What is dapagliflozin?

What is Dapagliflozin?

Dapagliflozin (trade name Farxiga) is a highly selective sodium-glucose cotransporter-2 (SGLT2) inhibitor approved for treating type 2 diabetes mellitus, chronic kidney disease, and heart failure (both reduced and preserved ejection fraction), working by blocking glucose reabsorption in the kidney to promote urinary glucose excretion while providing cardiovascular and renal protection independent of its glucose-lowering effects. 1

Mechanism of Action

• Dapagliflozin inhibits SGLT2 in the proximal renal tubule, reducing reabsorption of filtered glucose and promoting urinary glucose excretion of approximately 70 grams per day at therapeutic doses. 2

• Beyond glucose excretion, dapagliflozin reduces sodium reabsorption and increases sodium delivery to the distal tubule, which lowers cardiac pre- and afterload, downregulates sympathetic activity, and decreases intraglomerular pressure through increased tubuloglomerular feedback. 2

• These hemodynamic effects explain why cardiovascular and renal benefits persist even when glucose-lowering efficacy diminishes at lower eGFR levels. 1

Pharmacokinetic Profile

• Dapagliflozin is rapidly absorbed after oral administration, reaching peak plasma concentrations within 2 hours, with 78% oral bioavailability and dose-proportional exposure across the therapeutic range. 2, 3

• The drug has a half-life of approximately 12.9 hours, allowing once-daily dosing, and undergoes predominantly hepatic and renal metabolism via UGT1A9 to an inactive glucuronide metabolite. 3

• Less than 2% of the parent drug is excreted unchanged in urine; the glucuronide metabolite accounts for 61% of urinary recovery. 3

• Dapagliflozin exhibits minimal cytochrome P450-mediated metabolism, resulting in few clinically significant drug interactions. 3, 4

Approved Indications

• Type 2 diabetes mellitus (FDA-approved 2014): for glycemic control when eGFR ≥45 mL/min/1.73 m² without established cardiovascular disease or risk factors. 1, 2

• Chronic kidney disease (FDA-approved 2021): for patients with eGFR ≥25 mL/min/1.73 m² and albuminuria (UACR ≥200 mg/g), regardless of diabetes status. 1

• Heart failure with reduced ejection fraction (FDA-approved 2020): for patients with LVEF ≤40%. 1, 2

• Heart failure with preserved ejection fraction (FDA-approved 2023): for patients with LVEF >40%. 1, 2

Standard Dosing

• The fixed dose is 10 mg orally once daily for all cardiovascular and renal indications, with no titration required. 1

• For glycemic control alone in treatment-naïve patients with eGFR ≥45 mL/min/1.73 m², initiation at 5 mg once daily with optional increase to 10 mg may be considered. 1

• No dose adjustment is needed for age, sex, race, body weight, or mild-to-moderate hepatic impairment. 2

Clinical Efficacy Evidence

Renal Protection

• The DAPA-CKD trial demonstrated a 44% reduction in kidney-specific outcomes (sustained eGFR decline ≥50%, end-stage kidney disease, or renal death; HR 0.56,95% CI 0.45–0.68) in patients with CKD and albuminuria. 1

• The composite of sustained eGFR decline, end-stage kidney disease, or cardiovascular/renal death was reduced by 39% (HR 0.61,95% CI 0.51–0.72). 1

• Benefits were consistent in both diabetic (67.5% of participants) and non-diabetic (32.5%) patients. 1

Cardiovascular Protection

• Dapagliflozin reduced cardiovascular death or heart failure hospitalization by 29% (HR 0.71,95% CI 0.55–0.92) in the DAPA-CKD trial. 1

• All-cause mortality decreased by 31% (HR 0.69,95% CI 0.53–0.88). 1

• In the DAPA-HF trial (HFrEF), the composite of cardiovascular death or worsening heart failure was reduced by 26% (HR 0.74). 1

• In the DELIVER trial (HFpEF), worsening heart failure or cardiovascular death was reduced by 18% (HR 0.82,95% CI 0.73–0.92). 1

Glycemic Control

• Dapagliflozin reduces HbA1c by approximately 0.5–0.8% when used as monotherapy or add-on therapy in patients with adequate renal function. 5

• Glucose-lowering efficacy decreases progressively when eGFR falls below 45 mL/min/1.73 m², but cardiovascular and renal benefits persist. 1

Renal Function Thresholds

• Initiation is recommended when eGFR ≥25 mL/min/1.73 m² for cardiovascular and renal protection. 1

• For glycemic control without established cardiovascular disease, initiation requires eGFR ≥45 mL/min/1.73 m². 1, 2

• Once initiated, dapagliflozin may be continued even if eGFR falls below 25 mL/min/1.73 m² until dialysis is required. 1, 2

• An acute, reversible eGFR decline of 2–5 mL/min/1.73 m² within the first 2–4 weeks is expected and reflects hemodynamic changes rather than kidney injury; this should not prompt discontinuation. 1

Safety Profile and Adverse Effects

Common Adverse Events

• Genital mycotic infections occur in approximately 6% of patients versus 1% with placebo, predominantly in women; daily hygiene measures may reduce risk. 1, 5

• Urinary tract infections show a modest increase in some studies, though the magnitude varies. 5, 6

• Volume depletion may occur, particularly in elderly patients, those on diuretics, or those with baseline hypotension; volume status should be assessed before initiation. 1

Serious but Rare Adverse Events

• Euglycemic diabetic ketoacidosis can occur even with normal blood glucose levels; patients should be counseled to seek immediate care for malaise, nausea, vomiting, or abdominal pain. 1

• Fournier's gangrene (necrotizing fasciitis of the perineum) is rare but requires prompt recognition and treatment. 1, 4

• Bladder cancer cases were numerically higher in clinical trials (0.17% vs 0.03% with placebo/comparator), though causality was not established; dapagliflozin should not be used in patients with active bladder cancer. 6

Hypoglycemia Risk

• Dapagliflozin has a low intrinsic propensity to cause hypoglycemia when used alone. 5, 6

• When combined with insulin or sulfonylureas, dose reduction of these agents is recommended to mitigate hypoglycemia risk. 1

Critical Safety Precautions

• Withhold dapagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting to prevent postoperative ketoacidosis. 1

• Temporarily discontinue during acute illness with reduced oral intake, fever, vomiting, or diarrhea. 1

• Maintain at least low-dose insulin in insulin-requiring patients even when dapagliflozin is held during illness. 1

• Assess and correct volume depletion before initiation; consider reducing concurrent diuretic doses in high-risk patients. 1

Comparison with Other SGLT2 Inhibitors

• Dapagliflozin and empagliflozin are among the most selective SGLT2 inhibitors, with equivalent cardiovascular and renal benefits. 7

• Dapagliflozin can be initiated at eGFR ≥25 mL/min/1.73 m² (recently updated to ≥20 mL/min/1.73 m² in some guidelines), whereas empagliflozin's threshold is ≥30 mL/min/1.73 m². 7

• Compared with canagliflozin, dapagliflozin produces less urinary glucose excretion but may have more extended hemodynamic effects, contributing to stable sodium diuresis and reduced blood pressure fluctuations. 4

• Neither dapagliflozin nor empagliflozin significantly affects blood pressure, heart rate, or potassium levels. 7

Common Clinical Pitfalls to Avoid

• Do not discontinue dapagliflozin when eGFR falls below 45 mL/min/1.73 m²; cardiovascular and renal benefits persist despite reduced glucose-lowering efficacy. 1

• Do not stop dapagliflozin in response to the expected early eGFR dip of 2–5 mL/min/1.73 m² within the first 2–4 weeks; this change is hemodynamic and reversible. 1

• Do not reduce the dose below 10 mg for cardiovascular or renal indications; all outcome trials used the fixed 10 mg dose. 1

• Do not combine dapagliflozin with sulfonylureas in patients with HbA1c <8.5%, as this increases hypoglycemia risk without cardiovascular benefit. 1

Integration with Other Therapies

• Continue ACE inhibitors or ARBs unchanged when initiating dapagliflozin; more than 99% of DAPA-CKD participants were on renin-angiotensin-aldosterone system blockers, and the combination showed additive renal protection. 1

• Dapagliflozin is positioned as foundational therapy for slowing CKD progression and preventing cardiovascular events, irrespective of glycemic status. 1

• When combined with mineralocorticoid receptor antagonists (e.g., finerenone), dapagliflozin provides additive renal benefits and may lessen hyperkalemia risk. 1