Can a patient take Trjenta (linagliptin) and Synjardy (empagliflozin and metformin) to help with glucose control?

Can a Patient Take Tradjenta and Synjardy Together for Glucose Control?

Yes, combining Tradjenta (linagliptin, a DPP-4 inhibitor) with Synjardy (empagliflozin/metformin) is both rational and effective for glucose control in type 2 diabetes, with strong evidence supporting superior glycemic reduction compared to either agent alone, without increased hypoglycemia risk. 1, 2

Evidence for the Combination

Glycemic Efficacy

The combination of empagliflozin and linagliptin added to metformin produces superior HbA1c reduction compared to either drug alone:

• At 24 weeks, empagliflozin 25 mg + linagliptin 5 mg (with metformin) reduced HbA1c by -1.19% versus -0.62% with empagliflozin alone and -0.70% with linagliptin alone (P < 0.001 for all comparisons) 1
• 61.8% of patients achieved HbA1c <7% with the combination versus only 32.6% with empagliflozin alone and 36.1% with linagliptin alone 1
• Meta-analysis confirms a weighted mean difference of -0.72% greater HbA1c reduction with combination therapy versus monotherapy 2
• This efficacy was maintained through 52 weeks of treatment 1

Complementary Mechanisms

The combination addresses multiple pathophysiologic defects in type 2 diabetes simultaneously:

• Linagliptin (DPP-4 inhibitor) augments glucose-dependent insulin secretion and decreases elevated glucagon levels by preventing GLP-1 degradation 3
• Empagliflozin (SGLT2 inhibitor) causes glucosuria, ameliorates glucotoxicity, and works independently of insulin secretion 3
• Metformin (in Synjardy) reduces hepatic glucose production and improves insulin sensitivity 4

These three mechanisms work additively without overlapping pathways 3, 5

Safety Profile

Hypoglycemia Risk

No hypoglycemic adverse events requiring assistance were reported with the triple combination in clinical trials 1, 6:

• The glucose-lowering effects of both DPP-4 inhibitors and SGLT2 inhibitors are glucose-dependent, minimizing hypoglycemia risk 3
• Safety profiles were similar across combination and monotherapy groups 1, 2

Additional Benefits

Beyond glucose control, this combination offers:

• Weight reduction: Significantly greater with empagliflozin-containing regimens (-2.8 to -3.8 kg) compared to metformin alone 6
• Blood pressure reduction: Empagliflozin reduces both systolic and diastolic blood pressure 5
• Cardiovascular benefits: Empagliflozin has proven cardiovascular risk reduction in patients with established ASCVD 4
• Renal protection: SGLT2 inhibitors provide benefits in chronic kidney disease 4

Tolerability

• Adverse event rates were similar across all treatment groups (68.6-73.0% over 52 weeks) 1
• The once-daily combination reduces pill burden and may enhance adherence 2, 5

Clinical Application Algorithm

When to Use This Combination

Start this triple therapy when:

1. HbA1c remains ≥7% on metformin monotherapy after 3 months 4, 7
2. HbA1c is 1.5% or more above target, as single agents rarely reduce HbA1c by more than 1% 7
3. Patient has established cardiovascular disease or indicators of high CV risk, making empagliflozin particularly beneficial 4
4. Patient has heart failure or chronic kidney disease, where SGLT2 inhibitors are preferred 4

Dosing Considerations

Standard regimen:

• Tradjenta: 5 mg once daily 8
• Synjardy: Contains empagliflozin (10 or 25 mg) + metformin (500,850, or 1000 mg twice daily) 1, 6
• No dose adjustment needed for linagliptin based on renal function 8

Important Caveats

Monitor for:

• Genital mycotic infections (more common with SGLT2 inhibitors) 5
• Volume depletion in elderly patients or those on diuretics when starting empagliflozin 4
• Vitamin B12 deficiency with long-term metformin use—consider periodic testing 4

Avoid if:

• Patient has type 1 diabetes or diabetic ketoacidosis 4
• Severe renal impairment (adjust metformin dose accordingly) 4

Guideline Support

The 2018 ADA/EASD consensus and 2022 ADA Standards explicitly support combining agents from different classes when monotherapy fails to achieve targets 4:

• DPP-4 inhibitors and SGLT2 inhibitors are both recommended as second-line options after metformin 4
• The 2018 ACC Expert Consensus specifically advocates for SGLT2 inhibitors in patients with ASCVD, independent of baseline HbA1c 4
• Triple therapy is reasonable when dual therapy proves insufficient, particularly when combining complementary mechanisms 4

This combination represents evidence-based, guideline-concordant therapy that addresses multiple pathophysiologic defects while minimizing adverse effects and providing cardiovascular and renal benefits beyond glucose lowering. 4, 5