Can I add empagliflozin to my type 2 diabetic patient who is on metformin, has diabetic retinopathy, mild hepatic enzyme elevation, mild thrombocytopenia, alcohol use disorder, and an eGFR ≥ 45 mL/min/1.73 m²?

Can Empagliflozin Be Added to Metformin in a Type 2 Diabetic Patient with Diabetic Retinopathy, Mild Hepatic Enzyme Elevation, Mild Thrombocytopenia, Alcohol Use Disorder, and eGFR ≥ 45 mL/min/1.73 m²?

Yes, empagliflozin should be added to metformin in this patient for cardiovascular and renal protection, provided the eGFR is ≥ 45 mL/min/1.73 m² and the patient is not acutely decompensated from alcohol use. The presence of diabetic retinopathy, mild hepatic enzyme elevation, mild thrombocytopenia, and alcohol use disorder do not contraindicate empagliflozin therapy, though specific monitoring is required. 111

Guideline-Directed Rationale for Adding Empagliflozin

• SGLT2 inhibitors (empagliflozin, canagliflozin, or dapagliflozin) are recommended in patients with type 2 diabetes and cardiovascular disease or at very high/high cardiovascular risk to reduce cardiovascular events, with empagliflozin specifically recommended to reduce the risk of death. 1

• The 2022 ADA Standards of Care and 2022 KDIGO guideline recommend early initiation of metformin plus an SGLT2 inhibitor in most patients with type 2 diabetes and chronic kidney disease, independent of HbA1c or the need for additional glucose lowering. 1

• Empagliflozin reduced cardiovascular death by 38% (HR 0.62,95% CI 0.49–0.77) and the composite outcome of MI, stroke, and cardiovascular death by 14% (HR 0.86,95% CI 0.74–0.99) in the EMPA-REG OUTCOME trial. 1

Diabetic Retinopathy Considerations

• Diabetic retinopathy is not a contraindication to empagliflozin therapy. The presence of microvascular complications actually strengthens the indication for SGLT2 inhibitor use, as these patients are at very high cardiovascular risk. 1

• Preliminary evidence suggests SGLT2 inhibitors may contribute to preventing the development of preclinical diabetic retinopathy by preserving retinal microvascular density. In a prospective OCTA study, patients receiving metformin plus empagliflozin showed no deterioration in retinal vascular plexus densities over three months, whereas those on metformin alone showed decreased superficial perifoveal and deep parafoveal macular vascular plexus densities. 2

• The 2019 ESC guidelines recommend empagliflozin for patients with type 2 diabetes and cardiovascular disease or at very high/high cardiovascular risk, without excluding those with diabetic retinopathy. 1

Renal Function and Dosing Algorithm

• For patients with eGFR ≥ 45 mL/min/1.73 m², initiate empagliflozin 10 mg once daily, with the option to increase to 25 mg once daily if additional glycemic control is needed. 3

• Empagliflozin should not be initiated for glycemic control when eGFR < 45 mL/min/1.73 m², though it may be continued for cardiovascular and renal protection down to eGFR ≥ 20 mL/min/1.73 m². 11

• In patients with stage 2 chronic kidney disease (eGFR 60 to < 90 mL/min/1.73 m²), empagliflozin 10 mg or 25 mg provided statistically significant HbA1c reductions of -0.52% and -0.68% respectively versus placebo at week 24. 3

• The glucose-lowering efficacy of empagliflozin decreases with declining renal function, but cardiovascular and renal benefits are preserved at lower eGFR levels. 34

Hepatic Enzyme Elevation and Alcohol Use Disorder

• Mild hepatic enzyme elevation is not a contraindication to empagliflozin, as the drug is primarily renally eliminated and does not undergo significant hepatic metabolism. 3

• Active alcohol use disorder requires careful assessment before initiating empagliflozin. The primary concern is the risk of euglycemic diabetic ketoacidosis (DKA), which can be precipitated by reduced food intake, dehydration, or acute illness—all common in patients with active alcohol use. 5

• If the patient has stable alcohol use disorder without recent episodes of acute intoxication, dehydration, or reduced oral intake, empagliflozin can be initiated with close monitoring and patient education about sick-day rules. 1

• Patients must be counseled to withhold empagliflozin during any acute illness, particularly when experiencing reduced food and fluid intake, fever, vomiting, or diarrhea, and to stop the drug at least 3 days before major surgery or procedures requiring prolonged fasting. 6

• Metformin should be continued if eGFR ≥ 45 mL/min/1.73 m², but the dose should be reduced to maximum 1000 mg/day if eGFR falls to 30–44 mL/min/1.73 m², and metformin should be discontinued if eGFR < 30 mL/min/1.73 m². 11

Thrombocytopenia Considerations

• Mild thrombocytopenia is not a contraindication to empagliflozin therapy. SGLT2 inhibitors do not affect platelet function or coagulation pathways. 3

• The thrombocytopenia should be monitored as part of routine care, but it does not preclude empagliflozin initiation unless there is active bleeding or severe thrombocytopenia (platelet count < 50,000/μL). 3

Safety Monitoring and Expected Adverse Effects

• Genital mycotic infections occur in approximately 6% of patients on SGLT2 inhibitors versus 1% on placebo, with higher incidence in women. Patients should be educated about daily hygiene measures to reduce this risk. 65

• Urinary tract infections may occur more frequently with SGLT2 inhibitors, and patients should be counseled to seek prompt treatment if symptoms develop. 6

• Volume depletion is a potential risk, particularly in elderly patients or those on concurrent diuretics. Assess volume status before initiating empagliflozin and consider reducing concurrent diuretic doses. 65

• An acute, reversible eGFR dip of 2–5 mL/min/1.73 m² typically occurs within the first 2–4 weeks of empagliflozin initiation, which is hemodynamic and should not trigger discontinuation. Recheck eGFR within 1–2 weeks after initiation. 6

• Euglycemic diabetic ketoacidosis is a rare but serious risk. Patients should be warned to seek immediate medical attention for unexplained malaise, nausea, vomiting, or abdominal pain even when blood glucose is normal. 65

Common Pitfalls to Avoid

• Do not discontinue empagliflozin solely because eGFR falls below 45 mL/min/1.73 m² after initiation; cardiovascular and renal benefits persist despite loss of glycemic efficacy. 11

• Do not stop empagliflozin in response to the expected early eGFR dip; the change is hemodynamic and reversible, not indicative of kidney injury. 6

• Do not withhold empagliflozin due to concerns about hypoglycemia when used with metformin alone, as this combination has minimal hypoglycemia risk. If the patient is also on insulin or sulfonylureas, reduce those doses by approximately 20% when starting empagliflozin. 6

• Do not initiate empagliflozin during acute alcohol intoxication, dehydration, or reduced oral intake, as these conditions significantly increase the risk of euglycemic DKA. 6

Integration with Existing Therapy

• Continue metformin at the current dose if eGFR ≥ 45 mL/min/1.73 m², and add empagliflozin 10 mg once daily. 11

• If additional glycemic control is needed after 3 months, consider increasing empagliflozin to 25 mg once daily or adding a GLP-1 receptor agonist (e.g., semaglutide, dulaglutide, liraglutide) for additional cardiovascular protection. 11

• ACE inhibitors or ARBs should be continued unchanged when empagliflozin is started, as the combination provides additive renal protection. 17