Is it safe to add Jardiance (Empagliflozin) to a regimen of Janumet (Sitagliptin and Metformin) and Invokana (Canagliflozin) for a patient with a history of type 2 diabetes and potential kidney disease?

Adding Jardiance to Janumet and Invokana: Safety and Clinical Considerations

Critical Safety Concern: Dual SGLT2 Inhibitor Therapy is Contraindicated

Do not add Jardiance (empagliflozin) to a regimen already containing Invokana (canagliflozin), as both are SGLT2 inhibitors and combining them provides no additional benefit while substantially increasing risks of volume depletion, diabetic ketoacidosis, genital mycotic infections, and urinary tract infections. 1

Why This Combination is Problematic

Mechanism of Action Overlap

• Both Jardiance and Invokana work through the identical mechanism—inhibiting sodium-glucose cotransporter-2 in the proximal renal tubule to increase urinary glucose excretion 2
• Using two SGLT2 inhibitors simultaneously does not provide additive glycemic benefit but multiplies adverse effects 1

Compounded Safety Risks

Volume Depletion and Hypotension:

• SGLT2 inhibitors cause clinically significant osmotic diuresis 1
• Dual SGLT2 inhibitor therapy would dramatically increase risk of intravascular volume contraction, particularly dangerous in patients with kidney disease, those on diuretics, or elderly patients 1

Diabetic Ketoacidosis (DKA):

• SGLT2 inhibitors increase risk of euglycemic DKA, which can occur even with normal blood glucose levels (150-250 mg/dL range) 1
• Combining two SGLT2 inhibitors would substantially elevate this already serious risk 1

Genital Mycotic Infections:

• Occur in approximately 6% of patients on single SGLT2 inhibitor therapy versus 1% on placebo 1, 3
• Dual therapy would likely increase this risk further 1

Renal Function Concerns:

• Both agents require eGFR ≥30 mL/min/1.73 m² for safe use 1, 2
• Canagliflozin specifically requires caution in patients with history of amputation, severe peripheral arterial disease, or active diabetic foot ulcers 1

Recommended Clinical Algorithm

Step 1: Choose One SGLT2 Inhibitor Based on Patient Profile

Select Jardiance (empagliflozin) if:

• Primary concern is cardiovascular mortality reduction (38% reduction in CV death, 32% reduction in all-cause mortality in EMPA-REG OUTCOME) 4
• Patient has heart failure with reduced ejection fraction 1
• eGFR ≥30 mL/min/1.73 m² 2

Continue Invokana (canagliflozin) if:

• Patient has diabetic kidney disease with eGFR 30-60 mL/min/1.73 m² (FDA-approved for use down to eGFR 30 in DKD) 1
• Already tolerating medication well without adverse effects 1
• However, exercise extreme caution if patient has history of amputation, severe peripheral arterial disease, active diabetic foot ulcers, or history of fracture 1

Step 2: Optimize Current Regimen

Janumet (sitagliptin/metformin) can be safely continued with either SGLT2 inhibitor:

• No significant drug-drug interactions between DPP-4 inhibitors and SGLT2 inhibitors 1
• Low hypoglycemia risk with this combination 3
• Metformin remains foundational therapy unless contraindicated 1

Dosing adjustments based on renal function:

• If eGFR 45-59 mL/min/1.73 m²: Reduce metformin to half maximum dose 3
• If eGFR 30-44 mL/min/1.73 m²: Reduce metformin to maximum 1000 mg/day and sitagliptin to 50 mg once daily 3
• If eGFR <30 mL/min/1.73 m²: Discontinue metformin; further reduce sitagliptin to 25 mg once daily 1, 3

Step 3: Consider Alternative Intensification Strategies

If glycemic control remains inadequate on Janumet + one SGLT2 inhibitor:

Add GLP-1 receptor agonist (preferred):

• Liraglutide, semaglutide, or dulaglutide provide complementary cardiovascular benefits 1
• Greatest evidence for MACE reduction in patients with established atherosclerotic cardiovascular disease 1
• Can be used with eGFR >30 mL/min/1.73 m² 1

Add basal insulin:

• Reduce total daily insulin dose by approximately 20% when initiating or continuing SGLT2 inhibitor to prevent hypoglycemia 1, 5
• Monitor glucose closely for first 4 weeks 1

Step 4: Monitoring and Safety Precautions

Before initiating or switching SGLT2 inhibitors:

• Check eGFR, electrolytes, and volume status 1, 3
• Assess for contraindications: history of amputation, active foot ulcers (particularly with canagliflozin), recurrent genital infections, history of DKA 1
• Consider reducing diuretic dose if patient symptomatic or at high risk for volume depletion 1

Patient education is critical:

• Educate regarding genital hygiene to reduce mycotic infection risk 1
• Teach symptoms of DKA (nausea, vomiting, abdominal pain, weakness) and emphasize this can occur with normal glucose levels 1
• Instruct to hold SGLT2 inhibitor during acute illness, particularly with reduced oral intake, fever, vomiting, or diarrhea 1, 3
• Withhold at least 3 days before major surgery or procedures requiring prolonged fasting 1, 3
• Educate on foot care, especially in patients with diabetic neuropathy 1

Follow-up monitoring:

• Recheck eGFR within 1-2 weeks after initiation, then every 3-6 months 3, 5
• Monitor for symptoms of volume depletion (lightheadedness, orthostasis, weakness) 1
• Check HbA1c every 3 months until stable 6

Common Pitfalls to Avoid

• Never combine two SGLT2 inhibitors (Jardiance + Invokana) 1
• Do not discontinue SGLT2 inhibitor solely because eGFR falls below 45 mL/min/1.73 m²—cardiovascular and renal protective benefits persist even when glycemic efficacy diminishes 1, 3
• Do not forget to reduce insulin or sulfonylurea doses when adding SGLT2 inhibitor to prevent hypoglycemia 1, 5
• Do not ignore the increased amputation risk with canagliflozin in high-risk patients 1