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SODIUM–GLUCOSE CO-TRANSPORTERS (SGLTS) INHIBITORS

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INTRODUCTION

• T2DM progressive β-cell dysfunction & peripheral insulin resistance

• Persisting hyperglycemia β-cell dysfunction & worsens insulin resistance

• T2DM obese, HTN and dyslipidemia

• Need arises for new, well tolerated in all stages of disease

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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

• Sodium–glucose 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 (only in 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. ”

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• 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 & sulfonylureas

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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 1–3 hours.

• Once-daily administration of empagliflozin in patients with type 2 diabetes is well tolerated

• Dose :- Initial 10 mg once daily; may increase to 25 mg once daily

• No risk of hypoglycemia

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• C/I in renal impairement

• No hepatic impairement

• No drug interactions with CVS drugs like verapamil, ramipril, digoxin, and anticoagulant warfarin.

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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 diabetes

• Weight loss is a desirable side effect • Long term outcome studies are necessary to assess

risk of cardiovascular events

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