Mediators of ertugliflozin effects on heart failure and kidn
SGLT2 inhibitors have been shown to reduce risk of hospitalization for heart failure (HHF) and composite kidney outcomes, but the mediators underlying these benefits are unknown.

Among participants from VERTIS CV, a trial of patients with type 2 diabetes and atherosclerotic cardiovascular disease randomized to ertugliflozin versus placebo, Cox proportional hazards regression models were used to evaluate the percent mediation of ertugliflozin efficacy on first HHF and kidney composite outcome between changes during the trial in 26 potential mediators. Time-dependent approaches were used to evaluate associations between early (change from baseline to the first post-baseline measurement) and average (weighted average of change from baseline using all post-baseline measurements) changes in covariates with clinical outcomes.

For the HHF analyses, early changes in four biomarkers (haemoglobin, haematocrit, serum albumin, and urate) and average changes in seven biomarkers (early biomarkers + weight, chloride, and serum protein) were identified as fulfilling the criteria for mediators of ertugliflozin HHF efficacy. Similar results were observed for the composite kidney outcome, with early changes in four biomarkers (HbA1c, haemoglobin, haematocrit, and urate), and average changes in five biomarkers (early biomarkers [not HbA1c] + weight, serum albumin) mediating the effects of ertugliflozin on the kidney outcome.

In these analyses from the VERTIS CV trial, markers of volume status and haemoconcentration and/or haematopoiesis were the strongest mediators of the effect of ertugliflozin on reducing risk of HHF and composite kidney outcomes in the early and average change periods.