Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial

James L Januzzi^{1

2}, Reza Mohebi¹, Yuxi Liu¹, Naveed Sattar³, Hiddo J L Heerspink⁴, Eshetu Tefera⁵, Muthiah Vaduganathan⁶, Javed Butler^{7

8}, Yshai Yavin⁵, Jingwei Li^{9

10

11}, Carol A Pollock¹², Vlado Perkovic^{11

13

14}, Bruce Neal^{11

15

16}, Michael K Hansen⁵

Affiliations

¹ Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston (J.L.J., R.M., Y.L.).
² Heart Failure and Biomarker Trials, Baim Institute for Clinical Research, Boston, MA (J.L.J.).
³ BHF Glasgow Cardiovascular Research Centre, University of Glasgow, UK (N.S.).
⁴ Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands (H.J.L.H.).
⁵ Janssen Research & Development, LLC, Spring House, PA (E.T., Y.Y., M.K.H.).
⁶ Cardiology Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (M.V.).
⁷ University of Mississippi Medical Center, Jackson (J.B.).
⁸ Baylor Scott & White Institute, Dallas, TX (J.B.).
⁹ Department of Cardiology, People's Liberation Army General Hospital, Beijing, China (J.L.).
¹⁰ Department of Cardiology, Xinqiao Hospital, Army Military Medical University, Chongqing, China (J.L.).
¹¹ The George Institute for Global Health (J.L., V.P., B.N.), UNSW Sydney, Australia.
¹² Kolling Institute, Royal North Shore Hospital University of Sydney, NSW, Australia (C.A.P.).
¹³ Faculty of Medicine (V.P.), UNSW Sydney, Australia.
¹⁴ The Royal North Shore Hospital, Sydney, Australia (V.P.).
¹⁵ Charles Perkins Centre, University of Sydney, NSW, Australia (B.N.).
¹⁶ Imperial College London, UK (B.N.).

PMID: 37603600
DOI: 10.1161/CIRCULATIONAHA.123.065251

Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial

James L Januzzi et al. Circulation. 2023.

. 2023 Aug 22;148(8):651-660.

doi: 10.1161/CIRCULATIONAHA.123.065251. Epub 2023 Aug 21.

Authors

Affiliations

¹ Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston (J.L.J., R.M., Y.L.).
² Heart Failure and Biomarker Trials, Baim Institute for Clinical Research, Boston, MA (J.L.J.).
³ BHF Glasgow Cardiovascular Research Centre, University of Glasgow, UK (N.S.).
⁴ Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands (H.J.L.H.).
⁵ Janssen Research & Development, LLC, Spring House, PA (E.T., Y.Y., M.K.H.).
⁶ Cardiology Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (M.V.).
⁷ University of Mississippi Medical Center, Jackson (J.B.).
⁸ Baylor Scott & White Institute, Dallas, TX (J.B.).
⁹ Department of Cardiology, People's Liberation Army General Hospital, Beijing, China (J.L.).
¹⁰ Department of Cardiology, Xinqiao Hospital, Army Military Medical University, Chongqing, China (J.L.).
¹¹ The George Institute for Global Health (J.L., V.P., B.N.), UNSW Sydney, Australia.
¹² Kolling Institute, Royal North Shore Hospital University of Sydney, NSW, Australia (C.A.P.).
¹³ Faculty of Medicine (V.P.), UNSW Sydney, Australia.
¹⁴ The Royal North Shore Hospital, Sydney, Australia (V.P.).
¹⁵ Charles Perkins Centre, University of Sydney, NSW, Australia (B.N.).
¹⁶ Imperial College London, UK (B.N.).

PMID: 37603600
DOI: 10.1161/CIRCULATIONAHA.123.065251

Abstract

Background: People with type 2 diabetes and albuminuria are at an elevated risk for cardiac and renal events. The optimal biomarkers to aid disease prediction and to understand the benefits of sodium-glucose cotransporter-2 inhibition remain unclear.

Methods: Among 2627 study participants in the CREDENCE trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, growth differentiation factor-15, and IGFBP7 (insulin-like growth factor binding protein 7) were measured. The effect of canagliflozin on biomarker concentrations was evaluated. The prognostic potential of each biomarker on the primary outcome (a composite of end-stage kidney disease [dialysis, transplantation, or a sustained estimated glomerular filtration rate of <15 mL·min^-1·1.73 m^-2], doubling of the serum creatinine level, or renal death or cardiovascular death) was assessed.

Results: The median (quartiles 1 and 3) concentration of each biomarker was generally elevated: NT-proBNP, 180 ng/L (82, 442 ng/L); high-sensitivity cardiac troponin T, 19 ng/L (12, 29 ng/L); growth differentiation factor-15, 2595 ng/L (1852, 3775 ng/L); and IGFBP7, 121.8 ng/mL (105.4, 141.5 ng/mL). At 1 year, the biomarkers all rose by 6% to 29% in the placebo arm but only by 3% to 10% in the canagliflozin arm (all P<0.01 in multivariable linear mixed-effect models). Baseline concentrations of each biomarker were strongly predictive of cardiac and renal outcomes. When the biomarkers were analyzed together in a multimarker panel, individuals with high risk scores (hazard ratio [HR], 4.01 [95% CI, 2.52-6.35]) and moderate risk scores (HR, 2.39 [95% CI, 1.48-3.87]) showed a higher risk for the primary outcome compared with those with low risk scores. By 1 year, a 50% increase in NT-proBNP (HR, 1.11 [95% CI, 1.08-1.15]), high-sensitivity cardiac troponin T (HR, 1.86 [95% CI, 1.64-2.10]), growth differentiation factor-15 (HR, 1.45 [95% CI, 1.24-1.70]), and IGFBP7 (HR, 3.76 [95% CI, 2.54-5.56]) was associated with risk of the primary outcome.

Conclusions: Multiple cardiorenal stress biomarkers are strongly prognostic in people with type 2 diabetes and albuminuria. Canagliflozin modestly reduced the longitudinal trajectory of rise in each biomarker. Change in the biomarker level in addition to the baseline level augments the primary outcome prediction.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT02065791.

Keywords: albuminuria; biomarkers; canagliflozin; diabetes mellitus; renal insufficiency, chronic.

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Conflict of interest statement

Disclosures Dr Januzzi is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; is a director at Jana Care; has received grant support from Abbott, Applied Therapeutics, HeartFlow, Innolife, and Roche Diagnostics; has received consulting income from Abbott, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, Roche Diagnostics, and Siemens; and participates in clinical end point committees/data safety monitoring boards for Abbott, AbbVie, CVRx, Intercept, and Takeda. Dr Perkovic is employed by UNSW Sydney and the Royal North Shore Hospital and serves as a board director for St. Vincent’s Health Australia, George Clinical, and several medical research institutes. He has received honoraria for steering committee roles, scientific presentations, and/or advisory board attendance from AbbVie, Amgen, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Chinook, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe Pharma Corp, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pfizer, PharmaLink, Reata, Relypsa, Roche, Sanofi, Servier, Travere, and Tricida. Drs Tefera, Yavin, and Hansen are full-time employees of Jansen Research & Development, LLC. All other authors report no conflicts.

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Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial

Affiliations

Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial

Authors

Affiliations

Abstract

Conflict of interest statement

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Associated data

LinkOut - more resources

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