Can vildagliptin (DPP-4 inhibitor) and empagliflozin (SGLT2 inhibitor) be taken together in a patient with type 2 diabetes?

Can Vildagliptin and Empagliflozin Be Taken Together?

Yes, vildagliptin (DPP-4 inhibitor) and empagliflozin (SGLT2 inhibitor) can be safely taken together and represent an evidence-based combination therapy for type 2 diabetes with complementary mechanisms of action. 1, 2

Guideline Support for This Combination

• The American Diabetes Association explicitly recommends combining DPP-4 inhibitors and SGLT2 inhibitors as appropriate combination therapy options when intensifying treatment beyond metformin 2
• The 2024 ADA Standards of Care support combination therapy with these drug classes, noting they address multiple pathophysiologic pathways in type 2 diabetes 1
• The VERIFY trial demonstrated that initial combination therapy with a DPP-4 inhibitor (vildagliptin) is superior to sequential addition of medications for extending glycemic durability 1

Complementary Mechanisms of Action

• Vildagliptin increases insulin secretion and reduces glucagon secretion in a glucose-dependent manner, working through the incretin system 1
• Empagliflozin works independently by blocking glucose reuptake in the proximal renal tubule, causing urinary glucose excretion of 50-100 g per 24 hours 3
• These mechanisms do not interfere with each other pharmacokinetically—drug interaction studies show no significant changes in peak concentrations or total drug exposure when administered together 4, 5

Clinical Efficacy Evidence

• Dual therapy with a DPP-4 inhibitor and SGLT2 inhibitor is more potent than either monotherapy in patients already treated with metformin 4, 5
• A head-to-head comparison in the Pakistani population showed both empagliflozin and vildagliptin significantly reduced HbA1c (mean reduction -0.97% for empagliflozin, -0.82% for vildagliptin), fasting blood glucose, systolic blood pressure, and body weight with similar safety profiles 6
• The additional glucose-lowering effect is more marked when empagliflozin is added to vildagliptin than the reverse sequence 4, 5

Safety Profile of the Combination

• This combination does not cause hypoglycemia when used together, as both agents have glucose-dependent mechanisms 4, 5, 3
• Empagliflozin may increase the risk of hypoglycemia when combined with sulfonylureas, but vildagliptin does not share this interaction 3
• The combination is well tolerated with no clinically significant drug-drug interactions 4, 5
• Common side effects remain class-specific: genital mycotic infections with empagliflozin (especially in women) and minimal side effects with vildagliptin 3, 6

Cardiovascular and Renal Benefits

• For patients with established cardiovascular disease or chronic kidney disease, prioritize empagliflozin as the foundational agent given its proven mortality and cardiovascular event reduction benefits, then add vildagliptin if additional glycemic control is needed 2
• Empagliflozin provides a 38% reduction in cardiovascular death and significant reduction in heart failure hospitalization 2
• Empagliflozin reduces progression of diabetic kidney disease and can be used down to eGFR 30 mL/min/1.73m² 7, 8
• Vildagliptin has a neutral effect on cardiovascular outcomes and heart failure risk, making it safe to combine with empagliflozin 2

Practical Implementation Algorithm

Step 1: Verify Patient Eligibility

• Confirm eGFR ≥30 mL/min/1.73m² before initiating empagliflozin 8, 2
• Empagliflozin should be discontinued if eGFR falls below 45 mL/min/1.73m² for glycemic efficacy, though it can be continued for cardiovascular/renal benefits down to eGFR 30 3
• Vildagliptin requires dose adjustment based on renal function 1

Step 2: Initiate or Add Medications

• If starting both simultaneously: Begin empagliflozin 10 mg once daily and vildagliptin 50 mg once or twice daily with metformin 6
• If adding empagliflozin to existing vildagliptin: Start empagliflozin 10 mg once daily, may increase to 25 mg once daily 7
• If adding vildagliptin to existing empagliflozin: Start vildagliptin 50 mg once or twice daily 6

Step 3: Monitor for Safety

• Assess for volume depletion, especially if patient is on diuretics—consider reducing diuretic dose if dehydration symptoms present 8, 2
• Monitor renal function within the first several weeks of empagliflozin therapy; expect a small, reversible decrease in eGFR that is not a reason to discontinue 7, 8
• Educate patients about euglycemic diabetic ketoacidosis symptoms (nausea, vomiting, abdominal pain) and instruct them to stop empagliflozin and seek immediate care if these occur 7, 8
• Discontinue empagliflozin at least 3 days before planned surgery to prevent postoperative euglycemic ketoacidosis 2

Common Pitfalls to Avoid

• Do not withhold empagliflozin in patients with cardiovascular disease or CKD solely based on glycemic control—the cardiovascular and renal benefits occur independently of glucose-lowering effects 8, 2
• Do not confuse vildagliptin with saxagliptin—saxagliptin should be avoided in patients with heart failure risk, while vildagliptin has a neutral heart failure profile 2
• Do not start empagliflozin if eGFR <30 mL/min/1.73m² 8
• Monitor for genital mycotic infections with empagliflozin, particularly in women, though these are typically non-severe 3