What are the considerations for using Insulin and Jardiance (empagliflozin) together in a patient with type 2 diabetes, particularly those with comorbidities such as heart failure or impaired renal function?

Combining Insulin and Jardiance (Empagliflozin) in Type 2 Diabetes

Insulin and Jardiance (empagliflozin) can and should be used together in patients with type 2 diabetes, particularly those with established cardiovascular disease, heart failure, or chronic kidney disease, as this combination provides complementary glycemic control while delivering significant cardiovascular and renal protection independent of glucose-lowering effects. 1

Dosing and Initiation

Start empagliflozin at 10 mg once daily in the morning, with or without food, regardless of current insulin regimen. 2 The dose may be increased to 25 mg daily if additional glycemic control is needed and the patient tolerates the 10 mg dose well 2. No adjustment to the empagliflozin dose is required based on insulin type or dose 2.

Insulin Dose Adjustment When Adding Empagliflozin

• Reduce insulin doses by 10-20% when initiating empagliflozin to minimize hypoglycemia risk, particularly if baseline glucose control is already near target (HbA1c <8%). 1, 2
• The hypoglycemia risk increases when empagliflozin is combined with insulin or insulin secretagogues, necessitating proactive dose reduction 1, 2
• Monitor glucose levels closely during the first 1-2 weeks after adding empagliflozin, with further insulin adjustments based on individual response 2

Renal Function Considerations

eGFR Thresholds for Initiation and Continuation

• Do not initiate empagliflozin if eGFR <45 mL/min/1.73 m² for glycemic control purposes. 2
• For cardiovascular and renal protection, empagliflozin can be initiated if eGFR ≥25 mL/min/1.73 m². 3, 2
• If eGFR falls below 45 mL/min/1.73 m² during treatment, continue empagliflozin at the same dose (do not discontinue) as cardiovascular and renal benefits persist even when glucose-lowering efficacy diminishes. 3, 2
• Discontinue empagliflozin only if eGFR is persistently <25 mL/min/1.73 m² or if dialysis is initiated 2

Monitoring Protocol

• Assess renal function (eGFR and serum creatinine) before initiating empagliflozin 2
• Recheck eGFR within 1-2 weeks after initiation, as a transient dip of 3-5 mL/min/1.73 m² is expected and reversible 3
• Continue monitoring eGFR every 3-6 months if eGFR 45-59 mL/min/1.73 m², or annually if eGFR ≥60 mL/min/1.73 m² 3

Cardiovascular and Renal Benefits Beyond Glycemic Control

The primary rationale for combining empagliflozin with insulin extends beyond glucose control to include substantial mortality and morbidity benefits. 1

Cardiovascular Protection

• Empagliflozin reduces cardiovascular death by 38% (HR 0.62; 95% CI 0.49-0.77) in patients with type 2 diabetes and established cardiovascular disease 1, 4
• All-cause mortality is reduced by 32% (HR 0.68; 95% CI 0.57-0.82) 4, 5
• Hospitalization for heart failure is reduced by 35% 1
• These benefits occur independently of baseline HbA1c or degree of glucose lowering achieved 1

Renal Protection

• In patients with CKD (eGFR 25-75 mL/min/1.73 m² and albuminuria), empagliflozin reduces the composite outcome of sustained eGFR decline ≥50%, end-stage kidney disease, or renal/cardiovascular death by 39% 1, 6
• The renal-specific composite outcome is reduced by 44% 6
• These renal benefits are preserved even in patients with eGFR 25-44 mL/min/1.73 m², where glucose-lowering efficacy is minimal. 1, 3

Critical Safety Considerations

Volume Depletion and Hypotension

• Assess volume status before initiating empagliflozin and correct any volume depletion. 2
• Patients at highest risk include those with eGFR 30-60 mL/min/1.73 m², elderly patients, those with low baseline systolic blood pressure (<110 mmHg), and those on concurrent diuretics 1, 2
• Consider reducing diuretic doses by 25-50% when starting empagliflozin in high-risk patients. 3

Euglycemic Diabetic Ketoacidosis (DKA)

• Euglycemic DKA can occur even with normal blood glucose levels (<250 mg/dL) in patients taking empagliflozin with insulin. 3, 2
• Risk factors include insulin dose reduction, acute illness, reduced caloric intake, surgery, or prolonged fasting 2
• Withhold empagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting. 3, 2

Sick Day Management

• Instruct patients to stop empagliflozin immediately during any acute illness with fever, vomiting, diarrhea, or reduced oral intake. 3
• Maintain at least low-dose insulin even when empagliflozin is held, as complete insulin cessation dramatically increases DKA risk. 3
• Check blood or urine ketones if patients develop malaise, nausea, vomiting, or abdominal pain 3
• Resume empagliflozin only after recovery and restoration of normal oral intake 3

Genital Mycotic Infections

• Genital mycotic infections occur in approximately 6% of patients on empagliflozin versus 1% on placebo 3
• These infections are typically mild and respond to standard antifungal therapy 1
• Counsel patients on daily hygiene measures to reduce risk 3

Common Pitfalls to Avoid

• Do not discontinue empagliflozin solely because eGFR falls below 45 mL/min/1.73 m²—cardiovascular and renal protective benefits persist even when glycemic efficacy is lost 3, 2
• Do not reduce insulin doses excessively when adding empagliflozin—a 10-20% reduction is appropriate, but excessive reduction increases DKA risk 3
• Do not continue empagliflozin during acute illness—this is the most common precipitant of euglycemic DKA 3, 2
• Do not use empagliflozin in type 1 diabetes or for treatment of diabetic ketoacidosis—it is not indicated and increases risk 2

Clinical Decision Algorithm

1. Assess renal function: If eGFR ≥45 mL/min/1.73 m², initiate empagliflozin 10 mg daily for both glycemic control and cardiovascular/renal protection 2
2. If eGFR 25-44 mL/min/1.73 m²: Initiate empagliflozin 10 mg daily for cardiovascular/renal protection only (not for glycemic control) 3, 2
3. If eGFR <25 mL/min/1.73 m²: Do not initiate empagliflozin; consider GLP-1 receptor agonists instead 3
4. Reduce insulin by 10-20% at empagliflozin initiation if HbA1c <8% 1, 2
5. Assess volume status and reduce diuretics if needed 3, 2
6. Monitor glucose closely for first 1-2 weeks and adjust insulin as needed 2
7. Recheck eGFR within 1-2 weeks, expecting a transient 3-5 mL/min/1.73 m² dip 3
8. Continue empagliflozin even if eGFR falls below 45 mL/min/1.73 m² during treatment 3, 2