulin era.

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Familial Renal Glycosuria

A rare inherited condition caused by a mutation in the SGLT2 gene. Patients with this condition have varying degrees of glycosuria They remain asymptomatic They do not become dehydrated or become hypoglycemic They can excrete up to 125 g of glucose/day.

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SGLT2-INHIBITORS

Sodiumglucose co-transporters (SGLTs) are the newest drugs

MOA is by blocking the glucose reabsorption in the kidney, inhibitors of the sodium-glucose cotransporter 2 (SGLT2) increase the urinary glucose excretion

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HOW ARE SGLT2 INHIBITORS DIFFERENT FROM OTHER ANTI-HYPERGLYCEMIC AGENTS?

Non-insulin dependent mechanism

SGLT2 inhibitors can be used in early or late type 2 diabetes

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FDA APPROVED SGLT2 INHIBITORS

Canagliflozin (INVOKANA) Approved March 2013

Dapagliflozin (FARXIGA) Approved in Europe since 2012 FDA declined approval in 2012 due to possible cancer signal with drug FDA recommends approval December 2013 Approved January 2014

Empagliflozin ( Jardiance ) Approved in January 2014

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CANAGLIFLOZIN (INVOKANA) Reduces glucose absorption by 31% in first hour and 20% by next hour of food intake.

Dosage:- : Initial: 100 mg once daily prior to first meal of the day; may increase to 300 mg once daily (onlyin patients with GFR 60 mL/minute/1.73 m2)

Drug interactions :- UGT inducers (e.g., rifampin, phenytoin, phenobarbital, ritonavir) se metabolism of CFZ. C/I- renal impairement

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DAPAGLIFLOZIN (FARXIGA)

Improves glycemic control in patients with T2DM when used as monotherapy, or when added to metformin, glimepiride or insulin.

Helps in weight reduction

Decrease in systolic blood pressure noted

Less incidence of hypoglycemia

Controversy- higher rate of bladder and breast cancer in the groups treated with dapagliflozin

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An increased number of bladder cancers were diagnosed among Farxiga users in clinical trials so Farxiga is not recommended for patients with active bladder cancer.7/13/201516

Dose:- Initial: 5 mg once daily; may increase to 10 mg once daily.

C/I:- renal impairement, bladder cancer

Drug interactions:- may enhance hypoglycemic effects when used with insulin & sulfonylureas7/13/201517

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EMPAGLIFLOZIN ( JARDIANCE ) Pharmacokinetic studies of empagliflozin have shown that it is rapidly absorbed following oral administration, reaching maximal plasma concentrations within 13 hours.Once-daily administration of empagliflozin in patients with type 2 diabetes is well toleratedDose :- Initial 10 mg once daily; may increase to 25 mg once dailyNo risk of hypoglycemia7/13/201520

C/I in renal impairement

No hepatic impairement

No drug interactions with CVS drugs like verapamil, ramipril, digoxin, and anticoagulant warfarin.7/13/201521

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Advantages Vs. Disadvantages

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CONCLUSIONS

SGLT2 inhibitors are a new option in treatment for type 2 diabetes Insulin independent mechanism of action allows use in early and late stages of diabetesWeight loss is a desirable side effect Long term outcome studies are necessary to assess risk of cardiovascular events

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