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

• Published in: Journal of the American College of Cardiology Vol. 79; no. 5; pp. 432 - 444
• Main Authors: Vaduganathan, Muthiah, Sattar, Naveed, Xu, Jialin, Butler, Javed, Mahaffey, Kenneth W., Neal, Bruce, Shaw, Wayne, Rosenthal, Norman, Pfeifer, Michael, Hansen, Michael K., Januzzi, James L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.02.2022
• Subjects: Adult; biomarkers; Biomarkers - blood; canagliflozin; Canagliflozin - therapeutic use; Cardiovascular; diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Female; heart failure; Heart Failure - complications; Heart Failure - drug therapy; Humans; Kidney - metabolism; Male; Middle Aged; SGLT2 inhibitor; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Troponin T - blood; eGFR; heart failure; SGLT2; biomarkers; sST2; SGLT2 inhibitor; NT-proBNP; hs-cTnT; MACE; canagliflozin; IGFBP7; diabetes; HF; amino-terminal pro-B type natriuretic peptide; estimated glomerular filtration rate; soluble suppression of tumorigenesis-2; insulin-like growth factor binding protein 7; sodium-glucose cotransporter-2; high-sensitivity cardiac troponin T; major adverse cardiovascular events
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2021.11.027

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