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Randomized Controlled Trial
. 2020 Nov 1:318:126-129.
doi: 10.1016/j.ijcard.2020.06.011. Epub 2020 Jun 20.

The effects of combination canagliflozin and glucagon-like peptide-1 receptor agonist therapy on intermediate markers of cardiovascular risk in the CANVAS program

Clare Arnott  1 , Brendon L Neuen  2 , Hiddo J L Heerspink  3 , Gemma A Figtree  4 , Mikhail Kosiborod  5 , Carolyn S Lam  6 , Christopher P Cannon  7 , Norman Rosenthal  8 , Wayne Shaw  8 , Kenneth W Mahaffey  9 , Meg J Jardine  10 , Vlado Perkovic  10 , Bruce Neal  10
Affiliations
Randomized Controlled Trial

The effects of combination canagliflozin and glucagon-like peptide-1 receptor agonist therapy on intermediate markers of cardiovascular risk in the CANVAS program

Clare Arnott et al. Int J Cardiol. .

Abstract

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) reduce cardiovascular events, and improve intermediate markers of cardiometabolic health, in those with type 2 diabetes. We investigated these effects in the CANVAS Program.

Methods and results: The CANVAS Program comprised 2 double-blind, randomized, placebo-controlled trials (CANVAS and CANVAS-R) done in patients with type 2 diabetes and elevated cardiovascular risk. Effects were estimated using mixed-effects models for continuous measures and Cox regression models for other outcomes. Randomized treatment by subgroup interaction terms were used to compare effects of canagliflozin versus placebo across subgroups defined by baseline use of GLP1-RA. There were 10,142 participants, of whom 407 (4%) were using GLP1-RA therapy at baseline. Those using GLP1-RA at baseline were less likely to have a history of cardiovascular disease (60.4% vs 65.8%), had a longer duration of diabetes (15.2 vs 13.5 years) and a higher body mass index (BMI; 35.6 vs 31.8 kg/m2) but were otherwise similar. There were greater reductions with canagliflozin versus placebo for HbA1c (-0.75% versus -0.58%; P = .0091), SBP (-6.26 versus -3.83 mmHg; P = .0018), and body weight (-3.79 versus -2.18 kg; P < .0001) in those on baseline GLP1-RA therapy. Effects across subgroups were similar for UACR (P = .21), eGFR slope (P = .72), major adverse cardiac events (P = .94) and total serious adverse events (P = .74).

Conclusions: There may be a synergistic effect of SGLT2 inhibition when used on a background of GLP1-RA for intermediate cardiometabolic markers.

Keywords: Cardiovascular disease, type 2 diabetes; GLP1 receptor agonist; SGLT2 inhibition.

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Conflict of interest statement

Disclosures C. Arnott is an employee of the George Institute for Global Health. B.L. Neuen is supported by an Australian National Health and Medical Research Council Postgraduate Scholarship and a University Postgraduate Award from the University of New South Wales; he has received travel support from Janssen. H.J.L. Heerspink has served as a consultant for Abbvie, Astellas, AstraZeneca, Boehringer Ingelheim, Fresenius, Gilead, Janssen, Merck, and Mitsubishi-Tanabe; and has received grant support from Abbvie, AstraZeneca, Boehringer Ingelheim, and Janssen. G.A. Figtree has received research support from the cofunded Australian National Health and Medical Research Council and Heart Foundation fellowship and Heart Research Australia; and has received compensation from Janssen for serving on the adjudication panel of the CANVAS Program. M. Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on advisory boards for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Eli Lilly, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. C.S. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the advisory board, steering committee, or executive committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd. and Corpus; and serves as co-founder and non-executive director of eKo.ai. C.P. Cannon has received research grants from Amgen, Boehringer-Ingelheim (BI), Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck, and Pfizer, and consulting fees from Aegerion, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Corvidia, HLS Therapeutics, Innovent, Janssen, Kowa, Merck, Pfizer, and Sanofi. N. Rosenthal and W. Shaw are full-time employees of Janssen Research & Development, LLC. K.W. Mahaffey has received research support from Afferent, Amgen, Apple, Inc., AstraZeneca, Cardiva Medical, Inc., Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, and Tenax; and has served as a consultant (speaker fees for CME events only) for Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol Myers Squibb, Elsevier, GlaxoSmithKline, Johnson & Johnson, MedErgy, Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, Springer Publishing, and UCSF. M.J. Jardine is supported by a Medical Research Future Fund Next Generation Clinical Researchers Program Career Development Fellowship; is responsible for research projects that have received unrestricted funding from Baxter, Amgen, Eli Lilly, and Merck Sharpe Dohme; serves on a Steering Committee sponsored by CSL; has served on advisory boards sponsored by Akebia, Baxter, Boehringer Ingelheim, and Vifor; and has spoken at scientific meetings sponsored by Janssen, with any consultancy, honoraria, or travel support paid to her institution. V. Perkovic has received fees for Advisory Boards, Steering Committee roles, or Scientific Presentations from Abbvie, Astellas, AstraZeneca, Bayer, Baxter, BMS, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, Vifor, and Tricida. B. Neal is supported by an Australian National Health and Medical Research Council Principal Research Fellowship; holds a research grant for this study from Janssen; and has held research grants for other large-scale cardiovascular outcome trials from Roche, Servier, and Merck Schering Plough; and his institution has received consultancy, honoraria, or travel support for contributions he has made to advisory boards and/or the continuing medical education programs of Abbott, Janssen, Novartis, Pfizer, Roche, and Servier.

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