What is the mechanism of action of Dapagliflozin (Forxiga)?

Mechanism of Action of Dapagliflozin (Forxiga)

Dapagliflozin inhibits sodium-glucose co-transporter-2 (SGLT2) in the proximal renal tubules, blocking reabsorption of filtered glucose and promoting urinary glucose excretion, while also reducing sodium reabsorption and increasing distal tubular sodium delivery. 1

Primary Renal Mechanism

Glucose Excretion:

• SGLT2 is predominantly expressed in the S1 and S2 segments of the proximal convoluted tubule and is responsible for the majority (approximately 90%) of renal glucose reabsorption 1, 2
• By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose from the tubular lumen, leading to urinary glucose excretion (glucosuria) of approximately 70 grams per day at therapeutic doses 1, 3
• This mechanism is completely independent of pancreatic β-cell function and insulin sensitivity, making it complementary to other antidiabetic therapies 4, 3

Sodium Handling:

• Dapagliflozin also reduces sodium reabsorption in the proximal tubule and increases sodium delivery to the distal tubule 1
• This increased distal sodium delivery triggers tubuloglomerular feedback, which decreases intraglomerular pressure and provides renal protection 1

Selectivity Profile

• Dapagliflozin is highly selective for SGLT2 over SGLT1, distinguishing it from dual inhibitors like sotagliflozin 5, 2
• This selectivity means dapagliflozin acts primarily in the kidney rather than affecting intestinal glucose absorption (which would require SGLT1 inhibition) 5

Cardiovascular and Hemodynamic Effects

Beyond Glucose Lowering:

• The reduction in sodium reabsorption lowers both cardiac preload and afterload 1
• Dapagliflozin downregulates sympathetic nervous system activity 1
• These pleiotropic effects contribute to cardiovascular benefits that are disproportionate to glucose-lowering effects and persist even when glycemic efficacy is minimal at lower eGFR levels 6, 5

Pharmacodynamic Characteristics

Dose-Response:

• Urinary glucose excretion increases dose-dependently, with near-maximal excretion achieved at 20 mg daily 1
• The therapeutic doses of 5-10 mg daily produce clinically significant glucosuria in patients with type 2 diabetes 1, 3

Dependence on Renal Function:

• Efficacy depends on filtered glucose load (plasma glucose × glomerular filtration rate) 2
• Glucose-lowering efficacy progressively declines as eGFR falls below 45 mL/min/1.73 m², becoming minimal below 30 mL/min/1.73 m² 5
• However, cardiovascular and renal protective benefits persist at eGFR levels as low as 20-25 mL/min/1.73 m² 6, 7

Clinical Implications of Mechanism

Unique Therapeutic Profile:

• The insulin-independent mechanism allows safe combination with other antidiabetic agents without additive hypoglycemia risk when used alone or with metformin 3, 8
• Glucosuria leads to caloric loss (approximately 280 calories per day from 70 grams of glucose), contributing to weight reduction of 2-3 kg 3, 9
• Unlike most heart failure medications, dapagliflozin does not affect blood pressure, heart rate, or potassium levels, and requires no dose titration 6

Metabolic Pathway:

• Dapagliflozin is extensively metabolized primarily by UGT1A9 to dapagliflozin 3-O-glucuronide, an inactive metabolite 1
• Less than 2% is excreted unchanged in urine; the glucuronide metabolite accounts for 61% of urinary excretion 1
• The plasma half-life is approximately 12.9 hours, allowing once-daily dosing 1, 2

Additional Physiological Sites

• SGLT2 is also expressed in various brain regions (cerebellum, hippocampus, frontal cortex), though at lower levels than SGLT1, potentially contributing to neuroprotective effects, though clinical evidence remains limited 5