Physicians' Academy for Cardiovascular Education

SGLT2i attenuates longitudinal rises in CV biomarkers in T2DM patients

Stress Cardiac Biomarkers, Cardiovascular and Renal Outcomes, and Response to Canagliflozin

Literature - Vaduganathan M, Sattar N, Xu J, et al. - J Am Coll Cardiol. 2022 Feb 8;79(5):432-444. doi: 10.1016/j.jacc.2021.11.027

Introduction and methods


Patients with DM can be efficiently stratified by their risk of future CV events using CV biomarkers for different pathophysiological processes [1]. These biomarkers—either measured alone or in combination—have been projected to identify at-risk persons who may gain greater absolute treatment benefits from SGLT2is [1].

The CANVAS (CANagliflozin cardio-Vascular Assessment Study) trial was a CV outcomes study in which the effect of canagliflozin in T2DM patients with and without established CVD was evaluated [2]. A diverse panel of biomarkers targeting different axes of risk and pathophysiological abnormalities was assessed in the CANVAS biomarker substudy.

Aim of the study

The primary aims of the CANVAS biomarker substudy were: (1) to examine the effect of canagliflozin on the trajectory of 3 biomarkers for up to 6 years, (2) to analyze the association of baseline measurement of these biomarkers (either alone or collectively) with adverse CV and renal outcomes, and (3) to determine whether the treatment benefits of canagliflozin are modified by baseline levels of these biomarkers.


The CANVAS biomarker substudy was a post-hoc analysis of the CANVAS trial. In this RCT, 4330 T2DM patients with eGFR >30 mL/min per 1.73 m2 and high CVD risk were randomized (1:1:1 ratio) to canagliflozin 100 mg or 300 mg or placebo and followed for up to 6 years. In the substudy, the following biomarkers were studied: high-sensitivity cardiac troponin T (hs-cTnT; marker of myocardial injury), soluble suppression of tumorigenesis-2 (sST2; marker of vascular congestion, tissue inflammation, and fibrosis), and insulin-like growth factor–binding protein 7 (IGFBP7; marker of tissue senescence and remodeling). Availability of baseline measurements of these 3 biomarkers ranged from 71% to 83% of the participants.


The primary endpoint of the CANVAS trial was the occurrence of MACE (composite of CV death, non-fatal MI, and non-fatal stroke). Secondary endpoints included all-cause mortality, CV death, and a composite outcome of CV death or HF hospitalization. The renal composite endpoint comprised eGFR decrease ≥40%, need for kidney replacement therapy, or renal death. The additional renal composite endpoint included all of these components plus CV death.

Main results

Effect of canagliflozin on biomarker trajectory

Association of baseline biomarker level with CV and renal outcomes

Modification of canagliflozin treatment benefits by baseline biomarker levels


In this longitudinal study, canagliflozin delayed the increase in hs-cTnT and sST2 levels compared with placebo for up to 6 years. This treatment also reduced the incidence of HF and kidney disease events regardless of the baseline concentrations of the studied biomarkers. Based on their study results, the authors believe “there is a potential future role of biomarkers in more accurate risk stratification and identification of [T2DM] patients who stand to benefit from cardioprotective therapies.”


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Find this article online at J Am Coll Cardiol.

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