Potential drug-drug interaction between sodium-glucose co-transporter 2 inhibitors and statins: pharmacological and clinical evidence

ABSTRACT

Introduction

Recent case reports suggested that concomitant use of sodium-glucose co-transporter 2 (SGLT2) inhibitors with statins could lead to increased statin toxicity. We provide a comprehensive overview of the available pharmacological and clinical evidence on this potential drug–drug interaction (DDI).

Areas covered

We searched MEDLINE PubMed until November 2020 for (i) pharmacokinetic studies on SGLT2 inhibitors, statins, and their potential interaction, and (ii) case reports and clinical studies assessing the safety of concomitant use of SGLT2 inhibitors and statins. We also searched regulatory documents submitted to the United States Food and Drug Administration for unpublished data on this potential DDI.

Expert opinion

SGLT2 inhibitors are increasingly used for type 2 diabetes, chronic heart failure, and chronic kidney disease, and concomitant use with statins is common given the comorbidity of indications. While pharmacokinetic studies in healthy subjects showed no clinically relevant changes in statin levels during SGLT2 inhibitor co-administration, the published case reports and pharmacologic reasoning support the possibility of an interaction. Underlying mechanisms could be pharmacokinetic or pharmacodynamic, and canagliflozin appears to be the SGLT2 inhibitor with the highest interaction potential. Further research including ‘real-world’ pharmacoepidemiologic studies is needed to better understand the clinical significance of this DDI.

KEYWORDS:

• Drug–drug interaction
• pharmacology
• sodium-glucose co-transporter 2 inhibitors
• clinical evidence

Article highlights

• Pharmacokinetic studies conducted among healthy subjects have shown no clinically relevant increases in statin levels upon co-administration of sodium-glucose co-transporter 2 (SGLT2) inhibitors.

• Three recent case reports described the occurrence of muscle-related adverse effects ranging from myopathy to rhabdomyolysis in patients initiating SGLT2 inhibitors while being exposed to statins.

• Potential underlying mechanisms are mostly pharmacokinetic and include interactions between SGLT2 inhibitors and statins through permeability glycoprotein, breast cancer resistance protein, and organic anion transporting polypeptides.

• A hypothesized pharmacodynamic mechanism could involve enhancement of statin-induced myopathy via SGLT2 inhibitor-related sarcopenia.

• Large pharmacoepidemiologic studies are needed to better understand the safety of the interaction between SGLT2 inhibitors and statins.

This box summarizes key points contained in the article.

Acknowledgments

Dr. Douros is the recipient of Chercheur-Boursier Junior 1 Award from the Fonds de recherche du Québec – santé (FRQS).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.