Dapagliflozin
Dapagliflozin
Generic Name
Dapagliflozin
Mechanism
- Inhibits SGLT‑2 in the proximal renal tubules, blocking ~90 % of glucose re‑absorption.
- Lowers plasma glucose by increasing urinary glucose excretion (up to 60–70 g/day).
- Reduces intraglomerular pressure, promoting natriuresis and osmotic diuresis → ↓ blood pressure and ↓ albuminuria.
Pharmacokinetics
| Parameter | Detail |
| Absorption | Rapid; peak plasma concentration (Cmax) at ~2 h post‑dose.
| Food Effect | Co‑administration with food reduces Cmax by ~20 % but does not alter AUC. |
| Distribution | Protein‑bound ≈ 15 % (minimal binding). |
| Metabolism | Primarily hepatic via glucuronidation (UGT2B7); negligible CYP‑450 involvement. |
| Elimination | Renal excretion (~60 %) and fecal excretion (~30 %). |
| Half‑life | ~12 h; steady state reached after ~3 days. |
| Extrapolation | Adequate in mild–moderate renal impairment; dose adjustment in severe CKD. |
Indications
- Type 2 diabetes mellitus: adjunct to diet, exercise, and/or metformin.
- Heart failure with reduced ejection fraction (HFrEF): reduced risk of CV death and HF hospitalization.
- Diabetic kidney disease: slows progression of albuminuria and decline in eGFR when combined with ACE‑I/ARB.
Contraindications
- Contraindications: severe renal impairment (eGFR < 30 mL/min/1.73 m²), type 1 diabetes (risk of ketoacidosis).
- Warnings:
- Diabetic ketoacidosis (DKA), especially post‑surgery, trauma or in patients with low insulin.
- Genital mycotic infections, urosepsis.
- Volume depletion → hypotension, syncope.
- Rare episodes of acute kidney injury; monitor renal function.
Dosing
- Typical dose: 10 mg once daily (morning) for type 2 DM; 5–10 mg for HF/CKD.
- Titration:
- Start 5 mg in patients with eGFR 45–60 mL/min/1.73 m², increase to 10 mg if tolerated.
- Renal adjustment:
- eGFR > 45 mL/min/1.73 m² → 10 mg.
- 30–45 mL/min/1.73 m² → 5 mg; 10–30 mL/min/1.73 m² → 5 mg, only if benefits outweigh risks.
- Administration notes: Take with or without food; avoid in patients on dialysis.
Adverse Effects
- Common (≥ 5 %)
- Genital yeast infection (female)
- Urinary tract infection
- Micturition disorders (frequency, urgency)
- Mild hypoglycemia (when combined with insulin/ sulfonylureas)
- Serious (≤ 1 %)
- Diabetic ketoacidosis (increased glucose ketones without hyperglycemia)
- Severe volume depletion → hypotension, renal dysfunction
- Fournier’s gangrene (rare, genital necrotizing fasciitis)
- Hematologic: hemoconcentration, rare thrombosis.
Monitoring
| Parameter | Frequency | Rationale |
| eGFR | Every 3–6 mo (baseline, then as clinically indicated) | Detect renal decline early |
| Urine albumin‑to‑creatinine ratio | Every 6–12 mo | Evaluate renal protection |
| HbA1c | Every 3 mo | Adjust GLP‑1/insulin dose |
| Volume status | At each visit | Prevent hypotension |
| Serum electrolytes | Every 6–12 mo | Monitor sodium, potassium shifts |
| Lactate dehydrogenase/AST | Annually | Rare hepatic effect |
Clinical Pearls
- “Can’t‑treat‑without‑monitoring”: Because dapagliflozin lowers plasma volume and may mask hypoglycemia, check ketone levels in patients with sick day rules.
- Combo success: When added to metformin, the incremental HbA1c reduction averages 0.5 % and decreases weight by ~2–3 kg.
- Heart‑failure synergy: Up to 43 % reduction in HF hospitalizations—consider in patients with concomitant CKD to maximize both renal and CV protection.
- Dose‑response nuance: A 5 mg starting dose still delivers ~90 % of total glucose‑excretion benefit; many patients plateau at 10 mg, minimizing side‑effect risk.
- Food‑free option: Patients can safely take dapagliflozin without food, but if gastrointestinal side‑effects appear, administer with a light snack.
*Always cross‑check renal function and adjust dose; counsel patients on genital hygiene and signs of DKA.*