Cardiovascular and renal outcomes with canagliflozin according to baseline diuretic use: a post hoc analysis from the CANVAS Program

Abstract

Aims: The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes.

Methods and results: The CANVAS Program enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed-effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age ± standard deviation, 64.3 ± 8.0 vs. 62.5 ± 8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all Pdifference < 0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54-0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93-1.36), Pheterogeneity < 0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin-to-creatinine ratio, were similar between groups (all Pdifference > 0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (-0.52% vs. -0.64%, Pheterogeneity = 0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all Pheterogeneity > 0.07).

Conclusions: Participants on baseline diuretics derived a greater benefit for major cardiovascular events from canagliflozin, which was not fully explained by differences in participant characteristics nor risk factor changes.

Trial registration: ClinicalTrials.gov NCT01032629 NCT01989754.

Keywords: CANVAS Program; Canagliflozin; Diuretics; Sodium-glucose cotransporter 2 inhibitor (SGLT2i).

Conflict of interest statement

J.Y., C.A., Y.H., and C.L. are employees of the George Institute. C.A. is supported by an NHMRC/MRFF Priority Fellowship and a NSW Health EMC Grant. B.L.N. 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.H. 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. K.W.M. has received research support from Afferent, Amgen, Apple Inc., AstraZeneca, Cardiva Medical Inc., Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, National Institutes of Health (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 (GSK), Johnson & Johnson, MedErgy, Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, Springer Publishing, and UCSF. C.P.C. has received research grants from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Merck, Janssen, and Takeda and has received consulting fees from Aegerion, Alnylam, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Corvidia, GSK, Innovent, Eisai, Eli Lilly, Kowa, Merck, Pfizer, Regeneron, and Sanofi. G.A.F. reports receiving research support from the co‐funded National Health and Medical Research Council and Heart Foundation (Australia) Practitioner Fellowship and the Heart Research Australia and compensation from Janssen for serving on the Adjudication Panel of the CANVAS Program. V.P. has received fees for advisory boards, steering committee roles, or scientific presentations from AbbVie, Astellas, Astra Zeneca, 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. M.J.J. 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 Sharp & 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. B.N. 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 programmes of Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. M.H. has received grant support from the World Heart Federation via Boehringer Ingelheim and Novartis; the American Heart Association, Verily, and AstraZeneca; and the American Medical Association for work unrelated to this paper. He has plans for patents for heart failure fixed‐dose combination therapy products, including diuretics. He notes institutional relationships through his appointment at The George Institute with AbbVie, Actelion, and Janssen. None of the authors has any competing interests related to this study.

© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Figures

Figure 1

Effects of canagliflozin on cardiovascular and renal outcomes in participants in the CANVAS Program, stratified by baseline use of any diuretic. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with the use of Cox regression models, with stratification according to trial and history of cardiovascular disease for all canagliflozin groups combined versus placebo. CV, cardiovascular; HF, heart failure; MACE, major adverse cardiovascular event, including death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; MI, myocardial infarction. *40% reduction in estimated glomerular filtration rate, end‐stage kidney disease, or death from renal causes.

Figure 2

Effects of canagliflozin on major adverse cardiac events in participants in the CANVAS Program, stratified by baseline use of diuretic classes*. *In CANVAS Program, any diuretics were categorized as loop or non‐loop diuretics. In CANVAS trial, non‐loop diuretics were further categorized with specific drug classes. **Includes thiazide, thiazide‐like, or other diuretics.

Figure 3

Effect of canagliflozin* on (A) systolic blood pressure; (B) pulse; (C) body weight; (D) haemoglobin A1c; (E) urinary albumin‐to‐creatinine ratio; (F) serum uric acid; and (G) haematocrit in participants in the CANVAS Program, stratified by baseline use of any diuretic. *Calculated as mean change from baseline across the entire follow‐up period. The average change in these continuous outcomes from baseline by canagliflozin treatment and the difference in treatment effect between those on and not on diuretics at baseline were analysed using mixed‐effect models for repeated measures including all data up to Week 312 and covariates for study, visit, treatment, baseline measures, treatment‐by‐visit, and baseline‐by‐visit interactions.

Figure 4

Adverse events in the CANVAS Program participants stratified by baseline use of any diuretic. CANVAS indicates Canagliflozin Cardiovascular Assessment Study; CI, confidence interval. *The annualized event rates are reported with data from CANVAS alone through 7 January 2014, because after this time, only serious adverse events or adverse events leading to discontinuation were collected. In CANVAS‐R, only serious adverse events or adverse events leading to discontinuation were collected. Owing to the differences between the two trials in methods of collection of the data, an integrated analysis of these adverse events is not possible. §Data collected in CANVAS and CANVAS‐R.