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Sunday, July 27, 2025

Dapagliflozin


Dapagliflozin is an oral antidiabetic and cardioprotective drug classified under sodium-glucose co-transporter 2 (SGLT2) inhibitors. Originally developed for the management of type 2 diabetes mellitus, its therapeutic benefits have expanded into the fields of cardiology and nephrology, including treatment of heart failure and chronic kidney disease, regardless of diabetic status. By inhibiting renal glucose reabsorption, dapagliflozin facilitates glycosuria, reduces blood glucose levels, lowers body weight, and provides hemodynamic benefits through osmotic diuresis and natriuresis.

Pharmacological Classification

  • Therapeutic class: Antidiabetic agent / Heart failure therapy / Renoprotective agent

  • Pharmacologic class: Sodium-glucose co-transporter 2 (SGLT2) inhibitor

  • ATC code: A10BK01

  • Brand name: Farxiga® (global), Forxiga® (Europe, UK, MENA)

  • Regulatory status: Prescription-only (Rx), FDA and EMA approved

Mechanism of Action

Dapagliflozin selectively inhibits the SGLT2 transporters located in the proximal convoluted tubules of the nephron. These transporters are responsible for the reabsorption of around 90% of filtered glucose in the kidney. By blocking SGLT2:

  • Glucose reabsorption is reduced, increasing urinary glucose excretion (glycosuria)

  • Serum glucose levels decline, independent of insulin mechanisms

  • Caloric loss occurs through excreted glucose, promoting weight loss

  • Natriuresis and osmotic diuresis lead to reductions in intravascular volume and blood pressure

  • These systemic effects contribute to cardio-renal protection, beyond glycemic control

Therapeutic Indications

Dapagliflozin is used in both endocrine and cardiovascular settings. Indications vary based on regional regulatory approvals (e.g., FDA, EMA, NICE).

Approved Indications

  • Type 2 diabetes mellitus (T2DM) as monotherapy or combination therapy

  • Heart failure with reduced ejection fraction (HFrEF) with or without diabetes

  • Chronic kidney disease (CKD) with or without diabetes

Off-label or Investigational Uses

  • Heart failure with preserved ejection fraction (HFpEF)

  • Type 1 diabetes mellitus (T1DM) in specific cases (not broadly recommended due to DKA risk)

  • Polycystic ovary syndrome (PCOS)

  • Obesity management (as part of experimental regimens)

Dosage and Administration

  • Form: Oral tablet

  • Strengths: 5 mg and 10 mg

Type 2 Diabetes

  • Starting dose: 10 mg once daily

  • No need for titration; can be used alone or with metformin, sulfonylureas, DPP-4 inhibitors, insulin, or GLP-1 agonists

Heart Failure (HFrEF)

  • 10 mg once daily, regardless of diabetic status

  • Use with standard heart failure therapy (e.g., beta-blockers, ACE inhibitors, MRAs)

Chronic Kidney Disease

  • 10 mg once daily, approved down to eGFR 25 mL/min/1.73 m² (not for ESRD or dialysis)

  • No need for dose adjustment in mild-to-moderate renal impairment

Hepatic Impairment

  • Mild to moderate: no adjustment

  • Severe impairment: use with caution

Contraindications

  • Known hypersensitivity to dapagliflozin or formulation ingredients

  • Type 1 diabetes mellitus (absolute contraindication in most countries due to DKA risk)

  • Diabetic ketoacidosis (DKA) or history of DKA

  • Severe renal impairment (eGFR <25 mL/min/1.73 m²), ESRD, or dialysis

  • Active bladder cancer (due to theoretical risk – use caution)

Precautions and Monitoring

  • Volume status: Risk of hypovolemia; assess in elderly, diuretic users, or low BP

  • Renal function: Monitor eGFR regularly, especially in CKD patients

  • Ketoacidosis: May present euglycemically (normal blood glucose); educate patients

  • Genitourinary infections: Increased risk of fungal infections (especially in females)

  • Necrotizing fasciitis of the perineum (Fournier’s gangrene): rare but life-threatening

  • Fracture risk and bone mineral density: Observe in older populations

  • Lipid profile: May slightly increase LDL cholesterol

  • Urinary tract cancer: Conflicting data—monitor if patient has history of urologic malignancy

Adverse Effects

Common

  • Genital mycotic infections (vulvovaginal candidiasis, balanitis)

  • Urinary tract infections

  • Polyuria, nocturia

  • Mild volume depletion, dizziness

  • Back pain, dyslipidemia

  • Weight loss, typically 2–3 kg over 6–12 months

Uncommon to Rare

  • Euglycemic DKA (life-threatening; needs prompt diagnosis)

  • Hypoglycemia (only when combined with insulin or sulfonylureas)

  • Hypotension, especially in elderly or those on loop diuretics

  • Fournier’s gangrene

  • Increased hematocrit

  • Bladder cancer: under investigation

Drug Interactions

  • Diuretics: Additive volume-depleting effects → risk of hypotension and AKI

  • Insulin/sulfonylureas: Increased risk of hypoglycemia → may require dose reduction

  • Lithium: SGLT2 inhibitors may increase lithium clearance

  • Rifampin, phenytoin, carbamazepine: Enzyme inducers may reduce dapagliflozin levels

  • ACE inhibitors/ARBs: Additive effects on renal protection but monitor for hypotension

Use in Special Populations

Pregnancy

  • Not recommended. Animal studies show fetal toxicity; no human data.

  • Use insulin-based regimens for pregnant patients with diabetes.

Lactation

  • Unknown if excreted in human milk. Avoid use or discontinue breastfeeding.

Elderly

  • Greater risk of dehydration and hypotension. Monitor volume status closely.

Pediatrics

  • Not approved for patients under 18 years.

Clinical Benefits Beyond Glycemic Control

Dapagliflozin’s utility is increasingly recognized for non-glycemic endpoints:

Cardiovascular Protection

  • Reduces hospitalization for heart failure (HFrEF) by up to 30%

  • Reduces risk of cardiovascular death in at-risk patients

  • Improves quality of life (KCCQ scores) in HF patients

Renal Protection

  • Slows CKD progression

  • Reduces risk of end-stage kidney disease, doubling of serum creatinine, and renal death

  • Demonstrated benefit in both diabetic and non-diabetic populations (DAPA-CKD trial)

Weight Loss and BP Reduction

  • Weight loss of 2–3 kg, primarily from fluid and fat

  • Systolic blood pressure reduction of 3–5 mmHg

  • No significant increase in heart rate

Clinical Trial Evidence

DECLARE-TIMI 58

  • 17,000 patients with T2DM

  • Reduced hospitalization for heart failure

  • No significant reduction in MACE (CV death, MI, stroke)

DAPA-HF

  • Heart failure patients with reduced EF (LVEF <40%)

  • Risk of worsening HF or CV death reduced by 26%

  • Beneficial in both diabetic and non-diabetic patients

DAPA-CKD

  • eGFR 25–75 mL/min/1.73m², with or without diabetes

  • 39% risk reduction in composite endpoint (eGFR decline, ESKD, CV/renal death)

  • Trial stopped early due to overwhelming benefit

Comparison with Other SGLT2 Inhibitors

Dapagliflozin vs. Empagliflozin

  • Both reduce HF hospitalization; empagliflozin slightly stronger in CV mortality

  • Dapagliflozin has broader CKD indication

  • Empagliflozin used in type 1 diabetes in some countries

Dapagliflozin vs. Canagliflozin

  • Canagliflozin has slightly higher risk of amputation and fractures (CANVAS trial)

  • Dapagliflozin better tolerated in terms of genital infection rates

Dapagliflozin vs. Ertugliflozin

  • Dapagliflozin has broader outcome trial evidence in both CKD and HF

  • Ertugliflozin is newer, with fewer supportive trials

Counseling Points

  • Take once daily with or without food

  • Maintain hydration, especially in hot weather or illness

  • Monitor for symptoms of UTI or genital infections

  • Report symptoms of DKA (nausea, vomiting, abdominal pain, confusion, dyspnea), even with normal glucose

  • Avoid alcohol and very low-carb diets (increase DKA risk)

  • Discuss with healthcare provider before stopping during acute illness, surgery, or hospitalization

  • Blood glucose monitoring is essential if combined with other antidiabetics




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