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.
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 . 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).
- 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.