Side Effects of Dapagliflozin (an SGLT2 Inhibitor)

Mechanism-Driven Side Effects

1. Genitourinary Infections (Most Common)

• Genital mycotic infections (thrush/candidiasis): 3-5% increase over placebo - the most common side effect. Occurs because glucose-rich urine promotes fungal growth in the perineum. Usually mild and does not require drug discontinuation.
• Urinary tract infections (UTIs): approximately 2% increase. The glucosuria and increased urinary flow can facilitate bacterial colonization.

2. Volume Depletion and Hypotension

• Glycosuria triggers osmotic diuresis and natriuresis, leading to mild volume loss.
• Can cause hypotension, dizziness, and orthostatic symptoms, particularly in:
  • Elderly patients
  • Patients already on diuretics or ACE inhibitors
  • Those with low blood pressure at baseline

3. Diabetic Ketoacidosis (DKA) - Rare but Serious

• Dapagliflozin can precipitate euglycemic DKA - ketoacidosis with near-normal blood glucose levels, making it easy to miss.
• Risk is increased during concurrent illness, surgery, or significant caloric restriction.
• Perioperative risk: Patients should stop dapagliflozin at least 3 days before elective surgery to minimise the risk of perioperative DKA. - Morgan and Mikhail's Clinical Anesthesiology, 7e
• The FDA has issued a formal warning for this class.

4. Acute Kidney Injury / Reduced Efficacy in CKD

• SGLT2 inhibitors depend on glomerular filtration rate (GFR) to work - potency falls 40-80% across Stage 3 CKD (GFR 30-60 mL/min).
• Not recommended if eGFR < 30 mL/min (for glucose-lowering purposes).
• Patients may have mild, transient worsening of renal function at initiation due to initial diuresis (usually resolves).

5. Hypoglycemia

• Dapagliflozin does not cause hypoglycemia on its own because its effect is glucose-dependent (no effect when glucose is normal).
• However, it potentiates the hypoglycemic effects of insulin and sulfonylureas when used in combination.

6. Fournier's Gangrene (Necrotizing Fasciitis of the Genitals)

• A rare but life-threatening necrotizing infection of the perineum/genitalia.
• The FDA has issued a safety warning for the entire SGLT2 inhibitor class.
• Most cases reported in patients with diabetes, older age, and multiple comorbidities.

7. Lower Limb Amputation (Class Concern, Less Relevant to Dapagliflozin)

• Early trials with canagliflozin showed a doubled risk of lower extremity amputation. This warning has since been removed as further evidence did not confirm it.
• The amputation signal has not been reported for dapagliflozin or other SGLT2 inhibitors. - Goodman & Gilman's Pharmacological Basis of Therapeutics

8. Bone Fractures

• Initial concern from canagliflozin trials; not confirmed in subsequent studies and not seen with dapagliflozin.

Summary Table

Recent literature note: A 2025 network meta-analysis (PMID 40324721) comparing SGLT2 inhibitors in heart failure + type 2 diabetes did not identify new safety signals specific to dapagliflozin that alter the above profile.