Is it safe to use sitagliptin with empagliflozin (SGLT2 inhibitor) in a patient with type 2 diabetes and impaired renal function?

Sitagliptin with Empagliflozin Combination Therapy

The combination of sitagliptin and empagliflozin is safe and recommended for patients with type 2 diabetes, including those with impaired renal function down to eGFR ≥25 mL/min/1.73 m², with dose adjustments required only for sitagliptin based on kidney function. 1, 2

Guideline Support for Combination Therapy

• The American Diabetes Association explicitly endorses combining DPP-4 inhibitors (sitagliptin) with SGLT2 inhibitors (empagliflozin) as appropriate intensification therapy beyond metformin in patients with type 2 diabetes 2
• The European Society of Cardiology confirms that sitagliptin has a neutral effect on heart failure risk and may be safely combined with SGLT2 inhibitors like empagliflozin 2

Renal Function-Based Dosing Algorithm

For eGFR ≥45 mL/min/1.73 m²

• Continue sitagliptin 50 mg twice daily (or 100 mg once daily) without dose adjustment 1
• Initiate or continue empagliflozin 10 mg or 25 mg once daily for both glycemic control and cardiovascular/renal protection 1, 3

For eGFR 30-44 mL/min/1.73 m²

• Reduce sitagliptin to 50 mg once daily 1
• Continue empagliflozin 25 mg once daily, as the dose remains unchanged, though glycemic efficacy is substantially reduced 1, 3
• At this level of renal function, empagliflozin still provides cardiovascular and renal protection even when glucose-lowering effects diminish 3

For eGFR 25-29 mL/min/1.73 m²

• Reduce sitagliptin to 25 mg once daily 1
• Continue empagliflozin 25 mg once daily for cardiovascular/renal protection only, as glycemic benefit is lost 1

For eGFR <25 mL/min/1.73 m²

• Continue sitagliptin 25 mg once daily 1
• Do not initiate empagliflozin, but may continue if already established, until dialysis is required 1

Complementary Mechanisms Supporting Combination

• Sitagliptin enhances glucose-dependent insulin secretion and suppresses glucagon by inhibiting DPP-4 enzyme, increasing endogenous GLP-1 levels 1
• Empagliflozin works independently by inhibiting SGLT2 in the kidneys, increasing urinary glucose excretion and reducing hyperglycemia through an insulin-independent mechanism 4
• These complementary mechanisms allow for additive glycemic control without increasing hypoglycemia risk when used together 1

Cardiovascular and Renal Benefits

• Empagliflozin carries a Class I recommendation to reduce cardiovascular death by 38% and heart failure hospitalization in patients with type 2 diabetes and established cardiovascular disease 2, 5
• In the EMPA-REG OUTCOME trial, empagliflozin reduced incident or worsening nephropathy by 39% (HR 0.61; 95% CI 0.53-0.70; P<0.001) and reduced doubling of serum creatinine by 44% 5
• Sitagliptin has demonstrated cardiovascular safety with neutral effects on major cardiovascular events and heart failure risk, making it safe to combine with empagliflozin 1, 2

Critical Safety Considerations

Volume Status Assessment

• Assess volume status before initiating empagliflozin, and consider reducing concurrent diuretic doses to prevent excessive volume depletion 1
• Patients on diuretics are at higher risk for volume-related adverse effects when empagliflozin is added 1

Surgical Planning

• Discontinue empagliflozin at least 3 days before planned surgery to prevent postoperative euglycemic ketoacidosis 2
• Stop SGLT2 inhibitors immediately if symptoms of ketoacidosis develop 2

Renal Function Monitoring

• Check eGFR within 1-2 weeks after initiating empagliflozin, then every 3-6 months if eGFR 45-59 mL/min/1.73 m², or annually if eGFR ≥60 mL/min/1.73 m² 1
• Adjust sitagliptin dose as renal function changes, while maintaining empagliflozin dose for cardiorenal protection 1

Common Pitfalls to Avoid

• Do not discontinue empagliflozin solely because eGFR falls below 45 mL/min/1.73 m², as cardiovascular and renal protective benefits persist even when glycemic efficacy is lost 1
• Unlike saxagliptin, sitagliptin is not contraindicated in patients with heart failure and should be the preferred DPP-4 inhibitor when combining with empagliflozin in this population 2
• Monitor for genital mycotic infections, which are more common with SGLT2 inhibitors but are usually straightforward to manage 6
• Educate patients to withhold empagliflozin during acute illness with reduced oral intake, fever, vomiting, or diarrhea to prevent euglycemic ketoacidosis 1

Special Population Considerations

• In patients with established cardiovascular disease or chronic kidney disease, prioritize empagliflozin as the foundational agent given its mortality and cardiovascular event reduction benefits, then add sitagliptin if additional glycemic control is needed 2
• The combination may be particularly beneficial for patients not achieving glycemic targets on monotherapy while providing layered cardiorenal protection 2