Fig. 6: Reno-protective medication is associated with reduced circulating TMAO in MetaCardis participants with T2D.

A Swarm plots of impact on model eGFR predictions (SHAP values) for MetaCardis T2D individuals (N = 561) for the top 15 drugs, as determined by xgboost algorithms trained exclusively on prescribed medication. Mean absolute SHAP values from participants with T2D are shown (in descending order) next to each variable. Individual dots, representing each participant, are colored by the inverse-normalized value of the corresponding drug variable. B Comparison of circulating regularized TMAO levels between subjects with T2D prescribed GLP-1 receptor agonists (GLP-1Ras; N = 59) and non-GLP-1Ras treated subjects with T2D propensity-matched for age, sex, disease group, and hypertension status (N = 59) (Supplementary Table 6 for group characteristics). P value determined by two-sided Mann–Whitney U test. Center lines denote medians, box limits indicate the 25th and 75th percentiles, whiskers extend to the minimal and maximal values. C Summary of the main findings of our study. We demonstrate that eGFR, irrespective of disease stage, is the primary modifiable modulator of circulating TMAO. Far from being a bystander, TMAO significantly accelerates the rate of renal output decline by age, with its effect increasing at advanced stages of disease. TMAO promotes renal fibrosis in conjunction with established pathophysiology (two-hit” model) further negatively impacting renal clearance. Accordingly, medication with reno-protective properties (red arrows), such as GLP-1RAs, reduce circulating TMAO levels thereby potentially moderating its adverse effect on kidney function. Source data are provided as a Source Data file.