Stress Cardiac Biomarkers, Cardiovascular and Renal Outcomes, and Response to Canagliflozin

Abstract

Background: Circulating biomarkers reflecting different mechanistic pathways may identify at-risk individuals with diabetes who may benefit from sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Objectives: The purpose of this study was to determine if high-sensitivity cardiac troponin T (hs-cTnT), soluble suppression of tumorigenesis-2 (sST2), and insulin-like growth factor binding protein 7 (IGFBP7) levels, either alone or in combination, may modify the treatment benefits of canagliflozin.

Methods: In the CANVAS (CANagliflozin cardioVascular Assessment Study) biomarker substudy, we evaluated the prognostic significance of baseline biomarker measurements, the long-term trajectory of each, and response to canagliflozin on key cardiovascular and kidney outcomes.

Results: Among the 4,330 study participants, baseline hs-cTnT, sST2, and IGFBP7 were available in 3,503 (81%), 3,084 (71%), and 3,577 (83%). In total, 39% had elevated hs-cTnT ≥14 pg/mL, 6% had sST2 >35 ng/mL, and 49% had IGFBP7 >96.5 ng/mL. Canagliflozin significantly slowed increases of hs-cTnT (P = 0.027) and sST2 (P = 0.033) through 6 years. Each biomarker was significantly associated with cardiovascular and kidney outcomes, independent of clinical covariates. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Patients with hs-cTnT ≥14 ng/L and those with sST2 >35 ng/mL derived greater relative benefit for major adverse cardiovascular events (MACE) (both Pinteraction ≤0.05). A panel of all 3 biomarkers predicted each cardiac and kidney outcome evaluated; participants with an increasing number of abnormal circulating biomarkers appeared to have greater relative reductions in MACE from canagliflozin treatment (Pinteraction trend = 0.005).

Conclusions: Canagliflozin delays longitudinal rise in hs-cTnT and sST2 compared with placebo out to 6 years. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Elevated cardiovascular biomarkers, either alone or in combination, may identify individuals who may derive greater MACE benefit from SGLT2 inhibition. CANVAS (CANagliflozin cardioVascular Assessment Study; NCT01032629).

Keywords: SGLT2 inhibitor; biomarkers; canagliflozin; diabetes; heart failure.

Conflict of interest statement

Funding Support and Author Disclosures The CANVAS study and this substudy were funded by Janssen Research and Development, LLC. High-sensitivity cardiac troponin T and insulin-like growth factor binding protein 7 reagents were provided by Roche Diagnostics. Soluble suppression of tumorigenesis-2 reagents were provided by Critical Diagnostics. Canagliflozin was developed by Janssen Research and Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi; has speaker engagements with Novartis and Roche Diagnostics; and has participated on clinical endpoint committees for studies sponsored by Galmed and Novartis. Dr Sattar has consulted for Affimune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi; and has received grant support from Boehringer Ingelheim. Drs Xu, Shaw, Rosenthal, and Hansen are employees of Janssen Research and Development, LLC. Dr Butler has received research grants and/or served as a consultant or speaker for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceuticals, Innolife, Janssen, LivaNova, American Regent, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, V-Wave Ltd, and Vifor. Dr Mahaffey has served as a consultant for Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma; and has received research support from Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, and St. Jude Medical. Dr Neal has received research support and has served as a consultant and speaker for Janssen, with all fees paid to his employer, and interacts regularly on a nonfinancial basis with multiple large corporations in the pharmaceutical industry, the food processing industry, and the quick service restaurant industry in Australia and overseas. Dr Pfeifer is an employee of Janssen Scientific Affairs, LLC. Dr Januzzi is supported by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Novartis Pharmaceuticals, Roche Diagnostics, Abbott, Singulex, and Prevencio; has received consulting income from Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Janssen, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.