Using Ryzodeg with Empagliflozin and Linagliptin
This combination is generally acceptable but suboptimal—the linagliptin adds no meaningful benefit and should be discontinued when using Ryzodeg (insulin degludec/liraglutide) with empagliflozin. 1
The Core Issue: DPP-4 Inhibitor Redundancy
Do not combine GLP-1 receptor agonists with DPP-4 inhibitors—there is no added glucose-lowering benefit beyond the GLP-1 RA alone. 1 Since Ryzodeg contains liraglutide (a GLP-1 RA), adding linagliptin (a DPP-4 inhibitor) provides no incremental glycemic improvement and only increases pill burden and cost.
The Recommended Approach
Use Ryzodeg with empagliflozin only, and discontinue the linagliptin:
Ryzodeg (insulin degludec/liraglutide) provides robust glycemic control addressing both fasting and postprandial hyperglycemia with low hypoglycemia risk and favorable weight effects 2, 3, 4
Empagliflozin adds complementary cardiovascular and renal protection, particularly valuable for patients with established ASCVD, heart failure, or CKD 1
Linagliptin becomes redundant and should be stopped 1
Evidence Supporting Empagliflozin + Liraglutide
The combination of empagliflozin with liraglutide (the GLP-1 component of Ryzodeg) has demonstrated:
- Improved left atrial function and arterial stiffness compared to insulin alone 5
- Enhanced renal protection with reduced urinary albumin excretion and inflammatory markers 6
- Complementary mechanisms: empagliflozin reduces glucose reabsorption and provides SGLT2-mediated cardio-renal benefits, while liraglutide enhances insulin secretion and suppresses glucagon 5
Important Safety Considerations
Monitor for hypoglycemia risk: When combining empagliflozin with insulin-containing regimens like Ryzodeg, there is increased hypoglycemia risk 7. However, Ryzodeg itself has demonstrated lower hypoglycemia rates than multiple daily insulin injections (6.2% vs 31.3% with glucose <3.0 mmol/l) 4.
Volume depletion awareness: Empagliflozin increases urine volume, which may enhance volume depletion risk 7. Ensure adequate hydration, especially in elderly patients or those on diuretics.
Ketoacidosis vigilance: Although rare, SGLT2 inhibitors like empagliflozin carry a risk of euglycemic diabetic ketoacidosis 7. Educate patients about sick-day management.
Clinical Algorithm
- Discontinue linagliptin immediately (no benefit with concurrent GLP-1 RA)
- Continue Ryzodeg at current dose, adjusting based on fasting glucose targets
- Continue empagliflozin for cardio-renal protection (10-25 mg daily, if eGFR >20 mL/min/1.73 m²) 1
- Monitor closely for hypoglycemia in the first 2-4 weeks, particularly if insulin dose is high
- Assess volume status and ensure adequate hydration
When This Combination Excels
This dual therapy (Ryzodeg + empagliflozin, without linagliptin) is particularly appropriate for patients with:
- Type 2 diabetes requiring insulin intensification with established cardiovascular disease or CKD 1
- Concerns about weight gain with insulin therapy (liraglutide component mitigates this) 2, 3
- High hypoglycemia risk (Ryzodeg shows superior safety profile) 4
- Need for simplified regimen (once-daily Ryzodeg vs multiple daily injections) 3
The empagliflozin provides independent cardiovascular and renal benefits beyond glycemic control, making it a valuable addition even when glycemic targets are met 1.