Reports of Lactic Acidosis Attributed to Metformin, 2015-2018

Area of Science:

• Pharmacovigilance
• Nephrology
• Clinical Pharmacology

Background:

• In 2016, the U.S. Food and Drug Administration (FDA) updated metformin labeling, allowing its use in patients with mild-moderate chronic kidney disease.
• This change prompted an investigation into potential associations with metformin-associated lactic acidosis (MALA).

Observation:

• Analysis of FDA Adverse Event Reporting System (FAERS) data revealed an increase in MALA reports from 2015 to 2018.
• A subset of U.S. reports showed a less pronounced increase.
• The proportionate reporting ratio (PRR) for MALA remained stable, indicating no significant change relative to other adverse events.

Findings:

• While overall MALA reports surged, the stable PRR suggests the increase may be influenced by reporting biases rather than a true rise in MALA incidence.
• Limitations of the FAERS database, such as the absence of a denominator and control group, preclude definitive conclusions about increased MALA rates.

Implications:

• The stability of the PRR suggests that current pharmacovigilance systems may not accurately reflect changes in MALA incidence following label revisions.
• Further investigation using more robust data sources is crucial to ascertain the actual impact of the 2016 FDA label change on MALA rates.
• These findings highlight the importance of critically evaluating adverse event reporting data and the need for comprehensive post-marketing surveillance.