Side Effects of Empagliflozin
Empagliflozin is generally well tolerated with genital mycotic infections being the most common adverse effect, particularly in women, along with urinary tract infections, volume depletion-related events, and a rare but serious risk of euglycemic diabetic ketoacidosis. 1
Common Adverse Effects
Genitourinary Infections
- Genital fungal infections are the most frequently reported adverse effect, occurring more commonly in women than men 1
- Urinary tract infections occur with increased frequency compared to placebo 1
- These infections are typically mild to moderate in severity and respond to standard treatment 2, 3
- Hygienic counseling should be provided to mitigate risk of these infections 1
Volume Depletion and Hypotension
- Empagliflozin may contribute to intravascular volume contraction, particularly in the first days of treatment 1
- Mean 24-hour urine volume increases by 341 mL on Day 1 and 135 mL on Day 5 of treatment 4
- Monitor for hypotension, especially in patients with renal impairment (eGFR <60 mL/min/1.73 m²), elderly patients, those with low systolic blood pressure, or patients on diuretics 1, 5
- Consider stopping or reducing diuretic dose when initiating empagliflozin in at-risk patients 1
Serious but Rare Adverse Effects
Euglycemic Diabetic Ketoacidosis
- This is a rare but potentially life-threatening complication that can occur even with normal or near-normal blood glucose levels 1, 6
- Discontinue empagliflozin at least 3 days before planned surgery to prevent postoperative ketoacidosis 1, 5
- Withhold during times of prolonged fasting, surgery, or critical medical illness when patients may be at greater risk for ketosis 1
- Provide sick day rules and insulin guidance to reduce risk 1
Hypoglycemia
- Empagliflozin has no intrinsic risk of hypoglycemia due to its insulin-independent mechanism of action 2, 7, 3
- However, hypoglycemia can occur when combined with insulin or insulin secretagogues (sulfonylureas) 1, 7, 8
- Consider reducing doses of insulin or insulin secretagogues by approximately 20% when initiating empagliflozin to reduce hypoglycemia risk 1, 5
Renal Effects
Initial eGFR Decline
- SGLT2 inhibitor initiation is associated with a reversible decline in eGFR of 3-5 mL/min/1.73 m² in the first 4 weeks of therapy 1
- Following this initial "eGFR dip," GFR typically stabilizes during ongoing therapy 1
- This reversible decrease is generally not an indication to discontinue therapy 1
Renal Function Monitoring
- Do not initiate empagliflozin if eGFR is below 45 mL/min/1.73 m² for glycemic control 1, 5
- Empagliflozin is contraindicated in patients on dialysis, with ESRD, or severe renal impairment 1, 4
- Once initiated, it is reasonable to continue empagliflozin even if eGFR falls below 20 mL/min/1.73 m², unless not tolerated or kidney replacement therapy is initiated 1
Adverse Effects NOT Associated with Empagliflozin
Important Safety Distinctions
- Unlike canagliflozin, empagliflozin has not been associated with increased risk of lower limb amputation 2
- Unlike canagliflozin, empagliflozin has not been associated with increased risk of bone fractures 1, 2
- No increase in QTc interval was observed even at 8 times the maximum dose (200 mg) 4
Sex-Related Differences in Adverse Effects
- Women experience significantly higher incidence of adverse effects than men, particularly urosepsis and genital yeast infections 1
- Acute renal failure is more common in men than women 1
- Despite these differences, SGLT2 inhibitors provide comparable cardiovascular protection and similar risks of serious adverse events in both sexes 1
Monitoring Recommendations
- Monitor for signs and symptoms of volume depletion, particularly in elderly patients and those on diuretics 1, 5
- Educate patients about symptoms of ketoacidosis (nausea, vomiting, abdominal pain, fatigue) even with normal glucose levels 1
- Counsel patients on genital hygiene to reduce infection risk 1
- No alteration in frequency of CKD monitoring is required with SGLT2 inhibitor initiation 1