How does Jardiance (empagliflozin) work?

How Jardiance (Empagliflozin) Works

Jardiance works by blocking SGLT2 (sodium-glucose cotransporter 2) in the kidney's proximal tubules, which prevents glucose reabsorption and forces excess glucose into the urine, lowering blood sugar through an insulin-independent mechanism. 1

Primary Mechanism of Action

• SGLT2 is responsible for approximately 90% of glucose reabsorption from the kidney's glomerular filtrate back into the bloodstream 2
• By inhibiting this transporter, empagliflozin reduces renal glucose reabsorption and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion 1
• This mechanism is completely independent of insulin secretion or β-cell function, making it effective regardless of diabetes duration (provided kidney function is adequate) 2

Glucose-Lowering Effects

• Empagliflozin increases urinary glucose excretion by approximately 64 grams per day with the 10 mg dose and 78 grams per day with the 25 mg dose 1
• The glucose-lowering effect is more pronounced during hyperglycemia and diminishes as blood glucose normalizes, which explains the low intrinsic risk of hypoglycemia 2
• The efficacy decreases with worsening kidney function, particularly when eGFR falls below 45 mL/min/1.73 m² 1

Beyond Glucose: Additional Mechanisms

Diuretic and Natriuretic Effects

• Empagliflozin promotes both sodium and water excretion along with glucose 3
• This osmotic diuresis increases 24-hour urine volume by approximately 341 mL on Day 1 and 135 mL on Day 5 of treatment 1
• The natriuretic effect contributes to blood pressure reduction of approximately 4 mmHg systolic and 2 mmHg diastolic 3, 4

Cardiovascular Protection (Not Glucose-Mediated)

• The cardiovascular benefits occur within weeks of initiation and are independent of glucose-lowering effects 2
• The rapid mortality benefit suggests hemodynamic mechanisms rather than atherosclerosis prevention, as evidenced by early divergence of event curves for cardiovascular death and heart failure hospitalization 2
• Empagliflozin reduces the burden on proximal tubular epithelial cells, decreasing renal cortical hypoxia and improving kidney structure and function 2

Renal Protection Mechanisms

• By reducing glucose reabsorption workload, empagliflozin relieves proximal tubular cells from energy-intensive glucose transport, reducing oxygen consumption 2
• This leads to tubuloglomerular feedback, reduction in glomerular hypertension, and containment of hyperfiltration injury 2
• Despite a mild and transient drop in eGFR after initiation, empagliflozin offers long-term kidney protection 2

Unique Pharmacological Characteristics

• No effect on blood pressure, heart rate, or potassium levels in the context of heart failure management, making it uniquely easy to implement 2
• Requires no dose adjustment or up-titration, unlike other heart failure medications 2
• The glucose-lowering effect is glucose-dependent, meaning it becomes less potent as blood glucose normalizes, minimizing hypoglycemia risk 2

Clinical Implications of the Mechanism

When Glucose-Lowering Diminishes

• Continue empagliflozin even when eGFR falls below 45 mL/min/1.73 m² because cardiovascular and renal protective benefits persist despite minimal glucose-lowering effects 3
• The drug can be initiated if eGFR is above 20 mL/min/1.73 m² and should be continued until dialysis or transplantation 3

Common Pitfalls Related to Mechanism

• The persistent glucosuria creates a glucose-rich genitourinary environment, increasing mycotic genital infections to approximately 6% versus 1% with placebo 3
• The osmotic diuresis can cause volume depletion, particularly in elderly patients (≥75 years) where risk increases to 4.4% with the 25 mg dose 1
• Do not discontinue solely because glucose-lowering effects diminish with declining kidney function—the cardiovascular and renal benefits remain 3