JARDIANCE-10

Indications

• Type 2 diabetes mellitus
• Cardiovascular risk reduction in adults with type 2 diabetes and established cardiovascular disease
• Heart failure prevention

Dosage

Adults: The typical starting dose is 10 mg once daily, which may be increased to 25 mg once daily based

Mechanism of action

Empagliflozin inhibits the SGLT2 transporters in the proximal tubules of the kidneys, which are responsible for the reabsorption of approximately 90% of glucose filtered through the glomerulus. By blocking this transporter, empagliflozin increases glucose excretion in the urine (glucosuria) and lowers blood glucose levels. It may also exert cardiovascular benefits, potentially through the inhibition of Na⁺/H⁺ exchangers and diuretic effects, although further investigation is needed.

Pharmacodynamics

Empagliflozin effectively lowers blood glucose by preventing glucose reabsorption in the kidneys, which leads to increased glucosuria. The drug has a long duration of action, allowing for once-daily dosing. However, patients should be monitored for signs of diabetic ketoacidosis, which can occur even in the absence of hyperglycemia. The increased glucose in the urine can also elevate the risk of urogenital infections, necessitating close monitoring.

Pharmacokinetics

Empagliflozin is absorbed after oral administration, with peak plasma concentrations typically reached within 1.5 hours. It has a bioavailability of approximately 78% when taken with food. The drug is extensively metabolized by the liver, primarily via glucuronidation. It has a half-life of about 12 hours, allowing for once-daily dosing. Renal function significantly affects its pharmacokinetics; thus, dosage adjustments may be necessary in patients with renal impairment.

Contra-indications

• Severe renal impairment (eGFR < 30 mL/min)
• End-stage renal disease
• Dialysis
• History of serious hypersensitivity reactions to empagliflozin

Adverse effects

• Genital mycotic infections
• Urinary tract infections
• Ketoacidosis
• Dehydration
• Hypotension
• Renal impairment
• Elevated LDL cholesterol levels

Interactions

• Diuretics may increase the risk of dehydration and hypotension
• Insulin or insulin secretagogues may increase the risk of hypoglycemia
• ACE inhibitors may increase the risk of renal impairment when used concurrently

Precautions

• Monitor renal function before and during treatment
• Caution in patients with a history of urinary tract infections
• Regular monitoring for signs of ketoacidosis is recommended
• Consider holding the medication in cases of acute illness or dehydration

Pregnancy

Empagliflozin is not recommended during pregnancy. There is insufficient data on its safety in pregnant women.

Breast-feeding

It is unknown whether empagliflozin is excreted in human milk. Caution is advised when administering to breastfeeding women.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 10 mg, 25 mg

Mechanism of action

The vast majority of glucose filtered through the glomerulus is reabsorbed within the proximal tubule, primarily via SGLT2 (sodium-glucose linked co-transporter-2) which is responsible for ~90% of the total glucose reabsorption within the kidneys. Na⁺/K⁺-ATPase on the basolateral membrane of proximal tubular cells utilize ATP to actively pump Na+ ions into the interstitium surrounding the tubule, establishing a Na⁺ gradient within the tubular cell. SGLT2 on the apical membrane of these cells then utilize this gradient to facilitate secondary active co-transport of both Na+ and glucose out of the filtrate, thereby reabsorbing glucose back into the blood – inhibiting this co-transport, then, allows for a marked increase in glucosuria and decrease in blood glucose levels. Empagliflozin is a potent inhibitor of renal SGLT2 transporters located in the proximal tubules of the kidneys and works to lower blood glucose levels via an increase in glucosuria. Empagliflozin also appears to exert cardiovascular benefits - specifically in the prevention of heart failure - independent of its blood glucose-lowering effects, though the exact mechanism of this benefit is not precisely understood. Several theories have been posited, including the potential inhibition of Na⁺/H⁺ exchanger (NHE) 1 in the myocardium and NHE3 in the proximal tubule, reduction of pre-load via diuretic/natriuretic effects and reduction of blood pressure, prevention of cardiac fibrosis via suppression of pro-fibrotic markers, and reduction of pro-inflammatory adipokines.

Pharmacodynamics

Empagliflozin lowers blood glucose levels by preventing glucose reabsorption in the kidneys, thereby increasing the amount of glucose excreted in the urine. It has a relatively long duration of action requiring only once-daily dosing. Patients should be monitored closely for signs and symptoms of ketoacidosis regardless of blood glucose level as empagliflozin may precipitate diabetic ketoacidosis in the absence of hyperglycemia. As its mechanism of action is contingent on the renal excretion of glucose, empagliflozin may be held in cases of acute kidney injury and/or discontinued in patients who develop chronic renal disease. The overexcretion of glucose creates a sugar-rich urogenital environment which increases the risk of urogenital infections in both male and female patients - monitor closely for signs and symptoms of developing infection.