Side Effects of Ezetimibe, Rosuvastatin, and Dapagliflozin Combination Therapy
The combination of ezetimibe, rosuvastatin, and dapagliflozin can cause several important side effects including genital mycotic infections, volume depletion, diabetic ketoacidosis, liver enzyme elevations, myopathy, and gastrointestinal disturbances that require careful monitoring and management. 1, 2
Dapagliflozin-Related Side Effects
Dapagliflozin, as an SGLT2 inhibitor, carries several important potential adverse effects:
- Genital mycotic infections: Common side effect that can be mitigated with proper genital hygiene 1
- Diabetic ketoacidosis (DKA): Risk is higher in patients with insulin deficiency, though rare in Type 2 diabetes 1
- Requires prompt discontinuation, evaluation, and treatment if suspected
- May present as euglycemic DKA (ketoacidosis without significantly elevated blood glucose)
- Risk factors include surgery, critical illness, or prolonged fasting
- Volume depletion and hypotension: Particularly concerning when ill or fasting 1
- Necrotizing fasciitis of the perineum (Fournier gangrene): Rare but serious complication 1
- Contraindicated with eGFR <30 mL/min/1.73m²: Glucose-lowering effect is minimal at eGFR <45 mL/min/1.73m² 1
Rosuvastatin-Related Side Effects
Rosuvastatin, as a high-intensity statin, may cause:
- Myopathy and muscle symptoms: Including muscle pain, tenderness, and weakness 2
- Rhabdomyolysis: Rare but serious complication of statin therapy 2
- Liver enzyme elevations: Requires monitoring of liver function tests 2
- Increased risk of diabetes: Particularly with high-intensity statins
Ezetimibe-Related Side Effects
Ezetimibe generally has a favorable safety profile but may cause:
- Upper respiratory tract infections: Common side effect 3, 2
- Diarrhea and gastrointestinal symptoms: Generally mild 3, 2
- Arthralgia: Joint pain reported in clinical trials 3, 2
- Fatigue and flu-like symptoms: Reported in some patients 3, 2
- Rare hepatic effects: Cases of serious drug-induced liver injury have been reported 4
Combination Therapy Considerations
When these medications are used in combination, several important considerations emerge:
Enhanced risk of liver enzyme elevations: The combination of ezetimibe with statins may increase the risk of transaminase elevations 3, 5
Potential for myopathy: While ezetimibe alone rarely causes muscle symptoms, the combination with rosuvastatin may increase the risk of myopathy 3, 2
Drug interactions:
Additive lipid-lowering effects: The combination of rosuvastatin and ezetimibe can reduce LDL-C by 60-75%, which is significantly greater than either agent alone 6, 7, 8
Monitoring Recommendations
Based on the potential side effects, the following monitoring is recommended:
- Liver function tests: Baseline and periodic monitoring, especially with the statin-ezetimibe combination 3, 2
- Muscle symptoms: Instruct patients to report muscle pain, tenderness, or weakness promptly 3, 2
- Renal function: Regular monitoring of eGFR, particularly with dapagliflozin 1
- Signs of volume depletion: Monitor for hypotension, especially in elderly patients or those on diuretics 1
- Genital symptoms: Educate patients about the risk of genital mycotic infections and proper hygiene 1
- Ketoacidosis symptoms: Educate patients about the signs of DKA and when to seek medical attention 1
Special Population Considerations
- Renal impairment: Dapagliflozin is contraindicated with eGFR <30 mL/min/1.73m² 1
- Hepatic impairment: Ezetimibe should be avoided in moderate to severe hepatic disease 3
- Pregnancy and lactation: All three medications should be avoided during pregnancy and nursing 1, 3, 2
- Elderly patients: Increased risk of volume depletion with dapagliflozin; however, ezetimibe appears safe without dosage adjustments 1, 3
This combination therapy requires careful patient selection and monitoring to minimize adverse effects while maximizing cardiovascular and metabolic benefits.