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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1401103

Impact of SGLT2 Inhibitors on Lower Limb Complications: A Mendelian Randomization Perspective

Provisionally accepted
Baixing Chen Baixing Chen 1Mingling Huang Mingling Huang 2Bin Pu Bin Pu 3Hang Dong Hang Dong 4*
  • 1 Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Flemish Brabant, Belgium
  • 2 Department of Diabetes, Central Clinical School, Monash University, Victoria, Australia
  • 3 Suining City Traditional Chinese Medicine Hospital, Sichuan, China
  • 4 Department of Orthopaedics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong, China

The final, formatted version of the article will be published soon.

    Background: While Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective in managing diabetes and reducing cardiovascular risk, concerns about their association with lower limb complications, including, osteomyelitis, ulcers, and peripheral artery disease (PAD), persist. This study employs Mendelian Randomization (MR) to assess the causal relationship between SGLT2 inhibitors and these lower limb safety outcomes.Methods: A two-sample drug-target MR approach was used, complemented by a one-sample MR and genetic association analysis. Six SNPs were selected as instrumental variables to proxy the effect of SGLT2 inhibition. Primary outcomes were major limb safety outcomes, including osteomyelitis, lower limb ulcers, PAD, and cellulitis. The primary analytical method was the generalized inverse variance-weighted (IVW) approach, along with several sensitivity analyses.Results: The MR analysis indicated no significant causal association between genetically proxied SGLT2 inhibition and most of the studied lower limb safety outcomes. However, a significant association with PAD was observed, necessitating careful interpretation due to discrepancies between IVW and MR-Egger results. Sensitivity analyses supported these findings, showing little evidence of heterogeneity or directional pleiotropy.Conclusions: This study suggests that SGLT2 inhibitors may not be significantly associated with an increased risk of most lower limb safety outcomes, including osteomyelitis, lower limb ulcers, and cellulitis, in patients with type 2 diabetes. However, the complex relationship with PAD highlights the need for further research. These findings contribute to the understanding of the safety profile of SGLT2 inhibitors, supporting their continued use in diabetes management while underlining the importance of continuous safety monitoring.

    Keywords: SGLT2 inhibition, Osteomyelitis, peripheral artery disease, Ulcers, Cellulitis, Mendelian randomization

    Received: 14 Mar 2024; Accepted: 06 Sep 2024.

    Copyright: © 2024 Chen, Huang, Pu and Dong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Hang Dong, Department of Orthopaedics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.