Mechanism of Action of Empagliflozin (Jardiance)
Empagliflozin works primarily by inhibiting sodium-glucose co-transporter 2 (SGLT2), the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. 1
Primary Mechanism
- SGLT2 is located in the proximal tubules of the kidney and is responsible for approximately 90% of urinary glucose reabsorption
- By inhibiting SGLT2, empagliflozin:
- Reduces renal reabsorption of filtered glucose
- Lowers the renal threshold for glucose
- Increases urinary glucose excretion 1
- This results in approximately 64 grams per day of glucose excretion with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin 1
Pharmacodynamic Effects
Glycemic Effects
- Empagliflozin's mechanism is insulin-independent, making it effective regardless of beta-cell function or insulin resistance 2
- The glucose-lowering efficacy decreases in patients with renal insufficiency (eGFR <45 mL/min/1.73 m²) due to reduced filtered glucose 1
Hemodynamic and Renal Effects
- Empagliflozin promotes sodium excretion (natriuresis) along with glucosuria 3
- Increases urinary volume (341 mL increase on Day 1 of treatment) 1
- Reduces intraglomerular pressure by affecting tubuloglomerular feedback 4
- Reduces systemic blood pressure through osmotic diuresis and natriuresis 4
Cardiovascular and Renal Protection
- Reduces oxidative stress in the kidney by >50% 4
- Blunts increases in angiotensinogen and reduces NLRP3 inflammasome activity 4
- These effects contribute to cardiovascular and renal protection that appears to be independent of glycemic control 4
- Particularly effective at reducing heart failure hospitalizations, likely through its diuretic and hemodynamic effects 4
Metabolic Fate
- No major metabolites detected in human plasma 1
- Most abundant metabolites are three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide) 1
- Each metabolite represents less than 10% of total drug-related material 1
Clinical Implications of Mechanism
- Low inherent risk of hypoglycemia due to insulin-independent mechanism 2
- Can be used in combination with other antidiabetic medications with different mechanisms 2
- Cardiovascular benefits demonstrated in EMPA-REG OUTCOME trial with 14% reduction in major adverse cardiovascular events and 38% reduction in cardiovascular death 4
- Renal protection with 39% reduction in incident or worsening nephropathy 4
Practical Considerations
- Most common adverse effects related to the mechanism include genital mycotic infections due to glucosuria 3
- Increased urination due to osmotic diuresis 1
- Potential for volume depletion, especially when combined with diuretics 1
- Reduced efficacy in patients with impaired renal function (eGFR <45 mL/min/1.73 m²) 1
The unique mechanism of action of empagliflozin provides benefits beyond glycemic control, particularly for cardiovascular and renal outcomes, making it an important option for type 2 diabetes management, especially in patients with established cardiovascular disease or chronic kidney disease.