What is the mechanism of action of dapagliflozin (SGLT2 inhibitor)?

Dapagliflozin Mechanism of Action

Dapagliflozin works by selectively inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, which blocks the reabsorption of filtered glucose and promotes urinary glucose excretion, thereby lowering blood glucose levels independent of insulin secretion or action. 1

Primary Renal Mechanism

• SGLT2 is expressed predominantly in the S1 and S2 segments of the proximal convoluted tubule in the kidneys, where it is responsible for the majority of renal glucose reabsorption 2, 1
• By inhibiting SGLT2, dapagliflozin reduces renal glucose reabsorption and increases urinary glucose excretion (glucosuria) 2, 1
• This mechanism operates independently of pancreatic β-cell function and insulin secretion, making it effective regardless of diabetes duration (provided renal function is adequate) 3, 4

Selectivity Profile

• Dapagliflozin, empagliflozin, and ertugliflozin are the most selective inhibitors for SGLT2 compared to SGLT1 2
• This high selectivity distinguishes dapagliflozin from agents like canagliflozin (which has greater SGLT1 inhibition and affects intestinal glucose absorption) and sotagliflozin (a dual SGLT1/SGLT2 inhibitor) 2

Pharmacodynamic Effects

• Dapagliflozin 5 or 10 mg daily results in excretion of approximately 70 grams of glucose in urine per day at week 12 in patients with type 2 diabetes 1
• Near-maximal glucose excretion occurs at 20 mg daily dosing 1
• The urinary glucose excretion returns to near baseline approximately 3 days after discontinuation of the 10 mg dose 1

Additional Physiological Effects Beyond Glucose Lowering

Dapagliflozin also reduces sodium reabsorption and increases sodium delivery to the distal tubule, which triggers multiple cardiovascular and renal protective mechanisms: 1

• Lowers both cardiac preload and afterload 1
• Downregulates sympathetic nervous system activity 1
• Decreases intraglomerular pressure through increased tubuloglomerular feedback 1
• These pleiotropic effects likely contribute to cardiovascular and renal benefits observed in clinical trials 2

Pharmacokinetic Considerations

• Dapagliflozin is rapidly absorbed with peak plasma concentrations within 2 hours, has 78% oral bioavailability, and can be taken with or without food 1, 5
• Metabolism occurs primarily via UGT1A9 to form dapagliflozin 3-O-glucuronide (an inactive metabolite), with less than 2% excreted unchanged in urine 1, 5
• The plasma half-life is approximately 12 hours 1, 5

Clinical Implications of Mechanism

• The insulin-independent mechanism allows dapagliflozin to provide complementary therapy when combined with other antidiabetic agents 4, 6
• Low intrinsic risk of hypoglycemia when used alone or with metformin, as the mechanism does not stimulate insulin secretion 2, 4
• Efficacy depends on renal function and filtered glucose load (plasma glucose × GFR), requiring caution in patients with eGFR < 45 mL/min/1.73 m² 2, 7, 5

Central Nervous System Expression

• SGLT2 is also expressed in various brain regions including the cerebellum, hippocampus, frontal cortex, and other areas, though at lower levels than SGLT1 2
• This CNS expression may contribute to potential neuroprotective effects, though clinical evidence remains limited 2