Can ertugliflozin (SGLT2 inhibitor) cause liver enzyme elevations and do they return to normal after stopping the medication?

Ertugliflozin and Liver Enzyme Elevations

Yes, ertugliflozin can cause liver enzyme elevations, and these elevations typically return to normal after discontinuation of the medication.

Effect of Ertugliflozin on Liver Enzymes

• Ertugliflozin treatment is associated with elevations in liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), though these elevations are generally mild and transient 1
• In a post-hoc pooled analysis of seven phase 3 trials, ertugliflozin actually showed a reduction in liver enzyme levels compared to non-ertugliflozin treatments after 52 weeks 1
• The effects on liver enzymes appear to be dose-dependent, with ertugliflozin 15 mg showing slightly greater reductions in liver enzymes than the 5 mg dose 1

Normalization After Discontinuation

• When liver enzyme elevations occur with SGLT2 inhibitors like ertugliflozin, they typically resolve within 1-4 months after discontinuation of the medication 2
• Similar to other medications that can affect liver function, the normalization of enzymes follows a predictable pattern after removing the causative agent 2

Monitoring Recommendations

• For patients taking ertugliflozin who develop elevated liver enzymes, the following approach is recommended:
  • If liver enzymes increase to ≥3 times the upper limit of normal (ULN), hold ertugliflozin and repeat liver function tests within 48-72 hours 2
  • Assess for other potential causes of liver enzyme elevation (other medications, alcohol consumption, etc.) 2
  • If liver enzymes remain elevated or worsen, permanently discontinue ertugliflozin unless another explanation for liver injury is identified 2
  • If liver enzymes stabilize or improve and another cause is identified, ertugliflozin may be reinitiated with frequent monitoring 2

Risk Factors and Considerations

• Moderate hepatic impairment does not significantly affect the pharmacokinetics of ertugliflozin, with only a small decrease (13%) in AUC relative to subjects with normal hepatic function 3
• No dose adjustment is required for patients with mild to moderate hepatic impairment based on pharmacokinetic studies 4, 3
• Patients with pre-existing liver conditions, particularly those with non-alcoholic fatty liver disease (NAFLD), may actually benefit from ertugliflozin treatment, as it has been shown to improve liver fat content and liver enzyme profiles in these patients 5, 6

Comparative Effects with Other SGLT2 Inhibitors

• The effects of ertugliflozin on liver enzymes appear to be consistent with the SGLT2 inhibitor class 6
• In patients with type 2 diabetes and NAFLD, SGLT2 inhibitors including ertugliflozin have shown improvements in serum liver enzymes (ALT, AST, GGT) 6

Clinical Implications

• When liver enzyme elevations occur with ertugliflozin, the decision to continue or discontinue the medication should be based on:
  • The magnitude of enzyme elevation (≥3× ULN warrants holding the medication) 2
  • The presence of symptoms suggesting liver injury (fatigue, nausea, right upper quadrant pain, jaundice) 2
  • The availability of alternative glucose-lowering medications 2
• For patients who develop significant liver enzyme elevations on ertugliflozin, switching to a GLP-1 receptor agonist may be appropriate, especially in patients with eGFR <20 mL/min/1.73 m² 2

In conclusion, while ertugliflozin can cause liver enzyme elevations, these are generally mild, and the evidence suggests that discontinuation of the medication allows for normalization of these enzymes within 1-4 months in most cases.