How Farxiga (Dapagliflozin) Works
Farxiga works by blocking SGLT2 proteins in the kidney's proximal tubules, preventing glucose and sodium reabsorption, which causes the body to excrete excess glucose in urine while simultaneously reducing cardiac workload and protecting kidney function through multiple complementary mechanisms. 1
Primary Mechanism: Renal Glucose and Sodium Inhibition
Dapagliflozin selectively inhibits sodium-glucose cotransporter 2 (SGLT2) proteins expressed in the proximal renal tubules, which are responsible for reabsorbing approximately 90% of filtered glucose from the tubular lumen back into the bloodstream. 1
By blocking SGLT2, dapagliflozin reduces glucose reabsorption and promotes urinary glucose excretion of approximately 70 grams per day at the 10 mg dose. 1
This mechanism is completely independent of insulin secretion or action, making it effective even in patients with severe insulin resistance or beta-cell dysfunction. 2, 3
Cardiovascular and Hemodynamic Effects
Dapagliflozin reduces sodium reabsorption and increases sodium delivery to the distal tubule, which triggers several beneficial physiological responses beyond glucose lowering. 1
These sodium-related effects include:
The American College of Cardiology notes that these cardiovascular benefits occur rapidly, with clinical improvements observed within days to weeks of initiation, and are maintained regardless of diabetes status or baseline glucose levels. 4
Renal Protection Mechanisms
The reduction in intraglomerular pressure is mediated by increased tubuloglomerular feedback, a protective mechanism that helps preserve kidney function over time. 1
The American Diabetes Association emphasizes that dapagliflozin's renal protective effects are independent of glucose-lowering, with consistent benefits demonstrated in patients with and without diabetes across all HbA1c levels. 5
In the DAPA-CKD trial, dapagliflozin reduced the risk of sustained eGFR decline ≥50%, end-stage kidney disease, or renal/cardiovascular death by 39% over 2.4 years. 5
Pharmacokinetics Supporting Once-Daily Dosing
Dapagliflozin reaches peak plasma concentration within 2 hours of oral administration with 78% bioavailability. 1
The drug has a mean plasma half-life of approximately 12.9 hours, supporting once-daily dosing. 1
Food does not meaningfully affect absorption, so dapagliflozin can be taken with or without meals. 1
Metabolism occurs primarily via UGT1A9 (not cytochrome P450), producing an inactive metabolite (dapagliflozin 3-O-glucuronide) that accounts for 61% of the dose. 1, 6
Approximately 75% of the drug is eliminated renally and 21% via feces, with less than 2% excreted as unchanged drug in urine. 1
Clinical Implications of Mechanism
The glucose-lowering efficacy decreases as kidney function declines (because there is less filtered glucose to block reabsorption), but cardiovascular and renal protective benefits persist even at lower eGFR levels. 5, 7
The FDA label specifies that dapagliflozin is not recommended for glycemic control when eGFR <45 mL/min/1.73 m², but can be initiated for cardiovascular/renal protection at eGFR ≥25 mL/min/1.73 m². 1
Dapagliflozin causes increased urinary volume due to osmotic diuresis from glucose excretion, which explains why volume status assessment is critical before initiation. 1
Common Pitfalls Related to Mechanism
The urinary glucose excretion creates a favorable environment for genital mycotic infections (occurring in approximately 6% of patients), particularly in women. 2, 3
Euglycemic diabetic ketoacidosis can occur because the drug promotes glucose excretion without necessarily lowering glucose to hypoglycemic levels, allowing ketone production to continue unchecked during illness or fasting. 7
The Kidney International guidelines recommend withholding dapagliflozin during acute illness, fever, vomiting, or diarrhea to prevent volume depletion and ketoacidosis. 7