OBJECTIVE:The study was undertaken because it was unknown whether the duration of type 2 diabetes modifies the effects of sodium-glucose cotransporter 2 inhibitor canagliflozin on cardiovascular (CV) and kidney outcomes. RESEARCH DESIGN AND METHODS:This post hoc analysis of the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program (N = 10,142) and Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial (N = 4,401) evaluated hazard ratios and 95% CIs using Cox proportional hazards for the effects of canagliflozin on CV and kidney outcomes, including progression and regression of albuminuria over 5-year intervals of disease duration. RESULTS:Canagliflozin had ranges of benefit across intervals of diabetes duration, with no heterogeneity for major adverse CV events, CV death or heart failure hospitalization, and kidney failure requiring therapy or doubling serum creatinine. Furthermore, canagliflozin reduced albuminuria progression and increased albuminuria regression with no interaction across all diabetes duration subgroups. CONCLUSIONS:Our findings suggest that earlier treatment with canagliflozin confers consistent cardiorenal benefits to individuals with type 2 diabetes.

Background This study evaluated the effects of canagliflozin in patients with type 2 diabetes with and without prevalent cardiovascular disease (secondary and primary prevention). Methods and Results This was a pooled participant‐level analysis of the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. The CANVAS Program included participants with type 2 diabetes at elevated cardiovascular risk, whereas the CREDENCE trial included participants with type 2 diabetes and albuminuric chronic kidney disease. Hazard ratios (HRs) with interaction terms were obtained from Cox regression models to estimate relative risk reduction with canagliflozin versus placebo across the primary and secondary prevention groups. We analyzed 5616 (38.9%) and 8804 (61.1%) individuals in the primary and secondary prevention subgroups, respectively. Primary versus secondary prevention participants were on average younger (62.2 versus 63.8 years of age) and more often women (42% versus 31%). Canagliflozin reduced the risk of major adverse cardiovascular events (HR, 0.84 [95% CI, 0.76–0.94]) consistently across primary and secondary prevention subgroups (Pinteraction=0.86). Similarly, no treatment effect heterogeneity was observed with canagliflozin for hospitalization for heart failure, cardiovascular death, end‐stage kidney disease, or all‐cause mortality (all Pinteraction>0.5). Conclusions Canagliflozin reduced cardiovascular and kidney outcomes with no statistical evidence of heterogeneity for the treatment effect across the primary and secondary prevention subgroups in the CANVAS Program and CREDENCE trial. Although studies on the optimal implementation of canagliflozin within these populations are warranted, these results reinforce canagliflozin's role in cardiorenal prevention and treatment in individuals with type 2 diabetes. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01032629, NCT01989754, NCT02065791.

AIM:In the CANVAS Program and CREDENCE trials, the sodium glucose co-transporter 2 inhibitor canagliflozin reduced the risk of cardiovascular and kidney events in patients with type 2 diabetes. The current study analysed a pooled population to ascertain the kidney protection provided by canagliflozin across the full spectrum of kidney parameters. METHODS:This post-hoc pooled analysis of the CANVAS Program (N = 10 142) and CREDENCE trial (N = 4401), assessed the risk of the primary kidney composite (doubling of serum creatinine, end-stage kidney disease, renal death), in all patients and subgroups defined by baseline estimated glomerular filtration rate (<30, 30 to <45, 45 to <60 and ≥60 ml/min/1.73 m2 ), albuminuria [<30, 30-300, >300 mg/g (<3.39, 3.39-33.9, >33.9 mg/mmol)] and 2012 Kidney Disease: Improving Global Outcomes (KDIGO) classification of chronic kidney disease (low/moderate, high and very high risk). RESULTS:In the overall population, the risk for the primary kidney composite outcome was 37% lower in the canagliflozin group versus placebo (HR: 0.63; 95% CI: 0.53, 0.77; p < .001). There was no evidence of heterogeneity in the kidney protective effects of canagliflozin across a range of kidney risks when stratified by baseline estimated glomerular filtration rate, albuminuria or KDIGO risk category (all pinteraction > .05). A statistically significant risk reduction of the primary kidney composite outcome was sustained by approximately 18 months after randomization. CONCLUSIONS:These results emphasize a critical role of canagliflozin in kidney protection across a broad spectrum of participants with type 2 diabetes with varying levels of kidney function.

Diabetes, Obesity and MetabolismVolume 26, Issue 2 p. 758-762 RESEARCH LETTER Timing of statistical benefit of canagliflozin in patients with type 2 diabetes for cardiovascular and heart failure outcomes: Insights from the CANVAS Program and CREDENCE trial Abhinav Sharma MD, Corresponding Author Abhinav Sharma MD abhinav.sharma@mcgill.ca orcid.org/0000-0002-2346-8330 McGill University Health Centre, Montreal, Quebec, Canada Correspondence Abhinav Sharma, MD, Division of Cardiology, McGill University Health Centre, 1001 Decarie Blvd, H4A 3J1, Montreal, QC, Canada. Email: abhinav.sharma@mcgill.caSearch for more papers by this authorPedro Marques MD, Pedro Marques MD orcid.org/0000-0002-1120-5461 McGill University Health Centre, Montreal, Quebec, CanadaSearch for more papers by this authorBrendon L. Neuen PhD, Brendon L. Neuen PhD orcid.org/0000-0001-9276-8380 The George Institute for Global Health, UNSW Sydney, Sydney, Australia Royal North Shore Hospital, Sydney, AustraliaSearch for more papers by this authorRobert A. Fletcher MSc, Robert A. Fletcher MSc orcid.org/0000-0002-0885-1788 The George Institute for Global Health, UNSW Sydney, Sydney, AustraliaSearch for more papers by this authorApril Slee PhD, April Slee PhD orcid.org/0000-0003-2469-3916 New Arch Consulting, Seattle, Washington, USASearch for more papers by this authorWally Rapattoni MSc, Wally Rapattoni MSc orcid.org/0000-0001-6400-982X Janssen Inc., Toronto, Ontario, CanadaSearch for more papers by this authorFernando G. Ang MD, Fernando G. Ang MD orcid.org/0009-0003-6075-4525 Janssen Inc., Toronto, Ontario, CanadaSearch for more papers by this authorClare Arnott PhD, Clare Arnott PhD orcid.org/0000-0001-9370-9913 The George Institute for Global Health, UNSW Sydney, Sydney, Australia Faculty of Medicine, UNSW Sydney, Sydney, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, AustraliaSearch for more papers by this authorAdeera Levin MD, Adeera Levin MD orcid.org/0000-0003-2438-8401 St. Paul's Hospital, Division of Nephrology, University of British Columbia, Vancouver, British Columbia, CanadaSearch for more papers by this authorSubodh Verma MD, Subodh Verma MD orcid.org/0000-0002-4018-8533 Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, CanadaSearch for more papers by this authorVlado Perkovic PhD, Vlado Perkovic PhD orcid.org/0000-0002-4257-7620 The George Institute for Global Health, UNSW Sydney, Sydney, Australia Faculty of Medicine, UNSW Sydney, Sydney, Australia The Royal North Shore Hospital, Sydney, AustraliaSearch for more papers by this authorKenneth W. Mahaffey MD, Kenneth W. Mahaffey MD orcid.org/0000-0002-3791-2148 Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, California, USASearch for more papers by this author Abhinav Sharma MD, Corresponding Author Abhinav Sharma MD abhinav.sharma@mcgill.ca orcid.org/0000-0002-2346-8330 McGill University Health Centre, Montreal, Quebec, Canada Correspondence Abhinav Sharma, MD, Division of Cardiology, McGill University Health Centre, 1001 Decarie Blvd, H4A 3J1, Montreal, QC, Canada. Email: abhinav.sharma@mcgill.caSearch for more papers by this authorPedro Marques MD, Pedro Marques MD orcid.org/0000-0002-1120-5461 McGill University Health Centre, Montreal, Quebec, CanadaSearch for more papers by this authorBrendon L. Neuen PhD, Brendon L. Neuen PhD orcid.org/0000-0001-9276-8380 The George Institute for Global Health, UNSW Sydney, Sydney, Australia Royal North Shore Hospital, Sydney, AustraliaSearch for more papers by this authorRobert A. Fletcher MSc, Robert A. Fletcher MSc orcid.org/0000-0002-0885-1788 The George Institute for Global Health, UNSW Sydney, Sydney, AustraliaSearch for more papers by this authorApril Slee PhD, April Slee PhD orcid.org/0000-0003-2469-3916 New Arch Consulting, Seattle, Washington, USASearch for more papers by this authorWally Rapattoni MSc, Wally Rapattoni MSc orcid.org/0000-0001-6400-982X Janssen Inc., Toronto, Ontario, CanadaSearch for more papers by this authorFernando G. Ang MD, Fernando G. Ang MD orcid.org/0009-0003-6075-4525 Janssen Inc., Toronto, Ontario, CanadaSearch for more papers by this authorClare Arnott PhD, Clare Arnott PhD orcid.org/0000-0001-9370-9913 The George Institute for Global Health, UNSW Sydney, Sydney, Australia Faculty of Medicine, UNSW Sydney, Sydney, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia Sydney Medical School, University of Sydney, Sydney, AustraliaSearch for more papers by this authorAdeera Levin MD, Adeera Levin MD orcid.org/0000-0003-2438-8401 St. Paul's Hospital, Division of Nephrology, University of British Columbia, Vancouver, British Columbia, CanadaSearch for more papers by this authorSubodh Verma MD, Subodh Verma MD orcid.org/0000-0002-4018-8533 Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, CanadaSearch for more papers by this authorVlado Perkovic PhD, Vlado Perkovic PhD orcid.org/0000-0002-4257-7620 The George Institute for Global Health, UNSW Sydney, Sydney, Australia Faculty of Medicine, UNSW Sydney, Sydney, Australia The Royal North Shore Hospital, Sydney, AustraliaSearch for more papers by this authorKenneth W. Mahaffey MD, Kenneth W. Mahaffey MD orcid.org/0000-0002-3791-2148 Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, California, USASearch for more papers by this author First published: 26 October 2023 https://doi.org/10.1111/dom.15340Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat CONFLICT OF INTEREST AbS has received support from the FRSQ-Junior 1 clinician scientist award, the Alberta Innovates Health Solution Clinician Scientist fellowship, the European Society of Cardiology Young Investigator research grant, Janssen, Roche Diagnostics, AstraZeneca, Boehringer Ingelheim, Novartis, Servier, Novo Nordisk and the Canadian Cardiovascular Society Bayer Vascular award. PM has no disclosures. ApS is an employee of New Arch Consulting and received funding from Janssen for this analysis. FGA and WR are employees of Janssen. BLN received fees for travel support, advisory boards, scientific presentations and steering committee roles from AstraZeneca, Bayer, Boehringer Ingelheim, Cambridge Healthcare Research and Janssen, with all honoraria paid to his institution. RAF is supported by a PhD studentship from the Health Data Research UK-The Alan Turing Institute Wellcome Trust Programme in Health Data Science. This funding had no role in the production of this article. CA received honoraria from Amgen; received support from a National Health and Medical Research Council/Medical Research Future Fund, Priority Fellowship and an NSW Health EMC grant; and is an employee of the George Institute for Global Health. AL served as a scientific advisor to Boehringer Ingelheim, AstraZeneca, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), OccuRx and Chinook Therapeutics; served on a data safety monitoring board or scientific committee for NIDDK, NIH, Kidney Precision Medicine, CURE consortium and the University of Washington Kidney Research Institute Scientific Advisory Committee; received research funding from Canadian Institutes of Health Research, Kidney Foundation of Canada, GSK, AstraZeneca and Boehringer Ingelheim; and received fees for time as CREDENCE national coordinator from Janssen, directed to her academic team. SV holds a Tier 1 Canada Research Chair in Cardiovascular Surgery. SV has also received grants and personal fees for speaker honoraria and advisory board participation from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Amgen, HLS, Merck, EOCI Pharmacomm Ltd, Novartis, Sun Pharmaceuticals and Toronto Knowledge Translation Working Group. He also serves as President of the Canadian Medical and Surgical Knowledge Translation Research Group. VP received fees for an advisory board, steering committee, or scientific presentation from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook Therapeutics, CSL Vifor, Gilead, GSK, Janssen, MedImmune, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka and Travere Therapeutics, Inc.; received speaker fees from Janssen; served on a data and safety monitoring committee for Dimerix; served on the board of directors for George Clinical, Garvan Institute, George Institute, Victor Chang Cardiac Research Institute, Ingham Institute and Mindgardens Neuroscience Network; and has stock in George Clinical. KWM 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, Novartis, Sanofi, St Jude, and Tenax. Kenneth Mahaffey also has served as a consultant (speaker fees for continuing medical education events only) for Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol-Myers Squibb, Elsevier, GlaxoSmithKline, John-son & Johnson, MedErgy, Medscape, Mitsubishi, Myokardia, National Institutes of Health, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, Springer Publishing and University of California, San Francisco. Open Research PEER REVIEW The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15340. DATA AVAILABILITY STATEMENT The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. REFERENCES 1Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377(7): 644-657. 10.1056/NEJMoa1611925 CASPubMedWeb of Science®Google Scholar 2Verma S, Leiter LA, Zinman B, et al. Time to cardiovascular benefits of empagliflozin: a post hoc observation from the EMPA-REG OUTCOME trial. ESC Heart Fail. 2021; 8(4): 2603-2607. 10.1002/ehf2.13374 PubMedWeb of Science®Google Scholar 3Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; 380(24): 2295-2306. 10.1056/NEJMoa1811744 CASPubMedWeb of Science®Google Scholar 4McGuire DK, Shih W, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2020; 6(2): 148-158. 10.1001/jamacardio.2020.4511 Web of Science®Google Scholar 5Packer M, Anker SD, Butler J, et al. Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-reduced trial. Circulation. 2021; 143(4): 326-336. 10.1161/CIRCULATIONAHA.120.051783 PubMedWeb of Science®Google Scholar 6Fitchett D, Inzucchi SE, Zinman B, et al. Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial. ESC Heart Failure. 2021; 8(6): 4517-4527. 10.1002/ehf2.13615 PubMedWeb of Science®Google Scholar 7Li J, Woodward M, Perkovic V, et al. Mediators of the effects of canagliflozin on heart failure in patients with type 2 diabetes. JACC Heart Fail. 2020; 8(1): 57-66. 10.1016/j.jchf.2019.08.004 PubMedWeb of Science®Google Scholar 8Braunwald E. Gliflozins in the management of cardiovascular disease. N Engl J Med. 2022; 386(21): 2024-2034. 10.1056/NEJMra2115011 CASPubMedWeb of Science®Google Scholar 9Lee MM, Petrie MC, McMurray JJ, Sattar N. How do SGLT2 (sodium-glucose cotransporter 2) inhibitors and GLP-1 (glucagon-like peptide-1) receptor agonists reduce cardiovascular outcomes? Completed and ongoing mechanistic trials. Arterioscler Thromb Vasc Biol. 2020; 40(3): 506-522. 10.1161/ATVBAHA.119.311904 CASPubMedWeb of Science®Google Scholar 10Elharram M, Ferreira JP, Huynh T, et al. Prediction of heart failure outcomes in patients with type 2 diabetes mellitus: validation of the thrombolysis in myocardial infarction risk score for heart failure in diabetes (TRS-HFDM) in patients in the ACCORD trial. Diabetes Obes Metab. 2021; 23(3): 782-790. 10.1111/dom.14283 CASPubMedWeb of Science®Google Scholar 11Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022; 28(3): 568-574. 10.1038/s41591-021-01659-1 CASPubMedWeb of Science®Google Scholar 12Bedrouni W, Sharma A, Pitt B, et al. Timing of statistical benefit of mineralocorticoid receptor antagonists among patients with heart failure and post-myocardial infarction. Circulation: Heart Failure. 2022; 15(10):e009295. 10.1161/CIRCHEARTFAILURE.121.009295 CASPubMedWeb of Science®Google Scholar 13Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021; 385(24): 2252-2263. 10.1056/NEJMoa2110956 CASPubMedWeb of Science®Google Scholar Volume26, Issue2February 2024Pages 758-762 ReferencesRelatedInformation

Abstract BACKGROUND AND AIMS Type 2 diabetes mellitus (T2DM) is associated with comorbidities, such as chronic kidney disease (CKD) and peripheral vascular disease (PVD), which may increase risk of cardiovascular (CV) and kidney events. Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, reduced the risk of CV and kidney events in patients with T2DM and high CV risk or nephropathy in the CANVAS Program and CREDENCE trial, respectively. The effects of canagliflozin on CV and kidney outcomes in patients with CKD with and without PVD remain unknown. METHOD This post hoc analysis included integrated, pooled data from the CANVAS Program and the CREDENCE trial. The effects of canagliflozin compared with placebo on CV and kidney outcomes were assessed in patients with CKD with and without PVD at baseline. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and PVD was defined based on investigator classification on the electronic case report form without requirement for specific clinical evaluation or imaging. Propensity score (PS) matching was used to balance patient demographics and baseline clinical characteristics between groups. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox regression models. RESULTS A total of 14 543 participants from the CANVAS Program (N = 10 142) and CREDENCE (N = 4401) were included. Of these, 3514 had CKD alone (canagliflozin, n = 1792; placebo, n = 1722; mean eGFR, 46 mL/min/1.73 m2; symptomatic CV disease history, 49%; insulin use, 64%) and 1156 had CKD + PVD (canagliflozin, n = 626; placebo, n = 530; mean eGFR, 46 mL/min/1.73 m2; symptomatic CV disease history, 96%; insulin use, 74%) at baseline. Canagliflozin was associated with a reduced risk of major adverse cardiovascular events (MACE), the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death), doubling of serum creatinine (dSCr), end-stage kidney disease (ESKD) and the composite of ESKD or dSCr compared with placebo in patients with CKD with and without PVD (Figure 1A). After matching, 3210 patients had CKD alone (mean eGFR, 46 mL/min/1.73 m2; symptomatic CV disease history, 49%; insulin use, 64%) and 966 had CKD + PVD (mean eGFR, 46 mL/min/1.73 m2; symptomatic CV disease history, 98%; insulin use, 74%), with equal numbers in the canagliflozin and placebo groups. In the PS-matched groups, canagliflozin was associated with a reduced risk of MACE, HHF/CV death, dSCr, ESKD and the composite of ESKD or dSCr compared with placebo in patients with CKD with and without PVD (Figure 1B). CONCLUSION Canagliflozin significantly reduced the risk of MACE, HHF/CV death, dSCr, ESKD, and the composite of ESKD or dSCr in patients with CKD with and without PVD, suggesting that the beneficial effects of canagliflozin on CV and kidney outcomes are consistent and can be seen in patients regardless of these comorbidities.

In T2D, treatment targets include maintaining HbA1c ≤7.0%, LDL-C <2 mmol/L (<77 mg/dL) , and BP <130/80 mmHg. It is also recommended to improve urinary albumin:creatinine ratio (UACR) , a marker of renal damage and CV risk. We examined effects of CANA vs. placebo on CV and kidney outcomes in patients with T2D and high CV risk and/or chronic kidney disease according to BL treatment targets and risk factors. Pooled data from the CANVAS Program (N=10,142) and the CREDENCE trial (N=4401) were analyzed according to treatment target achievement and by number of targets achieved at BL. Hazard ratios and 95% CIs were estimated using Cox regression models. Of 14,432 participants at BL, 3683 (26%) had achieved 0, 5851 (41%) had achieved 1, 3680 (25%) had achieved 2, and 1218 (8%) had achieved either 3 or 4 targets. At BL, 8415 (58%) participants had UACR >2 mg/mmol. CANA consistently reduced risk of MACE, HHF/CV death, and ESKD or doubling of serum creatinine vs. placebo, regardless of whether BL targets were met or if UACR was elevated (Figure) . The number of uncontrolled targets at BL did not impact the beneficial effect of CANA on CV and kidney outcomes (all P interaction >0.17) . In conclusion, CANA demonstrated consistent CV and renal benefits in patients with T2D, regardless of risk factor control. Disclosure V.C.Woo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Speaker's Bureau; Janssen Pharmaceuticals, Inc. M.Tsoukas: Speaker's Bureau; AstraZeneca, Bausch Health, Canada, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Johnson & Johnson, Novo Nordisk Canada Inc. S.Tobe: Other Relationship; Bayer AG, Speaker's Bureau; AstraZeneca, Otsuka Pharmaceutical Co., Ltd. A.Slee: Consultant; Alydia Health, Elixir Medical , IHP Therapeutics , iLumen Scientific, Intuitive Surgical, Janssen Global Services, LLC, Laborie, Providence Medical, Pulse Biosciences, SonoMotion. W.Rapattoni: Employee; Janssen Pharmaceuticals, Inc. F.Ang: Employee; Bristol-Myers Squibb Company, Janssen Pharmaceuticals, Inc. J.Seufert: Advisory Panel; Abbott, Sanofi-Aventis Deutschland GmbH, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. D.C.Wheeler: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Global Services, LLC, Merck Sharp & Dohme Corp., Mundipharma, Tricida, Inc., Vifor Pharma Management Ltd., Consultant; AstraZeneca, Speaker's Bureau; Amgen Inc., Astellas Pharma Inc. Funding Janssen Inc., Toronto, ON, Canada

Management of type 2 diabetes mellitus (T2DM), a progressive metabolic disorder associated with substantial cardiovascular (CV) and kidney complications, includes risk factor optimization of glucose, blood pressure (BP) and lipids. Although there may be minor differences between guidance, treatment targets recommended by international clinical practice guidelines include maintaining glycated haemoglobin (HbA1c) ≤7.0% (with individual adaptation), BP <130/80 mmHg and low-density lipoprotein cholesterol (LDL-C) <2 mmol/L (<77 mg/dl), along with an annual evaluation of urinary albumin/creatinine ratio (UACR) to assess CV and kidney risk.1-4 The sodium-glucose co-transporter 2 inhibitor class showed improvements in CV and kidney outcomes in patients with T2DM in CV outcome trials.3 Canagliflozin reduced the risk of CV outcomes, including major adverse CV events (MACE; CV death, non-fatal myocardial infarction and non-fatal stroke), a composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and kidney outcomes in patients with T2DM and high CV risk [CANagliflozin cardioVascular Assessment Study (CANVAS) programme]5 and in patients with diabetic nephropathy [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial].6 Consequently, treatment guidelines now recommend sodium-glucose co-transporter 2 inhibitors for reducing the risk of CV and kidney events in patients with T2DM.1-4 As patients have varying control over their CV risk factors, it is important to know whether the clinical benefits of canagliflozin extend across the spectrum of attained treatment targets. This post-hoc analysis assessed the effects of canagliflozin versus placebo on CV and kidney outcomes in patients with T2DM and high CV risk, and/or chronic kidney disease according to baseline treatment target achievement and risk factors. This post-hoc analysis is an integrated, pooled, patient-level, meta-analysis from the CANVAS programme and CREDENCE. The CANVAS programme comprised two multicentre, double-blind, placebo-controlled, randomized trials: CANVAS and CANVAS-R.5, 7 Eligible participants had T2DM (HbA1c ≥7.0% and ≤10.5%) and an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73m2 and were either aged ≥30 years with a history of symptomatic atherosclerotic CV disease or aged ≥50 years with ≥2 CV disease risk factors.5, 7 CREDENCE included participants with T2DM (HbA1c ≥6.5% and ≤12.0%), an eGFR of 30 to <90 ml/min/1.73m2, and a UACR of >33.9 to ≤565.6 mg/mmol (>300 to ≤5000 mg/g).6, 8 Participants in all studies were randomized to canagliflozin or placebo. Participants had similar characteristics, with some differences related to inclusion criteria. In the CANVAS programme, 18% of participants had a history of nephropathy, ~20% had an eGFR <60 ml/min/1.73m2, and 70% had normoalbuminuria at baseline.5, 9 In contrast, all CREDENCE participants had advanced nephropathy at baseline.6 Lastly, 66% of CANVAS programme participants had established CV disease versus 50% in CREDENCE. This post-hoc analysis of the CANVAS programme and CREDENCE trial included participants who were randomized to canagliflozin or placebo and had values for all selected treatment targets.5, 6 Categorical variables are represented as percentages, and continuous variables are represented as mean (standard deviation) or median (interquartile range). The effects of canagliflozin versus placebo were examined for the time to the first occurrence of MACE, the composite of HHF/CV death, and the kidney composite of end-stage kidney disease (ESKD) or doubling of serum creatinine (dSCr). Patients were categorized by treatment target achievement and number of target levels achieved (0, 1, 2, and 3 or 4) at baseline. The targets were defined as: HbA1c ≤7.0%, LDL-C <2 mmol/L (<77 mg/dl), BP <130/80 mmHg, or UACR <2 mg/mmol (18 mg/g). Hazard ratios and 95% confidence intervals for each outcome were estimated using Cox regression models stratified by the achievement of treatment targets and, in separate models, by the number of targets achieved at baseline. Interaction p values were calculated by including the treatment group by achievement of treatment targets and treatment group by number of targets achieved at baseline in the model. A two-sided p < .05 for the interaction term was deemed probable to reflect a difference beyond chance. This post hoc analysis is not intended for inference, so no type 1 error adjustments were made. Thus, p values are descriptive only. Analyses were performed using SAS version 9.4 (SAS Institute). The pooled analysis included 14 543 participants from the CANVAS programme (n = 10 142) and CREDENCE trial (n = 4401), with mean (SD) baseline HbA1c of 8.3% (1.1), LDL-C of 2.4 (1.0) mmol/L [92.8 (38.7) mg/dl], and BP of 138/78 (16/10) mmHg, and median (range) baseline UACR of 3.8 (1.0–59.2) mg/mmol [33.6 (8.9–523.9) mg/g]. At baseline, 3683 (26%) participants had achieved no treatment targets, 5851 (41%) had achieved one, 3680 (25%) had achieved two, and 1218 (8%) had achieved three or four targets (Table 1). In addition, 8415 (58%) participants had a UACR >2 mg/mmol. Regardless of whether baseline targets were met or UACR was elevated, canagliflozin consistently reduced the risk of MACE, HHF/CV death, and ESKD/dSCr versus placebo (Figure 1). Among participants who experienced a CV event and did not achieve HbA1c, LDL-C or BP targets or a reduction in UACR, canagliflozin still reduced CV risk (all p interaction ≥.38). The beneficial effects of canagliflozin on ESKD/dSCr were observed irrespective of achievement of HbA1c, LDL-C and BP baseline targets (all p interaction ≥.45). Canagliflozin reduced kidney events similarly as to whether UACR was elevated (>2 mg/mmol), and reduced CV outcomes with elevated or normal UACR, at baseline. Furthermore, the number of uncontrolled targets at baseline did not impact the beneficial effect of canagliflozin on CV and kidney outcomes (all p interaction ≥.17; Figure S1). In this pooled analysis of the CANVAS programme and CREDENCE trial, participants with T2DM and high CV risk, and/or chronic kidney disease who were randomized to canagliflozin treatment showed consistent CV and kidney benefits versus placebo, regardless of whether T2DM-related or other CV-risk treatment targets were met at baseline. Our findings highlight the importance of canagliflozin's protective effect on key CV and kidney outcomes irrespective of baseline risk factor control. This is particularly important in outpatient clinical settings where, despite best efforts, patients with T2DM may only achieve partial composite target goals.10, 11 The DM-SCAN study, which included primary care physician surveys and chart data from adults with T2DM, showed that 50%, 57% and 36% of patients achieved target levels of HbA1c, LDL-C and BP, respectively, with only 13% achieving all three targets.10 Similarly, a low proportion of participants in the current analysis achieved the recommended treatment targets. Thus, our data show the benefits of canagliflozin for preventing cardiorenal complications in patients who have not yet achieved risk factor targets. Strengths of this study include the multicentre, randomized, controlled trial designs, which were conducted to a high standard and with many participants. CV and kidney outcomes were pre-specified and adjudicated by expert committees. This analysis also has inherent limitations applicable to any post-hoc analysis of a randomized trial. The CANVAS programme and CREDENCE trial were not designed specifically to test outcomes in these subgroups, nor were there adjustments for multiple baseline test comparators. Thus, our findings should be considered exploratory. In addition, generalizability of the results may be limited to individuals with previous CV events, high CV risk or nephropathy, similar to the patients enrolled in the CANVAS programme and CREDENCE trial. While control of CV and kidney risk factors in high-risk patients with T2DM is critical, this study showed that canagliflozin provides consistent CV and kidney benefits, regardless of whether treatment targets for these risk factors are met at baseline. MAT, SWT, WR, FGA, JS, BLN, CA, KWM and DCW contributed to the study design and data interpretation. AS performed the statistical analysis. MAT and VW drafted the manuscript, and the final version was critically revised and approved by all the authors. The CANVAS Program and CREDENCE trial were sponsored by Janssen Research & Development, LLC. This analysis was supported by Janssen Canada Inc. Medical writing support was provided by Kim Caldwell, PhD, of Lumanity Communications Inc., and was funded by Janssen, Inc. Canagliflozin was developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. MAT has received speakers bureau and advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk and Sanofi Genzyme. VW has received honoraria for speaking, advisory boards, and clinical research from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen and Novo Nordisk. SWT has received a KMH Clinic unrestricted grant and in-kind support for the Zero to Five study paid to Sunnybrook Research Institute; has received consulting fees from AstraZeneca paid to Sunnybrook Research Institute; has received payment or honoraria for lectures from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Novo Nordisk, Pfizer and Sanofi paid to the CHEP Plus education program; and has served as a volunteer for the American Hypertension Specialist Certification Program. AS is an employee of New Arch Consulting; and received funding from Janssen for this analysis. WR and FGA are employees of Janssen Inc. JS has received honoraria for talks and/or consultancy and/or research funding from Apitope, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GI-Dynamics, GlaxoSmithKline, Intarcia, Ipsen, Janssen, LifeScan, MedScape, Merck Sharp & Dohme, Novartis, Novo Nordisk, Omniamed, Pfizer, Roche, Sanofi, Servier, Takeda and Ypsomed. BLN has received fees for travel support, advisory boards, scientific presentations, and steering committee roles from AstraZeneca, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research and Janssen, with all honoraria paid to his institution. CA has received honoraria from Amgen; has received support from an NHMRC/MRFF Priority Fellowship and an NSW Health EMC Grant; and is an employee of The George Institute for Global Health. KWM's financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. DCW has received fees for advisory boards, committee work, educational activities, and scientific presentations form Amgen, Astellas, AstraZeneca (ongoing), Bayer, Boehringer Ingelheim, CSL Vifor, Gilead, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Mundipharma, Tricida, and Zydus. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. Figure S1. Effects of canagliflozin versus placebo on CV and kidney events by the number of T2DM treatment targets achieved at baseline. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.