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Effects of Canagliflozin on Amino-Terminal Pro-B-Type Natriuretic Peptide: Implications for Cardiovascular Risk
James L Januzzi1, Jialin Xu2, JingWei Li3
1Massachusetts General Hospital and Baim Institute for Clinical Research, Boston, Massachusetts.
Insights
Canagliflozin effectively lowers amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients with type 2 diabetes. While NT-proBNP reduction is linked to reduced heart failure hospitalizations, it only partially explains canagliflozin
Area of Science:
- Cardiology
- Endocrinology
- Pharmacology
Background:
- Elevated amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is linked to heart failure (HF) diagnosis and cardiovascular risk.
- Canagliflozin is known to reduce cardiovascular events, including hospitalization for heart failure (HHF), in patients with type 2 diabetes.
Purpose of the Study:
- To measure NT-proBNP levels in participants of the CANagliflozin cardioVascular Assessment Study (CANVAS).
- To investigate the association between baseline NT-proBNP and cardiovascular, renal, and mortality outcomes.
- To determine the impact of canagliflozin intervention on NT-proBNP levels and its relation to cardiovascular outcomes.
Main Methods:
- NT-proBNP levels were measured at baseline, 1 year, and 6 years in a subset of CANVAS trial participants.
- Associations between baseline NT-proBNP and various outcomes were analyzed using adjusted models.
- Mediation analyses were performed to assess the proportion of canagliflozin's effect on HHF explained by NT-proBNP reduction.
Main Results:
- A significant percentage of participants had elevated baseline NT-proBNP (median 91 pg/ml, 39.3% ≥125 pg/ml).
- Canagliflozin significantly reduced NT-proBNP by 11% at 1 year compared to placebo (p < 0.001), an effect sustained at 6 years.
- Elevated baseline NT-proBNP (≥125 pg/ml) was a strong predictor of HHF (HR: 5.40), HHF/cardiovascular death (HR: 3.52), and all-cause death (HR: 2.53).
Conclusions:
- Many patients in the CANVAS trial exhibited elevated NT-proBNP levels.
- Canagliflozin demonstrated a significant reduction in NT-proBNP compared to placebo.
- The reduction in NT-proBNP by canagliflozin accounted for only a small portion of the drug's overall benefit in reducing heart failure events.
Background:
Canagliflozin reduces cardiovascular events including hospitalization for heart failure (HHF) in patients with type 2 diabetes and cardiovascular risk. Elevated amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations are associated with HF diagnosis and predict cardiovascular risk.
Objectives:
The purpose of this study was to measure NT-proBNP in CANVAS (Canagliflozin Cardiovascular Assessment Study) participants.
Methods:
Associations between baseline NT-proBNP and cardiovascular, renal, and mortality outcomes and intervention-associated changes were determined.
Results:
Of the 4,330 participants in the CANVAS trial, NT-proBNP was measured in 3,587, 2,918, and 995 participants at baseline, 1 year, and 6 years, respectively. The median baseline NT-proBNP concentration was 91 pg/ml, and 39.3% had NT-proBNP ≥125 pg/ml. NT-proBNP was higher in those with investigator-reported HF (13% of participants at baseline) versus those without (187 pg/ml vs. 81 pg/ml), with substantial overlap between groups. By 1 year, NT-proBNP increased with placebo, whereas canagliflozin reduced NT-proBNP by 11% (geometric mean ratio for canagliflozin vs. placebo = 0.89 [95% confidence interval (CI): 0.84 to 0.94]; p < 0.001). Lower NT-proBNP with canagliflozin was also observed at 6 years (p = 0.004). In adjusted models, baseline NT-proBNP ≥125 pg/ml was prognostic for incident HHF (hazard ratio [HR]: 5.40; 95% CI: 2.67 to 10.9), HHF/cardiovascular death (HR: 3.52; 95% CI: 2.38 to 5.20), and all-cause death (HR: 2.53; 95% CI: 1.78 to 3.61). Mediation analyses suggested that 10.4% of the effects of canagliflozin on HHF were reflected in NT-proBNP lowering.
Conclusions:
A substantial percentage of patients in the CANVAS trial had elevated NT-proBNP values. Canagliflozin reduced NT-proBNP concentrations versus placebo; however, reduction in NT-proBNP explained only a small proportion of the benefit of canagliflozin on HF events. (CANVAS [CANagliflozin cardioVascular Assessment Study]; NCT01032629).
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