What is the mechanism of action (MOA) of Jardiance (Empagliflozin)?

Mechanism of Action of Jardiance (Empagliflozin)

Empagliflozin works by inhibiting sodium-glucose co-transporter 2 (SGLT2), which is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. 1

Primary Mechanism

Empagliflozin's mechanism of action involves:

• SGLT2 Inhibition: SGLT2 is expressed in the proximal tubules of the kidney and is responsible for approximately 90% of urinary glucose reabsorption 2
• Reduced Renal Glucose Reabsorption: By inhibiting SGLT2, empagliflozin reduces the reabsorption of filtered glucose in the kidney 1
• Lowered Renal Threshold for Glucose: This inhibition lowers the renal threshold for glucose excretion 1
• Increased Urinary Glucose Excretion: The result is increased glucosuria, with approximately 64-78 grams of glucose excreted per day depending on dosage 1

Physiological Effects

The inhibition of SGLT2 by empagliflozin leads to several important physiological effects:

1. Glucose Lowering: Promotes urinary glucose excretion, resulting in reduced fasting and postprandial glycemia 3

   • This effect is more pronounced in hyperglycemic states and diminishes as blood glucose normalizes
   • The glucose-lowering effect is insulin-independent, making it effective regardless of beta-cell function 4

2. Diuretic and Natriuretic Effects:

   • Increases urine volume (approximately 341 mL increase on Day 1 of treatment) 1
   • Promotes sodium excretion, contributing to blood pressure reduction 2

3. Blood Pressure Reduction:

   • Reduces systolic blood pressure by approximately 4 mmHg 3
   • Reduces diastolic blood pressure by approximately 2 mmHg 3

4. Weight Loss:

   • Promotes weight reduction of approximately 2 kg through caloric loss via glucosuria 3

5. Renal Hemodynamic Effects:

   • Reduces intraglomerular pressure 2
   • Blunts tubuloglomerular feedback 2
   • Reduces oxidative stress in the kidney by >50% 2
   • Reduces NLRP3 inflammasome activity 2

Clinical Implications of Mechanism

The unique mechanism of action of empagliflozin provides several clinical advantages:

• Low Hypoglycemia Risk: Because its action is insulin-independent, empagliflozin has a low inherent risk of hypoglycemia unless combined with insulin or insulin secretagogues 4

• Cardiovascular Benefits: The mechanism contributes to significant cardiovascular protection, particularly reduction in heart failure hospitalizations 2

• Renal Protection: The effects on intraglomerular pressure and oxidative stress contribute to slowing CKD progression 2

• Complementary Action: Works independently of insulin secretion or sensitivity, making it suitable for combination with other antidiabetic medications that have different mechanisms 4

Important Clinical Considerations

• Efficacy Limitations: The glucose-lowering efficacy decreases in patients with renal insufficiency (eGFR <45 mL/min/1.73 m²) 5

• Dosing Considerations: Available in 10 mg and 25 mg once-daily doses 1

• Safety Profile: Most common adverse effects related to the mechanism include genital mycotic infections due to glucosuria 2

• Contraindications: Not recommended in severe renal impairment, end-stage renal disease, or patients on dialysis 1

The unique insulin-independent mechanism of empagliflozin makes it a valuable addition to diabetes management, particularly for patients who would benefit from its additional effects on weight, blood pressure, cardiovascular outcomes, and renal protection.