Mechanism of Action of Dapagliflozin
Dapagliflozin selectively inhibits sodium-glucose co-transporter-2 (SGLT2) in the proximal renal tubules, blocking reabsorption of filtered glucose and promoting urinary glucose excretion through an insulin-independent mechanism. 1
Primary Renal Mechanism
SGLT2 is predominantly expressed in the S1 and S2 segments of the proximal convoluted tubule of the kidney, where it is responsible for the majority (approximately 90%) of renal glucose reabsorption. 2, 3
By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose from the tubular lumen and increases urinary glucose excretion (glucosuria), thereby lowering blood glucose levels. 1, 4
This mechanism operates independently of pancreatic β-cell function and insulin secretion, allowing dapagliflozin to work regardless of diabetes duration or degree of insulin resistance. 4, 5
Selectivity Profile
Dapagliflozin, empagliflozin, and ertugliflozin are the most selective inhibitors for SGLT2 compared to SGLT1. 2, 6
This high selectivity distinguishes dapagliflozin from canagliflozin (which has greater SGLT1 inhibition affecting intestinal glucose absorption) and sotagliflozin (a dual SGLT1/SGLT2 inhibitor). 2
The selectivity profile minimizes off-target effects while maximizing renal glucose excretion. 3
Additional Physiological Effects Beyond Glucose Lowering
Dapagliflozin reduces sodium reabsorption and increases delivery of sodium to the distal tubule, which influences multiple cardiovascular and renal protective mechanisms. 1
These pleiotropic effects include:
The osmotic diuresis from glucosuria leads to mild volume contraction, contributing to reductions in blood pressure (systolic 3-5 mmHg) and body weight (1.5-3.5 kg). 7, 8
Pharmacodynamic Characteristics
Dapagliflozin produces dose-dependent glucosuria, with doses of 5-10 mg daily resulting in excretion of approximately 70 grams of glucose per day. 1, 9
Near-maximal SGLT2 inhibition occurs at doses of 20-50 mg, providing sustained effect over 24 hours suitable for once-daily dosing. 9
The glucose-lowering efficacy depends on the filtered glucose load (plasma glucose × glomerular filtration rate), meaning efficacy progressively declines as eGFR falls below 45 mL/min/1.73 m². 6, 3
Central Nervous System Expression
SGLT2 is also expressed in various brain regions including the cerebellum, hippocampus, and frontal cortex, though at lower levels than SGLT1. 6
This CNS expression may contribute to potential neuroprotective effects observed in preclinical models, though clinical evidence remains limited and requires further investigation. 2, 6
Clinical Implications of Mechanism
The insulin-independent mechanism allows dapagliflozin to provide complementary therapy when combined with other antidiabetic agents, with low intrinsic risk of hypoglycemia when used alone or with metformin. 6, 5
Cardiovascular and renal benefits are out of proportion to glucose-lowering effects and persist even when glycemic efficacy is lost at lower eGFR levels. 6
Dapagliflozin can be continued down to eGFR 20 mL/min/1.73 m² for cardiorenal protection, despite minimal glucose-lowering effect at these levels. 6
Common Pitfalls to Avoid
Do not discontinue dapagliflozin solely because glucose-lowering efficacy has declined with reduced renal function—the cardiorenal benefits persist independently. 6
Assess volume status before initiating therapy, particularly in patients on diuretics or with compromised renal function, as the osmotic diuresis can lead to volume depletion. 1
The mechanism does not involve insulin secretion, so dapagliflozin carries minimal hypoglycemia risk when used as monotherapy but requires caution when combined with insulin or sulfonylureas. 7, 5