What are the considerations for adding imeglimin (DPP4 inhibitor adjunct) 500 mg twice daily to a DPP-4 (dipeptidyl peptidase-4) inhibitor for a patient with type 2 diabetes?

Adding Imeglimin 500 mg Twice Daily to DPP-4 Inhibitor Therapy in Type 2 Diabetes

Imeglimin 500 mg twice daily can be added to a DPP-4 inhibitor for patients with type 2 diabetes with inadequate glycemic control, with particular benefit for those with low insulin secretory capacity, but combination with DPP-4 inhibitors is not a first-line approach when other options like SGLT2 inhibitors or GLP-1 receptor agonists are available.

Efficacy Considerations

When considering adding imeglimin to a DPP-4 inhibitor regimen:

• Imeglimin combined with DPP-4 inhibitors has shown significant HbA1c reduction (0.92%) in Japanese patients with type 2 diabetes over 52 weeks, representing the greatest reduction among oral combination therapies studied 1

• Imeglimin works through a novel mechanism that improves both insulin secretion and insulin sensitivity, making it potentially complementary to DPP-4 inhibitors 2, 3

• Patients with low insulin secretory capacity (low C-peptide) and higher baseline glucose levels may benefit most from imeglimin addition 3

Safety and Dosing Considerations

• The standard dosing for imeglimin is 500 mg twice daily with meals for patients with normal renal function 4

• Dose adjustment is required for renal impairment:

  • eGFR 15-45 mL/min/1.73 m²: 500 mg twice daily
  • eGFR <15 mL/min/1.73 m²: 500 mg with extended dosing interval 4

• Main adverse effects are gastrointestinal disorders 3, 1

• Risk of hypoglycemia increases when combining imeglimin with insulin or glinide agents, but is generally low with DPP-4 inhibitor combinations 3

Alternative Treatment Pathways to Consider

Current guidelines strongly recommend considering other options before adding imeglimin to a DPP-4 inhibitor:

1. First-line preferred approach: The American College of Physicians strongly recommends adding an SGLT2 inhibitor or GLP-1 receptor agonist to metformin rather than a DPP-4 inhibitor for reducing mortality and cardiovascular events 5

2. For patients with cardiovascular disease: SGLT2 inhibitors reduce risk for all-cause mortality, major adverse cardiovascular events, CKD progression, and heart failure hospitalization 5

3. For patients with CKD: SGLT2 inhibitors are recommended to reduce progression of diabetic kidney disease 5

4. For patients with heart failure: DPP-4 inhibitors (especially saxagliptin) should be avoided, and SGLT2 inhibitors are preferred 6

Clinical Decision Algorithm

1. Assess current glycemic control and comorbidities:

   • If HbA1c >9% or persistent hyperglycemia despite DPP-4 inhibitor
   • Evaluate for cardiovascular disease, CKD, or heart failure

2. Consider preferred alternatives first:

   • If cardiovascular disease or CKD present: Add SGLT2 inhibitor (if eGFR allows)
   • If obesity or need for greater HbA1c reduction: Add GLP-1 receptor agonist
   • If cost is major concern: Consider sulfonylurea (with hypoglycemia risk)

3. When imeglimin is appropriate:

   • Patient cannot tolerate or has contraindications to SGLT2 inhibitors and GLP-1 receptor agonists
   • Patient has low insulin secretory capacity (common in East Asian populations)
   • Patient has inadequate response to DPP-4 inhibitor alone but wishes to avoid injectable therapy

Monitoring Recommendations

• Monitor HbA1c after 3 months of therapy
• Assess for gastrointestinal side effects
• Monitor for hypoglycemia, especially if patient is also on insulin or sulfonylureas
• Consider using intermittently scanned continuous glucose monitoring to evaluate daily glycemic profiles and response 3

Important Caveats

• The combination of imeglimin with DPP-4 inhibitors has been studied primarily in Japanese populations; efficacy may differ in other ethnic groups 1
• Current major diabetes guidelines (ADA, ESC, KDIGO) do not yet include specific recommendations for imeglimin use 5
• Consider cost implications, as newer agents like imeglimin may be more expensive than established therapies