Mediators of ertugliflozin effects on heart failure and kidney outcomes among patients with type 2 diabetes mellitus

Matthew W. Segar, Ahmed A. Kolkailah, Robert Frederich, Annpey Pong, Christopher P. Cannon, Francesco Cosentino, Samuel Dagogo-Jack, Darren K. McGuire, Richard E. Pratley, Chih Chin Liu, Mario Maldonado, Jie Liu, Nilo B. Cater, Ambarish Pandey, David Z.I. Cherney

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Aims: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of hospitalization for heart failure (HHF) and composite kidney outcomes, but the mediators underlying these benefits are unknown. Materials and methods: Among participants from VERTIS CV, a trial of patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease randomized to ertugliflozin versus placebo, Cox proportional hazards regression models were used to evaluate the percentage mediation of ertugliflozin efficacy on the first HHF and kidney composite outcome 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. Results: 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 as mediators of ertugliflozin effects on the risk of HHF. Similar results were observed for the composite kidney outcome, with early changes in four biomarkers (glycated haemoglobin, haemoglobin, haematocrit and urate), and average changes in five biomarkers [early biomarkers (not glycated haemoglobin) + weight, serum albumin] mediating the effects of ertugliflozin on the kidney outcome. Conclusions: 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. identifier: NCT01986881.

Original languageEnglish (US)
Pages (from-to)1829-1839
Number of pages11
JournalDiabetes, Obesity and Metabolism
Issue number9
StatePublished - Sep 2022


  • Ertugliflozin
  • SGLT2 inhibitor
  • hospitalization for heart failure
  • kidney outcomes
  • mediation analyses
  • type 2 diabetes mellitus

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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