Cardiovascular Effects of Canagliflozin in Relation to Renal Function and Albuminuria

Ashish Sarraju; George Bakris; Christopher P Cannon; David Cherney; C V Damaraju; Gemma A Figtree; Jagadish Gogate; Tom Greene; Hiddo J L Heerspink; James L Januzzi Jr; Bruce Neal; Meg J Jardine; Jaime Blais; Mikhail Kosiborod; Adeera Levin; Ildiko Lingvay; Matthew R Weir; Vlado Perkovic; Kenneth W Mahaffey

doi:10.1016/j.jacc.2022.08.772

Cardiovascular Effects of Canagliflozin in Relation to Renal Function and Albuminuria

J Am Coll Cardiol. 2022 Nov 1;80(18):1721-1731. doi: 10.1016/j.jacc.2022.08.772.

Authors

Ashish Sarraju¹, George Bakris², Christopher P Cannon³, David Cherney⁴, C V Damaraju⁵, Gemma A Figtree⁶, Jagadish Gogate⁵, Tom Greene⁷, Hiddo J L Heerspink⁸, James L Januzzi Jr⁹, Bruce Neal¹⁰, Meg J Jardine¹¹, Jaime Blais⁵, Mikhail Kosiborod¹², Adeera Levin¹³, Ildiko Lingvay¹⁴, Matthew R Weir¹⁵, Vlado Perkovic¹⁶, Kenneth W Mahaffey¹⁷

Affiliations

¹ Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
² Department of Medicine, University of Chicago Medicine, Chicago, Illinois, USA.
³ Cardiovascular Division, Brigham & Women's Hospital and Baim Institute for Clinical Research, Boston, Massachusetts, USA.
⁴ University of Toronto, Toronto, Ontario, Canada.
⁵ Janssen Scientific Affairs, LLC, Titusville, New Jersey, USA.
⁶ Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia; The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
⁷ Division of Biostatistics, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.
⁸ The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁹ Massachusetts General Hospital and Baim Institute for Clinical Research, Boston, Massachusetts, USA.
¹⁰ The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
¹¹ The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia; Concord Repatriation General Hospital, Sydney, New South Wales, Australia; NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
¹² The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia; Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, Missouri, USA.
¹³ Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁴ University of Texas Southwestern Medical Center, Dallas, Texas, USA.
¹⁵ Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
¹⁶ The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia; The Royal North Shore Hospital, Sydney, New South Wales, Australia.
¹⁷ Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. Electronic address: kenneth.mahaffey@stanford.edu.

PMID: 36302584
DOI: 10.1016/j.jacc.2022.08.772

Abstract

Background: People with type 2 diabetes mellitus (T2DM) have elevated cardiovascular (CV) risk, including for hospitalization for heart failure (HHF). Canagliflozin reduced CV and kidney events in patients with T2DM and high CV risk or nephropathy in the CANVAS (CANagliflozin cardioVascular Assessment Study) Program and the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial.

Objectives: The aim of this study was to assess the effects of canagliflozin on CV outcomes according to baseline estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (UACR) in pooled patient-level data from the CANVAS Program and CREDENCE trial.

Methods: Canagliflozin effects on CV death or HHF were assessed by baseline eGFR (<45, 45-60, and >60 mL/min/1.73 m²) and UACR (<30, 30-300, and >300 mg/g). HRs and 95% CIs were estimated by using Cox regression models overall and according to subgroups.

Results: A total of 14,543 participants from the CANVAS Program (N = 10,142) and the CREDENCE (N = 4,401) trial were included, with a mean age of 63 years, 35% female, 75% White, 13.2% with baseline eGFR <45 mL/min/1.73 m², and 31.9% with UACR >300 mg/g. Rates of CV death or HHF increased as eGFR declined and/or UACR increased. Canagliflozin significantly reduced CV death or HHF compared with placebo (19.4 vs 28.0 events per 1,000 patient-years; HR: 0.70; 95% CI: 0.62-0.79), with consistent results across eGFR and UACR categories (all P interaction >0.40).

Conclusions: Risk of CV death or HHF was higher in those with lower baseline eGFR and/or higher UACR. Canagliflozin consistently reduced CV death or HHF in participants with T2DM and high CV risk or nephropathy regardless of baseline renal function or level of albuminuria. (Canagliflozin Cardiovascular Assessment Study [CANVAS], NCT01032629; A Study of the Effects of Canagliflozin [JNJ-24831754] on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus [CANVAS-R], NCT01989754; and Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy [CREDENCE], NCT02065791).

Keywords: SGLT2 inhibitor; canagliflozin; cardiovascular outcomes; diabetes; heart failure.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Albuminuria / drug therapy
Canagliflozin / pharmacology
Canagliflozin / therapeutic use
Cardiovascular Diseases*
Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / drug therapy
Diabetic Nephropathies* / drug therapy
Female
Glomerular Filtration Rate
Heart Failure*
Humans
Kidney
Male
Middle Aged
Sodium-Glucose Transporter 2 Inhibitors* / pharmacology

Substances

Canagliflozin
Sodium-Glucose Transporter 2 Inhibitors

Associated data

ClinicalTrials.gov/NCT02065791