Elafibranor Side Effects
Primary Side Effect: Reversible Serum Creatinine Elevation
Elafibranor causes a mild, reversible increase in serum creatinine that is the most clinically significant adverse effect, with an average increase of 4.31 ± 1.19 μmol/L compared to placebo, which may limit its use in patients with concurrent renal disease. 1, 2
Common and Well-Tolerated Profile
The drug demonstrates a generally favorable safety profile in clinical trials:
- No weight gain occurs with elafibranor treatment, distinguishing it from other PPAR agonists like thiazolidinediones 1
- No cardiac events were observed in clinical trials, contrasting with concerns seen with other PPAR modulators 1
- The medication was well tolerated overall in the phase 2b trial involving 276 patients treated for 52 weeks 1
Metabolic and Lipid Effects
Elafibranor produces beneficial rather than adverse metabolic changes:
- Significantly reduces liver enzymes (ALT, GGT, ALP) 3
- Improves lipid profiles by reducing total cholesterol, triglycerides, and LDL cholesterol 1, 3
- Reduces markers of systemic inflammation 1
- Improves glucose profiles without causing hypoglycemia 1
Renal Considerations and Monitoring
The serum creatinine elevation requires specific clinical attention:
- The increase is mild and reversible upon discontinuation 1, 2
- This effect potentially limits use in patients with pre-existing renal disease 2
- Regular monitoring of renal function is essential during treatment 2
- The mechanism appears related to PPAR-mediated effects on renal hemodynamics rather than direct nephrotoxicity 1
Clinical Trial Discontinuation Context
The RESOLVE-IT phase 3 trial of elafibranor in NASH patients with stages 1-3 liver fibrosis failed to demonstrate therapeutic efficacy in interim results, leading to discontinuation of drug development. 4 This discontinuation was due to lack of efficacy rather than safety concerns, as the drug was well tolerated throughout clinical development 1, 2
Comparison to Other PPAR Agonists
Unlike thiazolidinediones (pioglitazone, rosiglitazone):
- Elafibranor does not cause fluid retention 1
- Does not cause weight gain (thiazolidinediones cause average 4 kg increase) 4, 1
- Does not exacerbate heart failure (major concern with thiazolidinediones) 4
- Does not increase cardiovascular mortality (concern with sulfonylureas and rosiglitazone) 4
Critical Clinical Pitfall to Avoid
Do not use elafibranor in patients with moderate to severe chronic kidney disease (CKD stage 3b or higher) without careful consideration and close monitoring, as the reversible creatinine elevation may complicate management and assessment of underlying renal function 2.