What are the side effects of Empagliflozin (Jardiance) and how can they be managed?

Empagliflozin Side Effects and Management

Empagliflozin is generally well-tolerated with genital mycotic infections being the most common side effect, occurring in approximately 6% of patients, while serious adverse events like ketoacidosis and acute kidney injury are rare but require vigilance. 1, 2

Common Side Effects

Genital Mycotic Infections

• Occur in approximately 6% of patients on SGLT2 inhibitors versus 1% on placebo, with higher rates in women 3
• Female patients may experience vulvovaginal candidiasis with symptoms including vaginal odor, white or yellowish discharge, and itching 2
• Male patients, especially uncircumcised, may develop balanitis or balanoposthitis with redness, itching, swelling, rash, or foul-smelling discharge from the penis 2
• Management: Most cases respond to over-the-counter antifungal medications; if symptoms persist after OTC treatment, seek medical evaluation 2
• Patients with chronic or recurrent genital infections are at higher risk and require closer monitoring 2

Urinary Tract Infections

• Urinary tract infections occur at similar rates to placebo in clinical trials 1
• Serious UTIs including urosepsis and pyelonephritis requiring hospitalization have been reported post-marketing 2
• Evaluate and treat promptly if symptoms develop (dysuria, frequency, urgency, fever) 2

Volume Depletion and Hypotension

• Empagliflozin causes osmotic diuresis leading to increased urine volume and potential dehydration 3, 2
• Patients at higher risk include: those over 65 years, taking diuretics or antihypertensives, on low-sodium diets, or with baseline kidney impairment 2
• Symptoms include dizziness, lightheadedness, weakness, or orthostatic hypotension 2
• Management: Consider temporarily discontinuing empagliflozin during acute illness, fasting, reduced oral intake, or excessive fluid losses (vomiting, diarrhea, heat exposure) 2

Metabolic Side Effects

Hypoglycemia

• Empagliflozin alone does not cause hypoglycemia due to its insulin-independent mechanism 4, 5
• Risk increases when combined with insulin or insulin secretagogues (sulfonylureas) 2, 6
• Reduce doses of insulin or sulfonylureas when initiating empagliflozin to minimize hypoglycemia risk 2

Lipid Changes

• Increases in LDL cholesterol can occur with empagliflozin 2
• Monitor lipid panels and treat elevations according to standard guidelines 2

Serious but Rare Side Effects

Ketoacidosis

• Euglycemic diabetic ketoacidosis can occur, particularly in patients with poor oral intake 7, 4
• Risk factors include acute illness, surgery, reduced carbohydrate intake, alcohol abuse, insulin dose reduction, or increased insulin requirements 7
• Presents with nausea, vomiting, abdominal pain, fatigue, and difficulty breathing, often with blood glucose <250 mg/dL 7
• Management: Discontinue empagliflozin immediately if ketoacidosis is suspected and treat per standard protocols 7

Acute Kidney Injury

• Post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, have been documented 2
• Risk factors include: hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant use of diuretics, ACE inhibitors, ARBs, or NSAIDs 2
• Monitor for signs and symptoms of acute kidney injury, especially during volume depletion states 2
• If acute kidney injury occurs, discontinue empagliflozin promptly and institute appropriate treatment 2

Fournier's Gangrene

• Necrotizing fasciitis of the perineum is extremely rare but has been reported with SGLT2 inhibitors 1
• Presents with severe perineal pain, tenderness, erythema, or fever 1
• Requires immediate surgical intervention and broad-spectrum antibiotics if suspected 1

Hypersensitivity Reactions

• Serious reactions including angioedema and urticaria have been reported post-marketing 2
• Empagliflozin is contraindicated in patients with previous serious hypersensitivity to empagliflozin or its excipients 2
• If hypersensitivity occurs, discontinue immediately and treat per standard care 2

Renal Function Considerations

Monitoring Requirements

• Assess renal function (eGFR) prior to initiation and monitor periodically thereafter 2
• More frequent monitoring is recommended when eGFR is below 60 mL/min/1.73 m² 2
• Empagliflozin causes transient increases in serum creatinine and decreases in eGFR, particularly in volume-depleted patients 2

Dosing Restrictions

• FDA labeling states use is not recommended when eGFR is persistently <45 mL/min/1.73 m² and is contraindicated when eGFR is <30 mL/min/1.73 m² 2
• However, current guidelines recommend continuing empagliflozin for cardiovascular and renal benefits even when eGFR falls below 45 mL/min/1.73 m² until dialysis or transplantation, despite reduced glucose-lowering efficacy 7, 3
• Empagliflozin can be initiated if eGFR is above 20 mL/min/1.73 m² according to recent diabetes guidelines 3

Special Population Considerations

Elderly Patients

• Patients ≥65 years are at higher risk for volume depletion and hypotension 2
• Monitor carefully for dehydration, orthostatic symptoms, and renal function changes 6
• Some caution is warranted in elderly and frail patients 6

Pregnancy and Breastfeeding

• Empagliflozin may harm the unborn baby; discontinue if pregnancy occurs 2
• Do not breastfeed while taking empagliflozin as it may pass into breast milk 2

Cardiovascular and Renal Benefits Context

Despite these side effects, empagliflozin provides substantial cardiovascular and renal protective benefits that often outweigh risks 7:

• 38% reduction in cardiovascular death 7, 8
• 35% reduction in heart failure hospitalization 7, 8
• 32% reduction in all-cause mortality 7, 8
• 39% reduction in incident or worsening nephropathy 7
• 34% reduction in kidney failure 9

These benefits persist across diabetes status, heart failure status, and levels of kidney function, supporting continuation of therapy even when glucose-lowering effects diminish 7, 9.