Can Januvia (sitagliptin) and Synjardy (empagliflozin and metformin) be used together in the treatment of type 2 diabetes?

Combining Januvia (Sitagliptin) and Synjardy (Empagliflozin/Metformin) for Type 2 Diabetes

Yes, Januvia (sitagliptin) and Synjardy (empagliflozin/metformin) can be used together for the treatment of type 2 diabetes, and this combination may provide complementary mechanisms of action for glycemic control. 1

Pharmacological Rationale

• Synjardy combines two medications: empagliflozin (an SGLT2 inhibitor) which enhances urinary glucose excretion, and metformin which decreases hepatic glucose production and improves insulin sensitivity 2
• Januvia (sitagliptin) is a DPP-4 inhibitor that increases circulating incretins, which stimulate insulin secretion and inhibit glucose production 3
• Empagliflozin pharmacokinetics are not affected by coadministration with sitagliptin, indicating no significant drug-drug interactions between these medications 4

Clinical Evidence Supporting Combination Therapy

• Triple therapy with metformin, sitagliptin, and empagliflozin has been studied in drug-naïve patients with type 2 diabetes, showing significant HbA1c reductions maintained for 24 months without severe hypoglycemia 1
• This triple combination led to achievement of glycemic targets (HbA1c <7.0%) in 61.7% of patients after 24 months, along with improvements in metabolic function and albuminuria 1
• Type 2 diabetes often requires combination therapy as maintenance of glycemic targets with monotherapy or dual therapy becomes insufficient over time 2

Safety Considerations

• The risk of hypoglycemia is low with this combination unless used with insulin or insulin secretagogues 2
• When using multiple agents, dose adjustment may be required to avoid hypoglycemia, particularly in patients at or near glycemic goals 2
• No serious adverse events, including ketoacidosis, were reported in studies examining the triple combination of metformin, sitagliptin, and empagliflozin 1

Cardiovascular and Renal Benefits

• Empagliflozin has demonstrated cardiovascular benefits in patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease 5, 2
• SGLT2 inhibitors (including empagliflozin) are recommended to reduce the risk of heart failure hospitalization and to reduce progression of diabetic kidney disease 5
• GLP-1 receptor agonists are preferred over DPP-4 inhibitors like sitagliptin for cardiovascular risk reduction, but sitagliptin has a neutral effect on heart failure risk 5

Monitoring Recommendations

• Treatment efficacy should be assessed within approximately 3 months of therapy initiation 2
• Regular monitoring for medication-specific adverse effects is essential, including genital mycotic infections (empagliflozin) and gastrointestinal effects (metformin) 2
• Self-monitoring of blood glucose might be unnecessary in patients receiving metformin combined with an SGLT2 inhibitor unless other medications that increase hypoglycemia risk are added 5

Important Precautions

• Empagliflozin should not be used in patients with eGFR <45 mL/min/1.73m² 2
• Avoid this combination in patients with severe renal impairment, as both metformin and empagliflozin have renal dosing considerations 6
• Be vigilant for rare risk of euglycemic diabetic ketoacidosis with empagliflozin, especially in insulin-deficient patients 2

Clinical Decision Making

• According to the American College of Physicians 2024 guidelines, when selecting therapy beyond metformin, clinicians should prioritize SGLT2 inhibitors in patients with heart failure or chronic kidney disease 5
• For patients with increased risk for stroke or for whom weight loss is an important treatment goal, GLP-1 receptor agonists would be preferred over DPP-4 inhibitors like sitagliptin 5
• If glycemic targets are not met with dual therapy, adding a third agent (like adding sitagliptin to empagliflozin/metformin) is a reasonable approach 2

This triple combination of metformin, empagliflozin, and sitagliptin offers complementary mechanisms of action and has demonstrated efficacy and safety in clinical studies, making it an appropriate option for patients with type 2 diabetes requiring multiple agents for glycemic control.