Is Imeglimin Safe in Diabetic Kidney Disease?
Imeglimin is safe in diabetic kidney disease with appropriate dose adjustment: use 1000 mg twice daily for eGFR ≥45 mL/min/1.73 m², reduce to 500 mg twice daily for eGFR 15-45 mL/min/1.73 m², and consider 500 mg with extended dosing intervals for eGFR <15 mL/min/1.73 m².
Evidence for Safety in Renal Impairment
Imeglimin has been specifically studied in patients with impaired renal function, demonstrating a favorable safety profile across the spectrum of chronic kidney disease 1, 2. The drug is primarily excreted unchanged by the kidneys, making renal function the key determinant of dosing 1, 2.
Pharmacokinetic Data Supporting Safety
In a phase 1 study of Japanese patients with varying degrees of renal impairment (eGFR 15 to >90 mL/min/1.73 m²), no adverse events were observed after single-dose administration 1.
Population pharmacokinetic analysis including patients with mild to severe CKD (eGFR >14 mL/min/1.73 m²) confirmed that plasma exposure increases predictably with declining renal function, allowing for rational dose adjustment 2.
The increase in plasma concentration and AUC in patients with moderate and severe renal impairment is directly related to decreased renal clearance, not to unexpected toxicity 1.
Dosing Algorithm by Renal Function
For eGFR ≥45 mL/min/1.73 m²:
For eGFR 15-45 mL/min/1.73 m²:
- Reduced dose: 500 mg twice daily 2
- This adjustment maintains comparable plasma exposure to standard dosing in patients with normal renal function 2
For eGFR <15 mL/min/1.73 m²:
- Consider 500 mg with longer dosing intervals 2
- Limited data exist in this population, requiring careful monitoring 2
Clinical Efficacy in CKD Populations
Meta-analysis demonstrated that imeglimin efficacy is maintained regardless of chronic kidney disease category 3.
Subgroup analysis showed a trend toward improved efficacy in patients with lower body mass index and in Japanese populations 3.
Imeglimin significantly improved HbA1c at doses ≥1000 mg twice daily as monotherapy (WMD -0.714% at 1000 mg, p<0.001) and as adjunctive therapy (WMD -0.600% at 1000 mg, p<0.001) 3.
Safety and Tolerability Profile
No significant differences were found between imeglimin and placebo in the risk of all-cause discontinuation or the proportion of patients experiencing at least one adverse event 3.
Imeglimin was safe and well tolerated across all renal function categories studied 1, 3.
The drug's mechanism of targeting mitochondrial bioenergetics may provide additional renal protection by reducing oxidative stress and improving mitochondrial dynamics, similar to metformin and SGLT2 inhibitors 4.
Critical Monitoring Parameters
Assess eGFR before initiating imeglimin and periodically thereafter to guide dose adjustments 1, 2.
Monitor for changes in renal function, particularly when eGFR approaches threshold values requiring dose modification 2.
In patients with moderate hepatic impairment, plasma exposure increases by 1.5-fold, but this is not considered clinically meaningful and does not require dose adjustment 5.
Comparison to Guideline-Recommended Agents
While current diabetes and CKD guidelines prioritize SGLT2 inhibitors (for eGFR ≥20 mL/min/1.73 m²) and GLP-1 receptor agonists as first-line agents for cardiovascular and renal protection 6, imeglimin represents a safe alternative or adjunctive option when these agents are contraindicated, not tolerated, or insufficient for glycemic control 3. Unlike SGLT2 inhibitors, which have specific contraindications and require sick-day management protocols 6, 7, imeglimin has a simpler safety profile with straightforward renal dose adjustment 1, 2.