What is the mechanism of action of Jardiance (empagliflozin)?

Mechanism of Action of Jardiance (Empagliflozin)

Jardiance (empagliflozin) works by inhibiting the sodium-glucose cotransporter-2 (SGLT2) in the proximal tubule of the kidney, which blocks approximately 90% of glucose reabsorption from the glomerular filtrate, thereby lowering the renal threshold for glucose and increasing urinary glucose excretion. 1

Primary Renal Mechanism

• SGLT2 is the predominant transporter responsible for reabsorbing filtered glucose back into the bloodstream from the kidney's proximal tubule. 1
• By inhibiting SGLT2, empagliflozin prevents this reabsorption and causes therapeutic glucosuria, resulting in approximately 64-78 grams of glucose excreted daily depending on the dose (10 mg vs 25 mg). 1
• This mechanism is completely insulin-independent, meaning it works regardless of β-cell function, insulin secretion, or diabetes duration. 2

Glucose-Dependent Effects

• The glucose-lowering effect is more pronounced during hyperglycemia and diminishes as blood glucose normalizes, which explains the low intrinsic risk of hypoglycemia when used alone. 3
• Hypoglycemia only becomes a concern when empagliflozin is combined with insulin or insulin secretagogues like sulfonylureas. 3
• Peak plasma concentrations occur at 1.5 hours post-dose, with steady-state achieved through once-daily dosing. 1

Beyond Glucose: Pleiotropic Mechanisms

Diuretic and Natriuretic Effects

• Empagliflozin promotes both sodium and water excretion along with glucose, resulting in osmotic diuresis. 3
• This leads to modest reductions in systolic blood pressure (approximately 4 mmHg) and diastolic blood pressure (approximately 2 mmHg). 2
• Mean 24-hour urine volume increases by 341 mL on Day 1 and 135 mL on Day 5 of treatment. 1

Cardiovascular Protection (Independent of Glucose-Lowering)

• The cardiovascular benefits occur within weeks of initiation and are independent of glucose-lowering effects, suggesting hemodynamic rather than atherosclerotic mechanisms. 2
• In the EMPA-REG OUTCOME trial, empagliflozin reduced cardiovascular death by 38% (HR: 0.62), all-cause mortality by 32% (HR: 0.68), and heart failure hospitalization by 35% (HR: 0.65). 3
• These benefits appear early, with separation of event curves within months, not years. 3

Renal Protection Mechanisms

• By reducing glucose reabsorption workload, empagliflozin relieves proximal tubular cells from energy-intensive glucose transport, decreasing oxygen consumption and reducing renal cortical hypoxia. 2
• This triggers tubuloglomerular feedback, which reduces glomerular hypertension and contains hyperfiltration injury. 2
• Despite causing a mild and transient drop in eGFR after initiation, empagliflozin provides long-term kidney protection. 2

Selectivity Profile

• Empagliflozin is highly selective for SGLT2 over SGLT1, distinguishing it from less selective agents like canagliflozin (which inhibits intestinal SGLT1) or sotagliflozin (a dual SGLT1/SGLT2 inhibitor). 3
• This selectivity minimizes gastrointestinal side effects related to intestinal glucose absorption inhibition. 3

Metabolic Pathway

• No major active metabolites are formed; the most abundant metabolites are three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide), each representing less than 10% of total drug-related material. 1
• Plasma protein binding is 86.2%, with red blood cell partitioning at approximately 36.8%. 1
• The apparent steady-state volume of distribution is 73.8 L. 1

Clinical Implications of the Mechanism

Weight Loss

• The caloric loss from urinary glucose excretion (approximately 280-312 calories per day at therapeutic doses) promotes weight reduction of approximately 2 kg. 4

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. 2
• The drug can be initiated if eGFR is above 20 mL/min/1.73 m² and should be continued until dialysis or transplantation. 2

Food Effects

• Administration with high-fat meals decreases AUC by 16% and Cmax by 37%, but this is not clinically relevant, so empagliflozin may be taken with or without food. 1