Dapagliflozin Significantly Increases Glucosuria
Dapagliflozin directly increases urinary glucose excretion by inhibiting SGLT2 in the proximal renal tubules, resulting in approximately 70 grams of glucose excreted in urine daily at therapeutic doses. 1
Mechanism of Action and Glucosuria
Dapagliflozin works through a specific mechanism that directly affects glucose handling in the kidneys:
SGLT2 Inhibition: Dapagliflozin selectively inhibits sodium-glucose cotransporter 2 (SGLT2), which is expressed in the proximal renal tubules and responsible for the majority of glucose reabsorption from the tubular lumen 1
Quantifiable Glucosuria: At standard therapeutic doses (5-10 mg daily), dapagliflozin causes excretion of approximately 70 grams of glucose in urine per day after 12 weeks of treatment 1
Dose-Dependent Response: The amount of glucose excreted is dose-dependent, with near maximum glucose excretion observed at 20 mg daily dosing 1
Rapid Onset: Significant glucosuria begins within 24 hours of the first dose and is sustained throughout treatment 2
Reversibility: After discontinuation of dapagliflozin, the elevation in urinary glucose excretion approaches baseline within approximately 3 days 1
Clinical Implications of Dapagliflozin-Induced Glucosuria
The induced glucosuria has several important clinical effects:
Glycemic Control: The glucosuric effect leads to reduced fasting serum glucose and improved oral glucose tolerance 3
Weight Loss: The caloric loss through glucosuria (approximately 280 kcal/day with 70g glucose excretion) contributes to weight reduction observed in clinical trials 4
Increased Urinary Volume: The glucosuria results in osmotic diuresis, leading to increased urinary volume 1
Low Hypoglycemia Risk: Because the mechanism is insulin-independent and self-limiting as blood glucose normalizes, hypoglycemic episodes are rare when used as monotherapy 4
Important Clinical Considerations
When prescribing dapagliflozin, be aware of these key points:
Renal Function: The glucosuric effect diminishes with declining renal function. Efficacy for glycemic control is reduced when eGFR is below 45 mL/min/1.73m² 1
Infection Risk: The increased glucose in urine creates an environment conducive to genital mycotic infections and urinary tract infections 4
Volume Status: The osmotic diuresis effect may contribute to volume depletion, particularly in elderly patients or those on diuretics 1
Medication Adjustments: When adding dapagliflozin to existing diabetes regimens, consider reducing sulfonylurea doses by 50% or insulin doses by 20% to prevent hypoglycemia 5
Comparative Glucosuric Effect
Dapagliflozin is highly selective for SGLT2 compared to some other medications in its class:
High Selectivity: Dapagliflozin, empagliflozin, and ertugliflozin are the most selective inhibitors for SGLT2 5
Differential Response: Interestingly, a single dose of dapagliflozin induces higher glucosuria in certain monogenic forms of diabetes (GCK-MODY and HNF1A-MODY) compared to type 2 diabetes 6
In conclusion, dapagliflozin's primary mechanism of action is to increase glucosuria substantially, which forms the basis for its therapeutic effects in type 2 diabetes, heart failure, and chronic kidney disease.