Advertisement

Influence of left ventricular ejection fraction on the reduction in N-terminal pro-brain natriuretic peptide by canagliflozin in patients with heart failure and type 2 diabetes: A sub analysis of the CANDLE trial

Published:December 14, 2022DOI:https://doi.org/10.1016/j.jjcc.2022.11.012

      Highlights

      • Baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) levels affected the extent of its decrease by canagliflozin.
      • Decrease in NT-proBNP levels was prominent in patients with a higher left ventricular ejection fraction (LVEF).
      • Baseline LVEF confounded those changes after adjusting for baseline NT-proBNP levels.

      Abstract

      Aim

      To investigate the effect of left ventricular ejection fraction (LVEF) on the behavior of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with heart failure and type 2 diabetes mellitus with the use of canagliflozin compared to glimepiride.

      Methods

      Patients (n = 233) from the CANDLE trial were randomly assigned to either the add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The patients were followed-up for 24 weeks. The NT-proBNP levels were measured at baseline and after 24 weeks. The LVEF was determined at baseline.

      Results

      There was a significant relationship between the baseline NT-proBNP level (X1) and the change in NT-proBNP levels from baseline to 24 weeks (Y) in the canagliflozin group (Y = −0.533 × X1 + 178; r = −0.860, p < 0.001). However, this relationship was not observed in the glimepiride group (p = 0.428). The baseline LVEF (X2) correlated with Y with a marginal significance in the canagliflozin group (Y = 7.72 × X2–549; r = 0.192, p = 0.054), but no relationship was observed in the glimepiride group. In the canagliflozin group, bivariate regression analysis showed a significant correlation between Y, X1, and X2; Y = −0.567 × X1–6.04 × X2 + 542 (R = 0.871, p < 0.001). The partial regression coefficients of X1 (p < 0.001) and X2 (p = 0.006) significantly explained the variance in Y. The correlation coefficient for X2 was negative. There was a significant relationship between the logarithmically transformed NT-proBNP [ln(NT-proBNP)] at baseline (X1′) and the change in ln(NT-proBNP) values from baseline to 24 weeks (Y′), a surrogate of the rate of change in NT-proBNP levels, in the canagliflozin group (Y′ = −0.18 × X1′ + 0.93; r = 0.450, p = 0.001).

      Conclusions

      The baseline NT-proBNP level significantly affected the extent and the rate of its decrease by canagliflozin. The reduction in NT-proBNP levels by canagliflozin was prominent in patients with a higher LVEF at baseline. However, its confounding effect of LVEF on canagliflozin treatment was not recognized without adjusting for the NT-proBNP level at baseline.

      Graphical abstract

      Abbreviations:

      DM (diabetes mellitus), HF (heart failure), HFpEF (heart failure with preserved ejection fraction), HFrEF (heart failure with reduced ejectionfraction), LV (left ventricular), LVEF (left ventricular ejection fraction), NT-proBNP (N-terminal pro-brain natriuretic peptide), SGLT2 (sodium-glucose cotransporter 2)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • de Zeeuw D.
        • Fulcher G.
        • Erondu N.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Packer M.
        • Anker S.D.
        • Butler J.
        • Filippatos G.
        • Pocock S.J.
        • Carson P.
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • Køber L.
        • Kosiborod M.N.
        • Martinez F.A.
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Anker S.D.
        • Butler J.
        • Filippatos G.
        • Ferreira J.P.
        • Bocchi E.
        • Böhm M.
        • et al.
        Empagliflozin in heart failure with a preserved ejection fraction.
        N Engl J Med. 2021; 385: 1451-1461
        • Butt J.H.
        • Adamson C.
        • Docherty K.F.
        • de Boer R.A.
        • Petrie M.C.
        • Inzucchi S.E.
        • et al.
        Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to N-terminal pro-B-type natriuretic peptide: insights from the DAPA-HF Trial.
        Circ Heart Fail. 2021; 14e008837
        • Januzzi Jr., J.L.
        • Zannad F.
        • Anker S.D.
        • Butler J.
        • Filippatos G.
        • Pocock S.J.
        • et al.
        Prognostic importance of NT-proBNP and effect of empagliflozin in the EMPEROR-Reduced Trial.
        J Am Coll Cardiol. 2021; 78: 1321-1332
        • Rådholm K.
        • Figtree G.
        • Perkovic V.
        • Solomon S.D.
        • Mahaffey K.W.
        • de Zeeuw D.
        • et al.
        Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS Program.
        Circulation. 2018; 138: 458-468
        • Januzzi Jr., J.L.
        • Butler J.
        • Zannad F.
        • Filippatos G.
        • Ferreira J.P.
        • Pocock S.J.
        • et al.
        Prognostic implications of N-terminal pro-B type natriuretic peptide and high-sensitivity cardiac troponin T in EMPEROR-Preserved.
        JACC Heart Fail. 2022; 10: 512-524
        • Januzzi Jr., J.L.
        • Xu J.
        • Li J.W.
        • Shaw W.
        • Oh R.
        • Pfeifer M.
        • et al.
        Effects of canagliflozin on amino-terminal pro-B-type natriuretic peptide: implications for cardiovascular risk reduction.
        J Am Coll Cardiol. 2020; 76: 2076-2085
        • Zhou H.
        • Peng W.
        • Li F.
        • Wang Y.
        • Wang B.
        • Ding Y.
        • et al.
        Effect of sodium-glucose cotransporter 2 inhibitors for heart failure with preserved ejection fraction: a systematic review and meta-analysis of randomized clinical trials.
        Front Cardiovasc Med. 2022; 9875327
        • Tanaka A.
        • Hisauchi I.
        • Taguchi I.
        • Sezai A.
        • Toyoda S.
        • Tomiyama H.
        • et al.
        Effects of canagliflozin in patients with type 2 diabetes and chronic heart failure: a randomized trial (CANDLE).
        ESC Heart Fail. 2020; 7: 1585-1594
        • Tanaka A.
        • Inoue T.
        • Kitakaze M.
        • Oyama J.
        • Sata M.
        • Taguchi I.
        • et al.
        Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial.
        Cardiovasc Diabetol. 2016; 15: 57
        • Iwanaga Y.
        • Nishi I.
        • Furuichi S.
        • Noguchi T.
        • Sase K.
        • Kihara Y.
        • et al.
        B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure.
        J Am Coll Cardiol. 2006; 47: 742-748
        • Grossman W.
        • Jones D.
        • McLaurin L.P.
        Wall stress and patterns of hypertrophy in the human left ventricle.
        J Clin Invest. 1975; 56: 56-64
        • Douglas P.S.
        • Reichek N.
        • Plappert T.
        • Muhammad A.
        • Sutton St John
        • MG
        Comparison of echocardiographic methods for assessment of left ventricular shortening and wall stress.
        J Am Coll Cardiol. 1987; 9: 945-951
        • Ueda T.
        • Kasama S.
        • Yamamoto M.
        • Nakano T.
        • Ueshima K.
        • Morikawa Y.
        • et al.
        Effect of the sodium-glucose cotransporter 2 inhibitor canagliflozin for heart failure with preserved ejection fraction in patients with type 2 diabetes.
        Circ Rep. 2021; 3: 440-448
        • Lee M.M.Y.
        • Brooksbank K.J.M.
        • Wetherall K.
        • Mangion K.
        • Roditi G.
        • Campbell R.T.
        • et al.
        Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF).
        Circulation. 2021; 143: 516-525