Sodium-glucose cotransporter 2 inhibitors and constipation: a two-sample mendelian randomization study

Objective Evidence regarding the effect of sodium-glucose cotransporter 2 (SGLT-2) inhibition on constipation is conflicting and the underlying mechanism unknown. We aimed to investigate the causal effect of SGLT-2 inhibition on constipation and the potential mediating role of circulating metabolites. Methods We conducted a two-sample Mendelian randomization (MR) study. Genetic instruments for SGLT-2 inhibition were constructed from variants associated with SLC5A2 gene expression and glycated hemoglobin (HbA1c) levels. Summary-level data for constipation and 452 circulating metabolites were obtained from large-scale genome-wide association studies (GWAS). The primary analysis used the inverse-variance weighted method, supplemented by extensive sensitivity analyses. A two-step MR approach was applied to quantify mediation. Results Genetically proxied SGLT-2 inhibition was associated with a reduced risk of constipation (OR 0.31, 95% CI 0.19–0.53, P < 0.0001). Of the 452 metabolites examined, DSGEGDFXAEGGGVR was significantly associated with both SGLT-2 inhibition and constipation. Mediation analysis indicated that DSGEGDFXAEGGGVR significantly mediated 22.76% of the protective effect. Conclusion This study provides genetic support for a causal relationship between SGLT-2 inhibition and reduced constipation risk, and identifies DSGEGDFXAEGGGVR as a potential mediating metabolite. These findings offer insights into a possible pharmacological pathway that may inform future approaches to constipation management.