Chen Baixing, Huang Mingling, Pu Bin, Dong Hang
Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Front Pharmacol. 2024 Sep 17;15:1401103. doi: 10.3389/fphar.2024.1401103. eCollection 2024.
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.
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.
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.
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.
虽然钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂在控制糖尿病和降低心血管风险方面有效，但人们对其与下肢并发症（包括骨髓炎、溃疡和外周动脉疾病（PAD））之间的关联仍存在担忧。本研究采用孟德尔随机化（MR）方法来评估SGLT2抑制剂与这些下肢安全性结局之间的因果关系。
采用两样本药物-靶点MR方法，并辅以单样本MR和基因关联分析。选择六个单核苷酸多态性（SNP）作为工具变量来代表SGLT2抑制的作用。主要结局为主要肢体安全性结局，包括骨髓炎、下肢溃疡、PAD和蜂窝织炎。主要分析方法为广义逆方差加权（IVW）方法以及多项敏感性分析。
MR分析表明，基因代表的SGLT2抑制与大多数研究的下肢安全性结局之间无显著因果关联。然而，观察到与PAD存在显著关联，由于IVW和MR-Egger结果之间存在差异，需要谨慎解释。敏感性分析支持了这些发现，几乎没有异质性或定向多效性的证据。
本研究表明，SGLT2抑制剂可能与2型糖尿病患者大多数下肢安全性结局（包括骨髓炎、下肢溃疡和蜂窝织炎）风险增加无显著关联。然而，与PAD的复杂关系凸显了进一步研究的必要性。这些发现有助于理解SGLT2抑制剂的安全性概况，支持其在糖尿病管理中的持续使用，同时强调持续安全监测的重要性。
