NT-proBNP lowering by SGLT2 inhibitor explains small proportion of benefit on HF events

Effects of Canagliflozin on Amino-Terminal Pro-B-Type Natriuretic Peptide: Implications for Cardiovascular Risk Reduction.

Literature - Januzzi JL Jr, Xu J, Li J, et al. - J Am Coll Cardiol. 2020, 76:2076-85.doi: 10.1016/j.jacc.2020.09.004.

Introduction and methods

NT-proBNP is released from cardiomyocytes after myocardial stress and is associated with increased risk of heart failure and adverse cardiovascular events in patients with type 2 diabetes [1-4]. Despite the use of NT-proBNP concentration levels in trials with new therapies to determine the association with CV benefits, large-scale data assessing the positive effects of SGLT2 inhibitors on NT-proBNP and other biomarkers in T2DM patients are limited. A previous study reported that canagliflozin, a SGLT2 inhibitor, delayed the rise in serum NT-proBNP levels and troponin I compared to placebo [5]. However, this study lacked data to associate these findings to CV outcomes.

This post-hoc analysis assessed the effects of canagliflozin on NT-proBNP over a longer time period and determined whether NT-proBNP was a prognostic marker for CV, renal and mortality outcomes in T2DM patients participating in the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial.

Participants in the CANVAS trial had T2DM and a high risk for CV events. Patients that were included in the trial were ≥30 years of age and a history of symptomatic ASCVD or ≥50 years of age with ≥2 risk factors for CVD. All patients had to have an eGFR of >30 ml/min/1.73m². Participants were randomized (1:1:1) to 100 mg or 300 mg canagliflozin or placebo. The primary outcome was MACE, which was a composite of CV death, non-fatal MI, or non-fatal stroke. Secondary outcomes included hospitalization for HF, the composite of HF hospitalization or CV death, all-cause mortality, CV death, non-fatal stroke, non-fatal MI, and the renal composite endpoint comprised of a sustained 40% reduction in eGFR after ≥2 consecutive measurements, dialysis or kidney transplantation, or renal death. The median follow-up was 5.75 years (2.03-6.13 years). Outcome of interest for this subanalysis was serum NT-proBNP concentration, which was measured at baseline (n=3587), 1 year (n=2918), and 6 years (n=995).

Main results

  • Baseline NT-proBNP levels were higher in patients with an history of HF compared to patients without (187 pg/mL vs. 81 pg/mL).
  • Patients treated with canagliflozin had lower NT-proBNP serum levels at 1 and 6 years compared to patients receiving placebo. A base model adjusted for baseline covariates showed an 11% reduction in NT-proBNP serum concentration by canagliflozin in the first year of treatment compared to placebo (adjusted geometric mean: 0.89, 95% CI: 0.84-0.94, P<0.001).
  • Log-transformed NT-proBNP levels at baseline were significantly associated with higher adjusted risk of MACE, hospitalization for HF, hospitalization for HF or CV death, all-cause mortality, CV death, non-fatal stroke, non-fatal MI, and the renal composite endpoint. Adding 1-year NT-proBNP concentration to the baseline values did not improve the risk prognoses.
  • Baseline NT-proBNP was prognostic for CV outcomes when patients were divided into a high (≥125 pg/mL) and low (<125 pg/mL) NT-proBNP concentration group. Adding 1-year NT-proBNP data to the baseline values did not result in enhanced prognostication.
  • Treatment effect of canagliflozin was independent of baseline NT-proBNP concentration levels.
  • 10.4% Of the treatment effect of canagliflozin on hospitalization for HF was achieved by reduction NT-proBNP levels at 1 year (P value for indirect effect, P=0.048).


Although the SGLT2 inhibitor canagliflozin reduced NT-proBNP serum levels after 1 year in T2DM patients in the CANVAS trial, reduction in CV and renal outcomes were independent of baseline NT-proBNP levels. The reduction in NT-proBNP levels only explained a small part (~10%) of the effect of canagliflozin on hospitalization for HF.


1. Willeit P, Kaptoge S, Welsh P, et al. for the Natriuretic Peptides Studies Collaboration. Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant data meta-analysis. Lancet Diabetes Endocrinol 2016;4:840–9.

2. Januzzi JL Jr. The role of natriuretic peptide testing in guiding chronic heart failure management: review of available data and recommendations for use. Arch Cardiovasc Dis 2012;105: 40–50.

3. Betti I, Castelli G, Barchielli A, et al. The role of N-terminal PRO-brain natriuretic peptide and echocardiography for screening asymptomatic left ventricular dysfunction in a population at high risk for heart failure. The PROBE-HF study. J Card Fail 2009;15:377–84.

4. Huelsmann M, Neuhold S, Strunk G, et al. NTproBNP has a high negative predictive value to rule-out short-term cardiovascular events in patients with diabetes mellitus. Eur Heart J 2008; 29:2259–64.

5. Januzzi JL, Butler J, Jarolim P, et al. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. J Am Coll Cardiol 2017;70:704–12.

Find this article online at J. Am. Coll. Cardiol

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