Canagliflozin and Stroke in Type 2 Diabetes Mellitus.: Results from the Randomized CANVAS Program Trials

Canagliflozin and Stroke in Type 2 Diabetes Mellitus.: Results From the Randomized CANVAS Program Trials

Zien Zhou, MD1,2, Richard Lindley, MD3, Karin Rådholm, MD, PhD3,4, Bronwyn Jenkins, BMed5, John Watson, MD, DPhil6, Vlado Perkovic, MB, BS, PhD1,7, Kenneth W. Mahaffey, MD8, Dick de Zeeuw, MD, PhD9, Greg Fulcher, MD7, Wayne Shaw, DSL10, Richard Oh, MD10, Mehul Desai, MD10, David R. Matthews, DPhil, BM, BCh11, and Bruce Neal, MB, ChB, PhD1,12-14 Statistical analyses were conducted by Z. Zhou and K. Rådholm. *A complete list of investigators in the CANVAS Program is provided in the Online Supplement. 1The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia; 2Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 3The George Institute for Global Health and University of Sydney, Sydney, Australia; 4Division of Community Medicine, Primary Care, Department of Medicine and Health Sciences, Faculty of Health Sciences, Linköping University, Department of Local Care West, County Council of Östergötland, Linköping, Sweden; 5Royal North Shore Hospital, St Leonards, Sydney, Australia; 6Sydney Adventist Hospital Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia; 7The Royal North Shore Hospital and University of Sydney, Sydney, Australia; 8Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; 9University of Groningen, University Medical Center Groningen, The Netherlands; 10Janssen Research & Development, LLC, Raritan, NJ, USA; 11Oxford Centre for Diabetes, Endocrinology and Metabolism and Harris Manchester College, University of Oxford, Oxford, UK; 12The Charles Perkins Centre, University of Sydney, Sydney Australia; 13Faculty of Medicine, University of New South Wales, Sydney, Australia; 14Imperial College London, London, UK. Corresponding author: Prof Richard Lindley The George Institute for Global Health Level 5, 1 King St Newtown NSW 2042 Australia Tel: +61 404 866 007 Fax: +61 2 8890 9731 Email: [email protected]

Twitter handle: @georgeinstitute Cover title: Canagliflozin effects on stroke in T2DM Manuscript word count: 5651 words Table and figure count: 6 (5 figures, 1 table) Key words: Diabetes, Type 2; Cardiovascular Diseases; Sodium Glucose Co-transporter 2 Inhibitor; Stroke; Transient Ischemic Attack Journal subject terms: Cardiovascular Disease; Cerebrovascular Disease/Stroke; Diabetes, Type 2

ABSTRACT

Background and Purpose: This study reports the detailed effects of canagliflozin on stroke, stroke subtypes, and vascular outcomes in participants with and without cerebrovascular disease

(stroke or TIA) at baseline from the CANVAS (CANagliflozin cardioVascular Assessment Study)

Program.

Methods: The CANVAS Program, comprising two similarly designed and conducted clinical trials, randomly assigned 10,142 participants with type 2 diabetes mellitus and high cardiovascular risk to canagliflozin or placebo. Its primary outcome was a composite of major adverse cardiovascular events. The main outcome of interest for this report was fatal or non-fatal stroke.

Additional exploratory outcomes were stroke subtypes and other vascular outcomes defined according to standard criteria.

Results: There were 1958 (19%) participants with prior stroke or TIA at baseline. These individuals were older, more frequently women, and had higher rates of heart failure, atrial fibrillation, and microvascular disease (all P<0.001) compared to those without such a history.

There were 309 participants with stroke events during follow-up (123 had prior stroke or TIA at baseline and 186 did not), at a rate of 7.93/1000 patient-years amongst those assigned canagliflozin and 9.62/1000 patient-years amongst placebo (hazard ratio [HR] 0.87, 95% confidence interval

[CI] 0.69-1.09). Analysis of stroke subtypes found no effect on ischemic stroke (n=253, HR 0.95,

95% CI 0.74-1.22), a significant reduction for hemorrhagic stroke (n=30, HR 0.43, 95% CI 0.20-

0.89) and no effect on undetermined stroke (n=29, HR 1.04, 95% CI 0.48-2.22). Effects on other cardiovascular outcomes were comparable amongst participants with and without stroke or TIA at baseline.

Conclusions: There were too few events in the CANVAS Program to separately define the effects of canagliflozin on stroke, but benefit is more likely than harm. The observed possible protective effect for hemorrhagic stroke was based on small numbers but warrants further investigation.

Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754

INTRODUCTION

The prevalence of type 2 diabetes mellitus (T2DM) has doubled over the past three decades and is likely to affect a half a billion people in the next three decades.1 Given that new medications for diabetes could potentially be given to some tens of millions of people, it is vital that these medications are safe, and in particular, not associated with an increased vascular risk.2,3 The sodium glucose co-transporter 2 (SGLT2) inhibitors have recently emerged as important new treatments for diabetes. The mechanism of action, by reducing the re-uptake of glucose in the kidney, lowers blood glucose, with other favorable effects on biomarkers, particularly weight loss.4

Evidence of the effect of SGLT2 inhibitors on vascular events has come from two trial programs, the EMPA-REG OUTCOME trial testing empagliflozin5 and the CANagliflozin cardioVascular

Assessment Study (CANVAS) Program trials testing canagliflozin.6 In the EMPA-REG

OUTCOME study, there was a non-significant increase in the risk of stroke (hazard ratio [HR]

1.18, 95% confidence interval [CI] 0.89 to 1.56), and in the CANVAS Program, there was a non- significant decrease in the risk of stroke (HR 0.87, 95% CI 0.69 to 1.09). Extensive subsidiary analyses of EMPA-REG OUTCOME have not identified any adverse effect of empagliflozin that might have caused an increase in stroke risk.7 Given that T2DM is associated with an approximate doubling in the risk of stroke compared to people without diabetes,8 it is important to understand more about the effects of these drugs on stroke and whether those with established cerebrovascular disease have any additional risks or benefits compared to those without. The aim of this study was to explore the detailed effects of canagliflozin on stroke, stroke subtypes, other vascular outcomes amongst CANVAS Program participants and to analyze whether these effects differed for those with and without a history of cerebrovascular disease (stroke or TIA) at baseline.

MATERIALS AND METHODS

Program design

The study design, characteristics of participants, and the main results of the CANVAS Program have previously been published.6,9-11 In brief, the CANVAS Program, comprising two similarly designed and conducted trials — CANVAS and CANVAS–Renal (CANVAS-R) — was designed to assess the cardiovascular and renal safety and efficacy of canagliflozin, and how any potential benefits might balance against risks. There were 667 centers in 30 countries in the two trials that were scheduled for joint close-out and analysis when at least 688 cardiovascular events and a minimum of 78 weeks follow-up had been accrued for the last randomized participant, which occurred in February 2017.

Data from the CANVAS Program will be made available in the public domain via the Yale

University Open Data Access Project (YODA; http://yoda.yale.edu/) once the product and relevant indication studied have been approved by regulators in the US and EU and the study has been completed for 18 months. The trial protocols and statistical analysis plans were published along with the primary CANVAS Program manuscript.6

Participants

Participants in the CANVAS Program were those with T2DM (glycated hemoglobin [HbA1c]

≥7.0% and ≤10.5%), aged ≥30 years with a history of symptomatic atherosclerotic cardiovascular disease, or ≥50 years with ≥2 risk factors for cardiovascular disease (duration of diabetes ≥10 years, systolic blood pressure [BP] >140 mmHg while on one or more antihypertensive agents, current smoker, microalbuminuria or macroalbuminuria, or high-density lipoprotein cholesterol

[HDL-C] <1 mmol/L). Patients treated with insulin and those with mild to moderate renal failure

(estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m2) were included. For the analyses presented in this report, a baseline diagnosis of cerebrovascular disease was based on a self-report of prior stroke or transient ischemic attack (TIA).

Randomization, treatment, and follow-up

After a 2-week, single-blind, placebo run-in period, participants were randomized centrally through an interactive web response system using a computer-generated randomization schedule prepared by the study sponsor using randomly permuted blocks. Participants in CANVAS were assigned in a 1:1:1 ratio to canagliflozin 300 mg, canagliflozin 100 mg, or matching placebo, and participants in CANVAS-R were randomly assigned in a 1:1 ratio to canagliflozin or matching placebo, administered at an initial dose of 100 mg daily with optional up-titration to 300 mg from week 13. Participants and all study staff were masked to individual treatment allocations until the completion of the study. Use of other background therapy for glycemic management, prevention of stroke and other cardiovascular outcomes, and other diseases was according to best practice instituted in line with local guidelines.

Participants were followed after randomization in a face-to-face follow-up that was scheduled for three visits in the first year and at 6-month intervals thereafter, with alternating telephone follow- up between face-to-face assessments. Every follow-up included inquiry about primary and secondary outcome events and serious adverse events. Serum creatinine measurement with eGFR was performed at least every 26 weeks in both trials. Participants who prematurely discontinued study treatment continued scheduled follow-up wherever possible, with extensive efforts made to obtain full outcome data for all during the final follow-up window that spanned from November

2016 to February 2017.

Outcomes

The main outcome of interest for this report is fatal or non-fatal strokes. These were originally part of the primary composite outcome of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction or cardiovascular death) used for the CANVAS Program6.

Additional exploratory outcomes for this report were fatal stroke; non-fatal stroke; ischemic stroke, hemorrhagic stroke, and stroke of undetermined type; TIA; stroke or TIA; major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke); fatal or non-fatal myocardial infarction; fatal or hospitalized heart failure; cardiovascular death; all-cause mortality; progression of albuminuria (defined as more than a 30% increase in albuminuria and a change from either normoalbuminuria to microalbuminuria or macroalbuminuria or from microalbuminuria to macroalbuminuria); and serious decline in kidney function (defined as a 40% reduction in eGFR sustained for at least two consecutive measures, end-stage kidney disease, or death from renal causes). Possible intermediate markers of stroke risk were also analyzed, which included systolic BP (SBP), diastolic BP (DBP), body weight,

HbA1c, cholesterol, triglycerides, hematocrit, urinary albumin-to-creatinine ratio (UACR), eGFR, and adverse event of atrial fibrillation reported during follow-up.

Endpoint Adjudication Committees (Online Supplement) adjudicated all cardiovascular outcomes, renal outcomes, and deaths, with stroke events adjudicated by experienced stroke physicians

(Online Supplement). Stroke was defined using the 2013 American Heart Association/American

Stroke Association criteria.12 Ischemic and hemorrhagic stroke were determined by the neuroimaging findings, whilst undetermined stroke represented a clinical stroke without acute imaging to confirm the cause. TIAs were defined as a transient impairment of neurological function lasting less than 24 hours and without evidence of stroke on any acute neuroimaging. The

Endpoint Adjudication Committee reviewed all suspected strokes and transient neurological events (including TIAs) as originally reported by the site investigators to determine whether the event met the criteria for a stroke. A reported TIA event could be adjudicated as a stroke event and it was removed from the analysis of TIA events if it was the case. Therefore, TIA events included in the analyses within this report were those not adjudicated to be stroke events.

Statistical analysis

Categorical variables were summarized as the number of patients (with corresponding percentages), and continuous variables were summarized as the mean and standard deviation or the median and interquartile range. Differences in baseline characteristics between participants with a history of cerebrovascular disease compared to participants with no history of cerebrovascular disease were evaluated using generalized Cochran-Mantel-Haenszel test, analysis of variance, or the Wilcoxon rank sum test. Efficacy analyses were based upon the full, integrated dataset and the intent-to-treat approach, with the comparison being between all participants assigned to canagliflozin (regardless of dose) and all participants assigned to placebo. Analyses were based on the occurrence of the first event under investigation. The trial was powered to detect an effect on the primary composite outcome and not for the analyses of stroke. Annualized incidence rates per 1000 patient-years of follow-up were calculated for all outcomes in addition to

HRs and 95% CIs determined from Cox regression models, with treatment as the exploratory variable and factors of trial and history of cardiovascular disease were included in the model. We tested the homogeneity of treatment effects across the two contributing trials using P values for interactions, and the same approach was used for testing comparability of effects across subgroups defined by baseline participant characteristics. Sensitivity analyses of fatal or non-fatal stroke were performed according to whether the events occurred on-treatment or within 7, 30, or 90 days

9 of treatment discontinuation. Effects of canagliflozin on continuous intermediate markers of stroke risk were analyzed using an analysis of covariance model with treatment as an independent effect and adjusting for trial and baseline value. Change in the continuous intermediate marker from baseline to the last measurement throughout the trials and the difference of canagliflozin compared to placebo in the least squares means were estimated from the model. For atrial fibrillation, the HR with 95% CI was estimated from the same Cox regression model that was used to determine effects on stroke. Analyses were performed using SAS Enterprise Guide version 7.1.

Standard protocol approvals, registrations, and patient consents

The protocols for the two trials were approved by the ethics committees at each site. All participants provided written informed consent. The trials were registered at ClinicalTrials.gov

(identifiers: NCT01032629, NCT01989754).

RESULTS

There were 10,142 patients in the CANVAS Program (Online Supplement Figure I), and the mean follow-up time was 188.2 weeks. Mean age was 63.3 years, 35.8% were women, mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. 1958 (19.3%) participants reported a history of cerebrovascular disease (stroke or TIA) at baseline. These participants were significantly different from other trial participants in most aspects of demography, disease history, and medication for the management of stroke risks, though the absolute magnitude of the differences was mostly small (Online Supplement Table I). Atrial fibrillation was reported at baseline in 8.6% of those with cerebrovascular disease compared to

5.4% amongst those without.

Effects of canagliflozin on stroke, transient ischemic attack, and stroke subtypes

There were 309 trial participants with a fatal or non-fatal stroke recorded during follow-up (123 had prior stroke or TIA at baseline and 186 did not), a rate of 7.93/1000 patient-years amongst those assigned canagliflozin and 9.62/1000 patient-years amongst those assigned placebo (HR

0.87, 95% CI 0.69 to 1.09) (Figures 1 and 2). Hemorrhagic stroke was uncommon (30 events), with an observed reduction in risk for those allocated to canagliflozin compared with placebo (HR

0.43, 95% CI 0.20 to 0.89; Figures 1 and 3). The rate of ischemic stroke was also lower amongst those treated with canagliflozin compared to placebo (n=253; HR 0.95, 95% CI 0.74 to 1.22), but this did not reach statistical significance. The rate of undetermined stroke events (n=29) was similar in both groups (HR 1.04, 95% CI 0.48 to 2.22). Point estimates of effect were consistent and below unity for fatal stroke (n=39; HR 0.84, 95% CI 0.44 to 1.59), non-fatal stroke (n=274;

HR 0.90, 95% CI 0.71 to 1.15), TIA (n=88; HR 0.86, 95% CI 0.56 to 1.32), and the composite of stroke or TIA (n=377; HR 0.89, 95% CI 0.73 to 1.10), but none of these individual results were statistically significant. The estimate of effect of canagliflozin on stroke risk did not vary with the time since the last dose of randomized treatment (Online Supplement Figure II). The use of antithrombotic agents at baseline had no effect on the risk of hemorrhagic stroke (HR 0.63, 95%

CI 0.22 to 1.76).

Effects on possible intermediate markers of stroke risk

There were favorable effects of canagliflozin compared to placebo on SBP, DBP, body weight,

HbA1c, HDL-C, UACR, and eGFR. Small increases were observed for hematocrit, low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides with null effects on the ratio of HDL-C to LDL-C. There was no detectable effect of canagliflozin compared to placebo on

11 atrial fibrillation (HR 0.84, 95% CI 0.64 to 1.12), which was also true for the subsets of participants with and without atrial fibrillation history at baseline (P interaction=0.99) (Table 1).

Effects of canagliflozin on stroke in patient subgroups

Effects of treatment on stroke were similar in CANVAS and CANVAS-R (HR 0.93, 95% CI 0.69 to 1.27 vs. HR 0.80, 95% CI 0.56 to 1.13; P interaction=0.51) and for most other participant subgroups (Figure 4). The exceptions were subsets defined by age (P interaction=0.006), eGFR

(P interaction=0.005), and use of antithrombotic therapy (P interaction=0.035), which indicated greater protection in older patients, those with lower eGFR, and those reporting antithrombotic use.

Effects of canagliflozin on cardiovascular, kidney, and death outcomes in patients with and without cerebrovascular disease at baseline

Patients with stroke or TIA at baseline were at higher absolute risk of subsequent stroke and all other vascular outcomes, with 123 stroke events occurring in those 1958 patients with prior stroke or TIA versus 186 in the 8184 patients without. The proportional effects of canagliflozin compared to placebo were comparable in patients with and without cerebrovascular disease at baseline for cardiovascular, kidney, and death outcomes (all P interaction >0.19) (Figure 5).

DISCUSSION

In the CANVAS Program, the composite of non-fatal stroke, non-fatal myocardial infarction and cardiovascular death was significantly reduced, with a favorable (but not statistically significant) reduction in each of the three components.6 Similarly, in these analyses, our primary outcome of stroke (fatal or non-fatal), although with a favorable point estimate of effect, was not statistically

12 significant (Figure 1). The CANVAS Program was not powered to examine the individual contributions of stroke, myocardial infarction and cardiovascular death to the primary outcome, but the observed effect on stroke events is consistent with that initially anticipated on the basis of the known BP-lowering effect of the compound.13 Analysis according to pathological stroke subtype identified separately statistically significant protection against hemorrhagic stroke, albeit with small numbers, though there was no clear effect on ischemic stroke or undetermined stroke.

The hemorrhagic stroke result, if confirmed, could be consistent with a BP-lowering mechanism of stroke prevention with canagliflozin, at least in part, as hemorrhagic stroke is more strongly determined by higher BP than ischemic stroke.13

Stroke, in particular, but also most other cardiovascular outcomes and death, occurred more frequently in patients with a baseline history of stroke or TIA compared to those without, though both sets of participants experienced comparable proportional reductions in the risks of these outcomes with use of canagliflozin.14

The effects of canagliflozin were broadly similar across a wide range of other participants, such as those using established treatments for the prevention of stroke, such as BP-lowering therapy, and patients of different ethnic background. The borderline significant interaction of canagliflozin treatment and stroke prevention with baseline use of an antithrombotic is likely to reflect a chance finding consequent upon the many comparisons made rather than a real effect. There was no corresponding evidence of an interaction by use of acetylsalicylic acid or anticoagulant therapy for stroke in EMPA-REG OUTCOME, though those participants all had a baseline history of cardiovascular disease and baseline use of these agents was greater.7 By contrast, the significance level of the interactions of canagliflozin and stroke with age and eGFR make chance a less likely explanation, though the strong correlation between age and lower eGFR mean that these

13 observations may not be independent of one another. A biological explanation for a greater effect of canagliflozin on stroke reduction in older compared to younger individuals or amongst individuals with impaired compared to preserved renal function is unknown, though comparable trends were noted in EMPA-REG OUTCOME.7 The ongoing CREDENCE trial, which is being done in patients with impaired renal function, will provide significant additional insight into these effects and may provide an indication of mechanism.15

Beneficial effects of canagliflozin on stroke might be anticipated based upon the BP lowering achieved with SGLT2 inhibition, since BP reduction is well known to significantly reduce both first and recurrent stroke, with greater reduction for hemorrhagic stroke.16-20 Theoretical risks of hypoperfusion attributable to hypovolemia or hypotension21 have not been observed in prior large trials of stroke prevention, and there was no evidence for such effects in the CANVAS Program.

Hemorrhagic stroke is especially BP dependent,13 so while the positive effect on this outcome observed in the CANVAS Program was based on relatively few events, a positive finding for hemorrhagic stroke is consistent with stroke epidemiology and clinical trials, albeit larger in magnitude than might have been expected for the observed BP reduction. Potential mechanisms for blood pressure lowering with SGLT2 inhibition include natriuresis, osmotic diuresis (leading to volume depletion and increased hematocrit) and body weight loss.22 The changes in lipid parameters with canagliflozin would tend to favor hemorrhagic stroke prevention, though effects on cholesterol were small. Additional anti-atherosclerotic effects of SGLT2 inhibition mediated through effects on glucose and obesity may also contribute to protection against stroke in the longer term.23 There was no evidence of an adverse effect mediated through hemoconcentration, with favorable directions of effect for strokes of ischemic as well as hemorrhagic origin. Likewise, there was no evidence of any adverse effect of withdrawal of randomized treatment on stroke risk,7

14 with constant HRs observed for strokes occurring on treatment and at various intervals after treatment discontinuation.

The findings reported here are strengthened by the rigorous design and conduct of the trial, the pre-specification of stroke as an outcome of interest, and the careful adjudication of all potential stroke events according to recognized subtypes by an expert committee. This included screening all events reported as TIA for possible stroke events by the Endpoint Adjudication Committee, which resulted in additional stroke events being identified. Our study has limitations, the chief one being that the study was not powered to detect significant differences in total stroke events.

The possible difference in effects by subtype of stroke needs to be interpreted with caution as a consequence but warrants further investigation. A further weakness is that TIAs were not themselves adjudicated, but all TIA events were screened by the stroke adjudicators to ensure stroke had not been misreported as TIA. Incomplete ascertainment of TIAs is possible because adverse event reporting in the CANVAS Program was streamlined from January 2014 to capture only serious adverse events and adverse events leading to discontinuation, and TIA events considered by the site investigator as non-serious would not be captured after this time. Missing

TIA events should, however, be distributed non-differentially between active and control groups and should not bias our results.

The unfavorable direction of effect reported for stroke in the EMPA-REG OUTCOME trial was not observed within the CANVAS Program, with a non-significant lower rate of all stroke events in those treated with canagliflozin and an indication of a possible beneficial effect for hemorrhagic stroke. The EMPA-REG OUTCOME trial recorded only about half as many hemorrhagic strokes as the CANVAS Program and did not report the effect of empagliflozin on that outcome, so comparability of the effects of the compounds on hemorrhagic stroke cannot be determined.

Additional data from ongoing trials of SGLT2 inhibitors will provide further insight, and the

CREDENCE trial, in particular, should clarify whether the effects of SGLT2 inhibition on stroke are enhanced in patients with chronic kidney disease.

SUMMARY

The CANVAS Program demonstrated a reduction in the primary composite outcome of non-fatal stroke, non-fatal myocardial infarction and cardiovascular death. There were too few events to separately define the effects of canagliflozin on stroke, but these analyses show that benefit is more likely than harm. The observed possible protective effect for hemorrhagic stroke was based on small numbers but warrants further investigation.

ACKNOWLEDGMENTS

This study was supported by Janssen Research & Development, LLC. The authors thank all investigators, study teams, and patients for participating in these studies. The authors thank the following people for their contributions to the statistical monitoring/analyses and the protocol development, safety monitoring, and operational implementation over the duration of both studies:

Lyndal Hones, Lucy Perry, Sharon Dunkley, Tao Sun, Hsiaowei Deng, George Capuano, Qiang

Li, Severine Bompoint, Laurent Billot, Mary Lee, Joan Lind, Roger Simpson, Mary Kavalam,

Terry Barrett, Ed Connell, Michele Weidner-Wells, Jacqueline Yee, Dainius Balis, Frank

Vercruysse, Elisa Fabbrini, Nicole Meyers, Gary Meininger, and Norm Rosenthal. Medical writing support was provided by Kimberly Dittmar, PhD, of MedErgy, and was funded by Janssen

Global Services, LLC. Canagliflozin has been developed by Janssen Research & Development,

LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.

AUTHOR CONTRIBUTIONS

Z.Z. and K.R. contributed to the analysis and interpretation of the data, and the revision of the manuscript. R.L., W.S., and M.D., contributed to the design of the study, the interpretation of the data, and the drafting and revising of the manuscript. B.J., J.W., and R.O. contributed to the interpretation of the data and the revision of the manuscript. V.P., K.W.M., D.d.Z., G.F., D.R.M., and B.N. contributed to the design of the study, acquisition and interpretation of the data, and the revision of the manuscript. All authors approved the final version of the manuscript for submission.

DISCLOSURES

Z.Z. reports receiving overseas visiting funding from Ren Ji Hospital, School of Medicine,

Shanghai Jiao Tong University and a Scientia PhD Scholarship from the University of New South

Wales, Sydney. R.L. reports research support from the National Health and Medical Research

Council of Australia and was a paid adjudicator for the CANVAS Program trials. K.R. reports receiving funding from a County Council of Östergötland International Fellowship. B.J. was a paid adjudicator for the CANVAS Program trials and has received payment for lectures and advisory boards for Novartis, TEVA and Allergan. J.W. was a paid adjudicator for the CANVAS

Program trials. V.P. reports receiving research support from the Australian National Health and

Medical Research Council (Senior Research Fellowship and Program Grant); serving on steering committees for AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Novartis, and Pfizer; and serving on advisory boards and/or speaking at scientific meetings for AbbVie, Astellas,

AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect, Eli Lilly,

Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa,

Retrophin, Roche, Sanofi, Servier, and Vitae. K.W.M.’s financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. D.d.Z. reports serving on advisory boards and/or as a speaker for Bayer, Boehringer Ingelheim, Fresenius, Mitsubishi-Tanabe; serving on steering committees and/or as a speaker for AbbVieand Janssen; and serving on data safety and monitoring committees for Bayer. G.F. reports receiving research support from Novo Nordisk, and serving on advisory boards and as a consultant for Janssen, Novo Nordisk, Boehringer

Ingelheim, and Merck Sharp and Dohme. W.S., R.O., and M.D. report being full-time employees of Janssen Research & Development, LLC. D.R.M. reports receiving research support from

Janssen; serving on advisory boards and as a consultant for Novo Nordisk, Novartis, Eli Lilly,

Sanofi-Aventis, Janssen, and Servier; and giving lectures for Novo Nordisk, Servier, Sanofi-

Aventis, Eli Lilly, Novartis, Janssen, Mitsubishi Tanabe, and Aché Laboratories. B.N. reports receiving research support from the Australian National Health and Medical Research Council

Principal Research Fellowship and from Janssen, Roche, Servier, and Merck Schering Plough; and serving on advisory boards and/or involvement in CME programs for Abbott, Janssen, Novartis,

Pfizer, Roche, and Servier, with any consultancy, honoraria, or travel support paid to his institution.

FUNDING AND REGISTRATION

Supported by Janssen Research & Development, LLC; ClinicalTrials.gov identifiers,

NCT01032629, NCT01989754.

REFERENCES

1. Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes

mellitus—present and future perspectives. Nat Rev Endocrinol. 2011;8:228-236.

2. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al.

Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med.

2016;374:1321-1331.

3. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide

and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med.

2016;375:1834-1844.

4. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al.

Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: A systematic review and

meta-analysis. Ann Intern Med. 2013;159:262-274.

5. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin,

cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-

2128.

6. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin

and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.

7. Zinman B, Inzucchi SE, Lachin JM, Wanner C, Fitchett D, Kohler S, et al. Empagliflozin

and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular

risk. Stroke. 2017;48:1218-1225.

8. Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di AE, et al. Diabetes mellitus, fasting

blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of

102 prospective studies. Lancet. 2010;375:2215-2222.

9. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, et al. Rationale,

design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study

(CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166:217-223.

10. Neal B, Perkovic V, Matthews DR, Mahaffey KW, Fulcher G, Meininger G, et al.

Rationale, design and baseline characteristics of the CANagliflozin cardiovascular

assessment study-renal (CANVAS-R): A randomized, placebo-controlled trial. Diabetes

Obes Metab. 2017;19:387-393.

11. Neal B, Perkovic V, Mahaffey KW, Fulcher G, Erondu N, Desai M, et al. Optimizing the

analysis strategy for the CANVAS Program—a pre-specified plan for the integrated

analyses of the CANVAS and CANVAS-R trials. Diabetes Obes Metab. 2017;19:926-935.

12. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated

definition of stroke for the 21st century: A statement for healthcare professionals from the

American Heart Association/American Stroke Association. Stroke. 2013;44:2064-2089.

13. Lawes CM, Rodgers A, Bennett DA, Parag V, Suh I, Ueshima H, et al. Blood pressure and

cardiovascular disease in the asia pacific region. J Hypertens. 2003;21:707-716.

14. Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin

for primary and secondary prevention of cardiovascular events: Results from the

CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation.

2018;137:323-334.

15. Jardine MJ, Mahaffey KW, Neal B, Agarwal R, Bakris G, Brenner BM, et al. The

Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical

Evaluation (CREDENCE) tudy rationale, design, and baseline characteristics. Am J

Nephrol. 2017;46:462-472.

16. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-

pressure-lowering regimens on major cardiovascular events: Results of prospectively-

designed overviews of randomised trials. The Lancet. 2003;362:1527-1535.

17. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, et al. Effects of different

blood pressure-lowering regimens on major cardiovascular events in individuals with and

without diabetes mellitus: Results of prospectively designed overviews of randomized

trials. Arch Intern Med. 2005;165:1410-1419.

18. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-

pressure-lowering regimen among 6105 individuals with previous stroke or transient

ischaemic attack. The Lancet. 2001;358:1033-1041.

19. Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T, et al. Effects of intensive blood

pressure lowering on cardiovascular and renal outcomes: updated systematic review and

meta-analysis. Lancet. 2016;387(10017):435-43.

20. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering

in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015;313(6):603-15.21.

21. Malyszko J, Muntner P, Rysz J, Banach M. Blood pressure levels and stroke: J-curve

phenomenon? Curr Hypertens Rep. 2013;15:575-581.

22. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of

sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-

analysis. J Am Soc Hypertens. 2014;8(4):262-75.e9.

23. Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, et al. SGLT-2 inhibitors

and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab

Vasc Dis Res. 2015;12:90-100.

Figure Legends

Figure 1. Effects of canagliflozin on stroke and transient ischemic attack

HR, hazard ratio; CI, confidence interval; TIA, transient ischemic attack.

*TIAs were not adjudicated but based upon adverse event reports made by site investigators.

Incomplete ascertainment of TIAs is possible because adverse event reporting in the CANVAS

Program was streamlined from January 2014 to capture only serious adverse events and adverse events leading to discontinuation, and TIA events considered by the site investigator as non-serious would not be captured after this time.

Figure 2. Effects of canagliflozin on fatal and non-fatal stroke

HR, hazard ratio; CI, confidence interval.

Figure 2B is reprinted from New England Journal of Medicine, Neal B, et al., Canagliflozin and

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 3. Effects of canagliflozin on stroke subtypes

HR, hazard ratio; CI, confidence interval.

Figure 4. Effects of canagliflozin on stroke in patient subgroups

BMI, body mass index; CANVAS, CANagliflozin cardioVascular Assessment Study; CANVAS-

R, CANagliflozin cardioVascular Assessment Study–Renal; CI, confidence interval; CV, cardiovascular; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; pt-yr, patient-years; PVD, peripheral vascular disease; RAAS, renin–angiotensin–aldosterone system;

SBP, systolic blood pressure.

Figure 5. Effects of canagliflozin on cardiovascular and renal outcomes in patient with and without cerebrovascular (stroke or TIA) disease at baseline

HR, hazard ratio; CI, confidence interval; MACE, major adverse cardiovascular events (death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke); eGFR, estimated glomerular filtration rate.

*Composite of 40% reduction in eGFR sustained for at least two consecutive measures, end-stage kidney disease, or death from renal causes.

Table 1. Effects of canagliflozin on possible intermediate markers of stroke risk Change from baseline to the last measurement* Mean treatment Canagliflozin Placebo difference (95% CI)† P value Systolic blood pressure (mmHg) -4.86 (0.19) -1.73 (0.22) -3.14 (-3.71, -2.57) <0.001 Diastolic blood pressure (mmHg) -3.21 (0.11) -2.39 (0.13) -0.82 (-1.15, -0.48) <0.001 Body weight (kg) -3.21 (0.08) -0.81 (0.09) -2.40 (-2.64, -2.17) <0.001 HbA1c (%) -0.42 (0.02) -0.03 (0.02) -0.39 (-0.44, -0.34) <0.001 HDL cholesterol (mmol/L) 0.04 (0.00) -0.01 (0.00) 0.05 (0.04, 0.06) <0.001 LDL cholesterol (mmol/L) 0.08 (0.01) -0.03 (0.01) 0.12 (0.08, 0.15) <0.001 Ratio of LDL to HDL (%) 0.32 (1.09) -0.70 (1.31) 1.02 (-2.33, 4.36) 0.55 Triglycerides (mmol/L) 0.08 (0.02) 0.02 (0.02) 0.06 (0.00, 0.11) 0.04 Total cholesterol (mmol/L) 0.14 (0.01) -0.04 (0.02) 0.18 (0.14, 0.22) <0.001 Hematocrit (%) 1.63 (0.05) -0.90 (0.06) 2.53 (2.38, 2.68) <0.001 Albumin:creatinine ratio (mg/g) 21.01 (6.30) 84.55 (7.49) -63.55 (-82.73, -44.36) <0.001 eGFR (mL/min/1.73 m2) -1.82 (0.19) -3.87 (0.23) 2.05 (1.47, 2.62) <0.001 Participants Participants with an with an Hazard ratio‡ Events event per Events event per P (n) 1000 pt-yr (n) 1000 pt-yr (95% CI) interaction Reported AF§ 125 5.64 84 6.08 0.84 (0.64, 1.12) Without AF history|| 100 4.75 67 5.11 0.82 (0.60, 1.11) 0.99 With AF history# 25 21.90 17 23.37 0.93 (0.50, 1.74)

AF, atrial fibrillation; CI, confidence interval; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; pt-yr, patient-years.

*Change from baseline to the last measurement was analyzed for participants with both baseline and at least one post-baseline measurement using an analysis of covariance (ANCOVA) model with treatment as an independent effect and adjusting for trial and baseline value. Data are the change of least squares means (standard error).

†The mean treatment difference of canagliflozin compared to placebo in the least squares means and associated 95% CIs were estimated from the model.

‡Hazard ratio and 95% CIs are determined from Cox regression models, with treatment as the exploratory variable and stratification according to trial and history of cardiovascular disease.

§Atrial fibrillation events were identified from site investigator reported adverse events.

||Atrial fibrillation events occurred during follow-up in participants without atrial fibrillation history.

#Atrial fibrillation events occurred during follow-up in participants with atrial fibrillation history.

Figure 1. Effects of canagliflozin on stroke and transient ischemic attack

HR, hazard ratio; CI, confidence interval; TIA, transient ischemic attack.

*TIAs were not adjudicated but based upon adverse event reports made by site investigators.

Incomplete ascertainment of TIAs is possible because adverse event reporting in the CANVAS

Figure 2. Effects of canagliflozin on fatal and non-fatal stroke

HR, hazard ratio; CI, confidence interval.

Figure 2B is reprinted from New England Journal of Medicine, Neal B, et al., Canagliflozin and

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 3. Effects of canagliflozin on stroke subtypes

HR, hazard ratio; CI, confidence interval.

Figure 4. Effects of canagliflozin on stroke in patient subgroups

BMI, body mass index; CANVAS, CANagliflozin cardioVascular Assessment Study; CANVAS-

SBP, systolic blood pressure.

Figure 5. Effects of canagliflozin on cardiovascular and renal outcomes in patient with and without cerebrovascular (stroke or TIA) disease at baseline

HR, hazard ratio; CI, confidence interval; MACE, major adverse cardiovascular events (death from

cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke); eGFR, estimated

glomerular filtration rate.

*Composite of 40% reduction in eGFR sustained for at least two consecutive measures, end-stage

kidney disease, or death from renal causes.

ONLINE SUPPLEMENT

Canagliflozin and Stroke in Type 2 Diabetes: Results From the Randomized CANVAS Program Trials

1The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia; 2Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 3The George Institute for Global Health and University of Sydney, Sydney, Australia; 4Division of Community Medicine, Primary Care, Department of Medicine and Health Sciences, Faculty of Health Sciences, Linköping University, Department of Local Care West, County Council of Östergötland, Linköping, Sweden; 5Royal North Shore Hospital, St. Leonards, Australia; 6Sydney Adventist Hospital Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia; 7The Royal North Shore Hospital and University of Sydney, Sydney, Australia; 8Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; 9University of Groningen, University Medical Center Groningen, The Netherlands; 10Janssen Research & Development, LLC, Raritan, NJ, USA; 11Oxford Centre for Diabetes, Endocrinology and Metabolism and Harris Manchester College, University of Oxford, Oxford, UK; 12The Charles Perkins Centre, University of Sydney, Sydney Australia; 13Faculty of Medicine, University of New South Wales, Sydney, Australia; 14Imperial College London, London, UK. Corresponding author: Prof Richard Lindley The George Institute for Global Health Level 5, 1 King St Newtown NSW 2042 Australia Tel: +61 404 866 007 Fax: +61 2 8890 9731 Email: [email protected]

CANVAS Program sites and investigators

CANVAS Argentina: Pablo Arias, Maria Rosa Ulla, Andres Alvarisqueta, Laura Maffei, Jose Osvaldo Fretes, Silvia Gorban De Lapertosa, Virginia Visco, Georgina Sposetti, Javier Farias, Eduardo Francisco Farias, Maria Cecilia Cantero, Rodolfo Feldman, Maria Carolina Ridruejo, Pedro Calella, Cesar Zaidman; Australia: Stephen Stranks, Peak Man Mah, Alison Nankervis, Duncan Topliss, Georgia Soldatos, Richard Simpson, Murray Gerstman, David Colquhoun, Ferdinandus De Looze, Robert Moses, Michael Suranyi, Samantha Hocking, David Packham, Duncan Cooke, Karam Kostner; Belgium: Eric Weber, Chris Vercammen, Luc Van Gaal, Jozef Tits, Bart Keymeulen, Chantal Mathieu; Canada: Naresh Aggarwal, Dan Dattani, Francois Blouin, Richard Dumas, Sam Henein, Patrick Ma, Ali Najarali, Michael Omahony, Tracy Pella, Wilson Rodger, Daniel Shu, Vincent Woo, Brian Zidel, Lew Pliamm, Brian Ramjattan, Ronald Akhras, Jasmin Belle-Isle, Stuart Ross, Geza Molnar; Colombia: Juan Manual Arteaga, Ivonne Jarava; Czech Republic: Alena Andresova, Miloslava Komrskova, Cyril Mucha, Tomas Brychta, Dagmar Bartaskova, Romana Urbanova, Tomas Spousta, Jana Havelkova, Tomas Sedlacek, Milan Kvapil; Estonia: Ülle Jakovlev, Verner Fogel, Liina Viitas, Mai Soots, Maire Lubi, Marju Past, Jelena Krasnopejeva; Germany: Hasan Alawi, Klaus Busch, Felix Klemens Pröpper, Andrea Thron, Stephan Jacob, Andreas Pfützner, Ludger Rose, Thomas Segiet, Christine Kosch, Andrea Moelle; Great Britain: Melanie Davies, Hamish Courtney, Martin Gibson, Luigi Gnudi, Frances Game, John Wilding, Thozhukat Sathyapalan, Miles Fisher, Shenaz Ramtoola, Satyan Rajbhandari, Maurice Okane; Hungary: Eleonora Beke, Ferenc Poor, Karoly Nagy, Gyozo Kocsis, Tamas Oroszlan, Peter Faludi, Mihaly Gurzo; India: Sathyanarayana Srikanta, Mala Dharmalingam, Bala Murugan, Pramod Gandhi, Bipin Sethi, Sosale Aravind, Sharda Ardhanareeshwaran, Arpan Bhattacharyya, Ganapathi Bantwal, Vijay Viswanathan, Paramesh Shamanna, Banshi Saboo, Viswanathan Mohan, Reshma Parmaj, Kirti Kumar Modi, Sindhu Joshi, Sunil Jain, Sanjay Kalra, Arun Chankramath Somasekharan, Prabha Adhikari, Ajay Kumar, Harshada Kudalkar, Rajiv Passey, Mathew John, Sadasivarao Yalamanchi, Keyur Parikh, K.P. Rajesh, Rajesh Nair, Ajay Kumar, Sasi Kumar, Lily Rodrigues, Pawan Gangwal, Pankaj Agarwal, Sandeep Kumar Gupta, Abhay Amrutlal Mutha, Shailaja Dilip Kale, Ravindra Laxman Kulkarni, Sandip Chudasama, Kamal Sharma, Anoop Nambiar, Aniruddha Tangaonkar, Vaishali Deshmukh, Biswakesh Majumdar, Rajendran Veerappan, Deepak Namjoshi; Israel: Itamar Raz, Julio Weinstein, Ilana Harman Boehm, Victor Vishlitzky; Luxembourg: Frederic Dadoun; Malaysia: Rajesh P. Shah, Lai Seong Hooi, Alexander Tan, Wan Mohamad Wan Bebakar, Mafauzy Mohamed, Amir S. Khir, Norlela Sukor, Khalid Abdul Kadir; Mexico: Enrique Morales, Sergio Zuñiga, Melchor Alpizar, Cesar Calvo, Rolando Zamarripa, Juan Rosas, Armando Vargas; The Netherlands: Max Nieuwdorp, Vicdan Kose, Susanne Kentgens, Gloria Rojas, Wouter Van Kempen, Jacqueline Hoogendijk, Mazin Alhakim, Victor Gerdes, Marcel Hovens, Johan Berends, A. Woittiez, Cees Jan Smit, B. Dekkers, Wilco Spiering, Marcel K. Van Dijk-Okla, Ben P.M. Imholz, Ruud J.M. Van Leendert, Marije Ten Wolde, Peter J.H. Smak Gregoor; New Zealand: Russell Scott, Jeremy Krebs, John Baker, Joe Singh, Calum Young; Norway: Gisle Langslet, Hans Olav Hoivik, Torbjorn Kjaernli, Sigbjorn Elle, Eric Gjertsen, Knut Risberg, Andreas Tandberg, Leidulv Solnoer, Per Anton Sirnes; Poland: Tadeusz Derezinski, Malgorzata Arciszewska, Edward Franek, Ewa Szyprowska, Dariusz Sowinski, Robert Petryka, Beata Czakanska-Dec, Grazyna Pulka, Katarzyna Jusiak, Mariusz Dabrowski, Piotr Kubalski, Malgorzata Wojciechowska, Andrzej Madej, Danuta Pupek-Musialik; Russia: Natalia Blinova, Ludmila Kondratjeva, Anatoly Kuzin, Mikhail Boyarkin, Tatyana Gomova, Alexander Khokhlov, Sergey Vorobjev, Olga Mirolyubova, Svetlana Boldueva, Olga Ershova, Marina Ballyzek, Olga Smolenskaya, Sergey S. Yakushin, Dmitry Zateyshchikov, Mikhail Arkhipov, Alexandr Kuzmenko, Ivan Maksimov, Igor Motylev, Vladimir Rafalskiy, Leonid Strongin, Tatyana Treshkur, Natalya Volkova, Olga Barbarash, Tatiana Raskina, Leonid Bartosh, Inna Nikolskaya, Elena Shutemova, Viktor Gurevich, Natalia Burova, Elena Vorobyeva, Denis Andreev, Boris Bart, Tatiana Khlevchuk, Lyudmila Gapon, Ivan Gordeev, Nikolai Gratsiansky, Alsu Zalevskaya, Sergey Sayganov, Oleg Solovyev, Galina Reshedko, Natalia Shilkina, Petr Chizhov, Julia Shapovalova, Alexander Sherenkov, Olga Reshetko, Vladimir Simanenkov; Spain: Juan Garcia Puig, Jose Saban, Jose Pascual, Jose Dominguez, Elias Delgado, Carlos Calvo, Manuel Vida, Santiago Duran, Francisco Tinahones, Jordi Salas, Jose Miguel Gonzalez, Manuel Monreal, Armand Grau, Andreu Nubiola, Pere Alvarez; Sweden: Kaj Stenlöf, Pekka Koskinen, Carl-Johan Lindholm, Ulrik Mathiesen, Katarina Berndtsson Blom, Bengt-Olov Tengmark, Hans Jul-Nielsen; Ukraine: Oleksandr Larin, Svetlana Panina, Svitlana Kovalenko, Olena Voloshyna, Vera Tseluyko, Olga Gyrina, Vadim Vizir, Olga Barna, Maryna Dolzhenko, Yuriy Mostovoy, Vadim Korpachev, Boris Mankovskiy, Mykola Vatutin; United States: Charles Arena, Basil Akpunonu, Rahfa Zerikly, Claire Baker, Toby Briskin, Darlene Bartilucci, Joshua Barzilay, Christian Breton, John Buse, Richard Cherlin, Michael Cobble, Clarence Ellis, Raymond Fink, Alan Forker, Ronald Garcia, Priscilla Hollander, Angela House, Daniel Hyman, Richard Ingebretsen, David Jack, Judith Kirstein, Kerri Kissell, Daniel Lorber, Donald McNeil, Wendell Miers, Alex Murray, Robert Call, Stephen T. Ong, Fernando Ovalle, Robert Pearlstein, Veronica Piziak, Daniel Pomposini, David Robertson, Julio Rosenstock, Ulrich Schubart, Shaukat Shah, Rodney Stout, Mark Turner, James Wallace, Leonard Chuck, Edmund Claxton, Emily Morawski, Alan Wynne, Carol Wysham, Michael Alderman, Walter Patton, Bryan Pogue, Arnold Silva,

Roger Guthrie, Sam Lerman, Robert Madder, Wendy Miller, Daniel Weiss, Dean Kereiakes, Ronald J Graf, Negah Rassouli, James Greenwald, Hanna Abu-Nassar, Derek Muse, Vicki Kalen, Natalia Hegedosh, Richard Dobrusin, Glover Johnson, Tami Bruce, Gary Gleason.

CANVAS-R Argentina: Marisa Vico, Sonia Hermida, Lucrecia Nardone, Laura Maffei, Javier Farias, Elizabeth Gelersztein, Maximiliano Sicer, Andres Alvarisqueta, Georgina Sposetti, Virginia Visco, Rodolfo Feldman, Silvia Orio; Australia: Christopher Nolan, Michael Suranyi, Samantha Hocking, Stephen Stranks, Duncan Cooke, Ferdinandus de Looze, Ashim Sinha, Timothy Davis, Anthony Russell, Acharya Shamasunder, Murray Gerstman, Richard MacIsaac; Belgium: Chris Vercammen, Luc Van Gaal, Chantal Mathieu, Xavier Warling, Jan Behets, Andre Scheen, Guy T’Sjoen, Ann Verhaegen, Isabelle Dumont, Youri Taes, Francis Duyck, Fabienne Lienart; Brazil: Adolfo Sparenberg, Adriana Costa e Forti, Andressa Leitao, Cariolina Jungers di Siqueira Chrisman, César Hayashida, Daniel Panarotto, Fabio Rossi dos Sanos, Fadlo Fraige Filho, Flávia Coimbra Maia, Gilmar Reis, Hugo Lisboa, Joao Felicio, Joselita Siqueira, Lilia Nigro Maia, Luiz Alberto Andreotti Turatti, Maria José Cerqueira, Maria Tereza Zanella, Patricia Muszkat, Miguel Nasser Hissa, Teresa Bonansea; Canada: Igor Wilderman, Vincent Woo, Richard Dumas, Francois Blouin, Pierre Filteau, George Tsoukas, Peter Milne, Dan Dattani, Chantal Godin, Michael Omahony, Daniel Shu, Jasmin Belle-Isle, Douglas Friars, Anil Gupta, Ted Nemtean, Andrew Steele; China: Zhan-Quan Li, Changsheng Ma, Linong Ji, Shuguang Pang, Yan Jing, Ruiping Zhao, Ruifang Bu; Czech Republic: Tomas Spousta, Tatana Souckova, Dagmar Bartaskova, Pavlina Kyselova, Lea Raclavska, Milan Kvapil, Jana Havelkova, Emilia Malicherova; France: Philippe Zaoui, Didier Gouet, Jean-Pierre Courreges, Salha Fendri, Samy Hadjadj, Bruno Verges, Bogdan Nicolescu Catargi, Sylvaine Clavel, Jean-Jacques Altman, Agnes Hartemann, Gaétan Prevost; Germany: Diethelm Tschöpe, Elena Henkel, Rolf Göbel, Jochen Seufert, Hermann Haller, Thomas Behnke, Andreas Pfützner, Gerhard Klausmann, Klaus Busch, Baerbel Hirschhaeuser, Stephan Jacob; Great Britain: Melanie Davies, Rob Andrews, Narayan Annamalai, Hamish Courtney, Srikanth Bellary, Mark Blagden, John Clark, Steven Creely, Ken Darzy, Iskandar Idris, Richard Falk, Lucinda Summers, Njaimeh Asamoah, Andrew Johnson, See Kwok, Shenaz Ramtoola, Gerry Rayman, Jamie Smith, John Wilding; Hungary: Marietta Baranyai, Katalin Csomos, Mihaly Gurzo, Eleonóra Harcsa, Nikosz Kanakaridisz, Nóra Késmárki, Tamas Oroszlan, József Pátkay, Eva Peterfai, Balázs Gaszner, Ildiko Jozsef; Italy: Stefano Genovese, Antonio Ettore Pontiroli, Enzo Bonora, Dario Giugliano, Domenico Cucinotta, Giorgio Sesti, Paola Ponzani, Giuseppe Pugliese, Giulio Marchesini Reggiani, Paolo Pozzilli, Sergio Leotta, Emanuela Orsi, Carlo Giorda, Paolo Di Bartolo; Korea: Tae-Sun Park, Chung-Gu Cho, In-Joo Kim, Il Seong Nam-Goong, Choon Hee Chung, Ho Chan Cho, Dong- Seop Choi, Kun-Ho Yoon, Nan-Hee Kim, Kyung-Mook Choi, Kyu-Jeung Ahn, Ji-Oh Mok, Soon-Jib Yoo, Tae-Keun Oh, Kwan-Woo Lee, Hak-Chul Jang, Jeong-Hyun Park, In-Kyu Lee, Byung-Joon Kim, Doo-Man Kim, Ho Sang Shon, Moon-Kyu Lee, ShinGon Kim; Malaysia: Mafauzy Mohamed, Paranthaman Vengadasalam, Alexander Tong Boon Tan, Wan Mohd Izani Wan Mohamed, Rajesh P Shah, Khalid Yusoff, Amir Sharifuddin Mohd Khir, Florence Tan, Mansor Yahya; Mexico: Rafael Violante, Manuel Odin De los Rios, Marco Alcocer, Enrique Morales, Juan Rosas, Armando Vargas, Manuel González, Esperanza Martinez, Jorge Antonio Aldrete, Guillermo Gonzalez, Cynthia Mustieles Rocha, Leobardo Sauque, Paul Frenk, José Luis Arenas; The Netherlands: Peter Tichelaar, A Kooy, Albert Van de Wiel, Gerben Lochorn, Peter De Vries, Hans Feenstra, Max Nieuwdorp, Wouter Van Kempen, Mazin Alhakim, Ben Imholz, Ruud van Leendert, Peter Smak Gregoor, Joop Brussen, Hanno Pijl, Manuel Castro Cabezas, F Gonkel, P Smits, Daan Lansdorp, Susanne Kentgens, Aletha Veenendaal, Gloria Rojas; New Zealand: John Richmond, Russell Scott, Mike Williams, Dean Quinn, Jeremy Krebs, John Baker, Veronica Crawford, Calum Young; Poland: Malgorzata Arciszewska, Krystyna Jedynasty, Dariusz Sowinski, Ewa Szyprowska, Andrzej Madej, Miroslawa Polaszewska- Muszynska, Danuta Zytkiewicz-Jaruga, Katarzyna Wasilewska, Piotr Romanczuk, Anna Ocicka-Kozakiewicz, Czeslaw Marcisz, Boguslaw Okopien, Anna Bochenek, Lukasz Wojnowski, Teresa Sliwinska, Barbara Rewerska, Witold Zmuda, Katarzyna Klodawska, Ewa Skokowska, Jacek Fabisiak, Cezary Danilkiewicz; Puerto Rico: Elba Perez Vargas, Elizabeth Barranco Santana; Russia: Tatiana Raskina, Olga Barbarash, Leonid Bartosh, Igor Motylev, A Kuzin, Olga Reshetko, Tatyana Zykova, Olga Ershova, Marina Balyzek, Vladimir Rafalsky, Natalya Volkova, Nina Nosova, Natalia Burova, Alsu Zalevskaya, Galina Reshedko, Natalia Shilkina, Petr Chizhov, Alexander Sherenkov, Vladimir Simanenkov, Tatiana Lysenko, Irina Ipatko, Mikhail Boyarkin, Sergey Vorobyev, Lyudmila Gapon, Andrey Obrezan, Valeria Esip, Zhanna Paltsman, Andrey Verbovoy, Fatima Khetagurova, Yuri Shvarts; Spain: Pere Alvarez-Garcia, Francisco Martinez Deben, Josep M Grinyo, Carlos Calvo, Carmen Suarez, JM Pascual, Jose Dominguez, Anna Oliveras, Armand Grau, Fernando Gómez Peralta, Luis Alvarez-Sala, Cañizo Francisco, Jorge Gómez Cerezo, Juan Garcia Puig, Carlos Trescolí, Francisco Jose Fuentes Jimenez, Santiago Tofé, Judith López, Javier Nieto Iglesias, Luis Vigil, Santiago Duran Garcia, Jose Luis Gorriz, Pilar Saavedra Vallejo, Francisco Tinahones Madueno, Jose Luis Blanco Coronado, Alfonso Soto, Luis De Teresa, Jose Miguel Gonzalez, Antonio Rodriguez Botaro, Carmina Cuesta; Sweden: Bjorn Bragée, Bengt-Olov Tengmark, Hans Jul-Nielsen, Pekka Koskinen, Linda Moris, Fredrik Huss, Pär

Jennersjö, Katarina Berndtsson-Blom, Bo Liu, Kaj Stenlöf, Carl-Johan Lindholm, Johan Jendle; Taiwan: Dee Pei, Wayne H-H Shue, Chern-En Chiang, Ching-Chu Chen, Ming-Nan Chien, Ping-Yen Liu, Ching-Ling Lin, Yi-Jing Sheen; Ukraine: Dmytro Reshotko, Nikolay Rishko, Olexander Samoylov, Valentina Serkova, Ivan Smirnov, Liubov Sokolova, Vira Tseluyko, Vadym Vizir, Tetiana Zlova, Vitaliy Maslyanko, Oleksandr Larin, Valentina Velichko, Lyudmila Prystupa, Nadiya Yarema, Galina Mishanich, Iryna Bondarets, Nataliya Virstyuk, Olexander Serhiyenko, Stepan Pavlyk, Olena Levchenko, Orest Abrahamovych, Volodymyr Botsurko, Maryna Dolzhenko, Victoria Chernikova, Yuriy Karachentsev, Vitaliy Katerenchuk, Vadym Korpachov, Yaroslav Malynovsky, Boris Mankovsky, Yuriy Mostovoy, Larisa Pererva, Nataliya Pertseva; United States: Vicki Conrad, Kenneth Fox, David Jack, Robert Buynak, Michael Dever, John Kirby, Larry Odekirk, Priyantha Wijewardane, Robert Carson, Bruce Seaton, Ann Elizabeth Mohart, Salvatore Bianco, Michael R Cox, Andrew Kim, Steven Geller, Jakkidi Reddy, Derek Muse, Alan Wynne, Harold Bays, Judith Kirstein, James Riser, Ahmed Arif, Claire Baker, Kim Barbel-Johnson, Gary Bedel, Pierre Blemur, Christian Breton, Anna Chang, Brian Naccari, Nancy Jo Coburn, Lisa Cohen, Eric Dedeke, Charles Diederich, John Earl, Anu George, Matthew Gilbert, Gary Gleason, Gregory Haase, Rodney Ison, Mahendra Jain, Imtiaz Alam, Sam Lerman, Lawrence Levinson, Lon D Lynn, Michael Oliver, Barry Kusnick, Robert Pearlstein, Sanford Plevin, Samuel Mujica Trenche, Vernon Young, Michael Jutovsky, Ralph Wade, James Wallace, Albert Weisbrot, Duane Wombolt, Alan Forker, Jalal Taslimi, Roger Guthrie.

CANVAS Program committees Steering Committee David R. Matthews (Co-chair), Bruce Neal (Co-chair), Greg Fulcher, Kenneth W. Mahaffey, Vlado Perkovic, Mehul Desai (Sponsor), Dick de Zeeuw

Independent Data Monitoring Committee Philip Home (Chair), Jeffrey L. Anderson, Ian W. Campbell, John Lachin (withdrew in September 2015), Daniel Scharfstein, Scott D. Solomon, Robert G. Uzzo

Cardiovascular Adjudication Committee Greg Fulcher (Chair), John Amerena, Clara Chow, Gemma Figtree, John French, Graham Hillis, Mark A. Hlatky, Bronwyn Jenkins, Nicholas J. Leeper, Richard Lindley, Barry McGrath, Alison Street, John Watson

Renal Adjudication Committee Greg Fulcher (Chair), Shahnaz Shahinfar, Tara Chang, Arjun D. Sinha, Phyllis August

Safety Adjudication Fracture Adjudication: Bioclinica Diabetic Ketoacidosis Adjudication: Baim Institute for Clinical Research Pancreatitis Adjudication Committee: Adam Cheifetz (Chair), Sunil Sheth, Joseph Feuerstein

Definitions of stroke and stroke subtypes used by Endpoint Adjudication Committee Stroke A non-fatal stroke was an event that met the current classification definition below and does not result in death within 30 days from onset. The definition was based on the new “tissue” definition of stroke (Sacco et al. Stroke 2013;44:2064). Stroke will also be classified by the Endpoint Adjudication Committee (EAC) according to historical criteria. Any recurrence or exacerbation of the condition within 30 days is considered part of the original episode, whereas beyond that time period it is considered a separate event. Adjudications were based on the best available evidence from the clinical care of the patient with a stroke-like event, with anonymised copies of the medical record sent to stroke experts on the adjudication committee. Events were confirmed if two independent assessors agreed. The documents were sent to a third adjudicator in the event of a disagreement. Three way disagreements were resolved by a full meeting of the adjudication committee.

1. Historical classification An acute disturbance of focal neurological function resulting in symptoms lasting more than 24 hours. 2. Current classification Stroke is defined as an acute episode of neurological dysfunction caused by focal or global brain, spinal cord, or retinal vascular injury. a. Ischemic stroke Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by an infarction of central nervous system tissue. Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke. b. Hemorrhagic stroke Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal dysfunction caused by a nontraumatic intraparenchymal, intraventricular, or subarachnoid hemorrhage. c. Undetermined stroke Undetermined stroke is defined as a stroke with insufficient information to allow categorization as ischemic or hemorrhagic.

Transient Ischemic Attack Transient ischemic attack (TIA) is defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. The distinction between a TIA and an ischemic stroke is the presence of infarction, not the transience of the symptoms. In addition to laboratory documentation of infarction, persistence of symptoms is an acceptable indicator of infarction. Thus, symptoms lasting ≤24 hours versus >24 hours may be used by the EAC to distinguish between transient ischemia and infarction. The committee will endeavor to review any relevant documentation of the cerebrovascular event. However, in the absence of documentation regarding duration of the symptoms, the committee may on occasion use any other reliable source of information such as the diagnosis of the treating physician to determine if the event was a TIA or stroke.

General Considerations Evidence of vascular central nervous system injury without recognized neurological dysfunction may be observed. Examples include microhemorrhage, silent infarction, and silent hemorrhage. When encountered, the clinical relevance of these findings may be unclear. If observed, they should be precisely defined and categorized by the EAC.

Table I. Baseline characteristics of participants with and without cerebrovascular disease (stroke or TIA) at baseline P value§§(w With cerebrovascular disease Without cerebrovascular disease ith vs. without) Canagliflozin Placebo Total Canagliflozin Placebo Total* (N=1113) (N=845) (N=1958) (N=4682) (N=3502) (N=8184) Age — y, mean±SD 63.9±8.5 64.5±8.3 64.1±8.4 63.0±8.2 63.2±8.2 63.1±8.2 <0.001† Female — no. (%) 433 (38.9) 348 (41.2) 781 (39.9) 1603 (34.2) 1249 (35.7) 2852 (34.8) <0.001‡ Race — no. (%) <0.001‡ White 934 (83.9) 711 (84.1) 1645 (84.0) 3574 (76.3) 2725 (77.8) 6299 (77.0) Asia 99 (8.9) 75 (8.9) 174 (8.9) 678 (14.5) 432 (12.3) 1110 (13.6) Black 34 (3.1) 31 (3.7) 65 (3.3) 142 (3.0) 129 (3.7) 271 (3.3) Other§ 46 (4.1) 28 (3.3) 74 (3.8) 288 (6.2) 216 (6.2) 504 (6.2) Region — no. (%) <0.001‡ North America 220 (19.8) 158 (18.7) 378 (19.3) 1205 (25.7) 847 (24.2) 2052 (25.1) Central and South America 68 (6.1) 55 (6.5) 123 (6.3) 469 (10.0) 429 (12.3) 898 (11.0) Europe 352 (31.6) 292 (34.6) 644 (32.9) 1691 (36.1) 1274 (36.4) 2965 (36.2) Rest of the world 473 (42.5) 340 (40.2) 813 (41.5) 1317 (28.1) 952 (27.2) 2269 (27.7) Current smoker — no. (%) 179 (16.1) 137 (16.2) 316 (16.1) 841 (18.0) 649 (18.5) 1490 (18.2) 0.03‡ Hypertension — no. (%) 1035 (93.0) 791 (93.6) 1826 (93.3) 4153 (88.7) 3146 (89.8) 7299 (89.2) <0.001‡ Heart failure — no. (%) 280 (25.2) 216 (25.6) 496 (25.3) 523 (11.2) 442 (12.6) 965 (11.8) <0.001‡ Atrial fibrillation — no. (%) 95 (8.5) 74 (8.8) 169 (8.6) 256 (5.5) 188 (5.4) 444 (5.4) <0.001‡ Duration of diabetes 13.1±8.1 13.5±8.0 13.3±8.1 13.6±7.6 13.7±7.8 13.6±7.7 0.07† Microvascular—yr, mean±sd disease — no. (%) (N=1113) (N=845) (N=1958) (N=4677) (N=3496) (N=8173) Retinopathy 340 (30.5) 243 (28.8) 583 (29.8) 863 (18.4) 683 (19.5) 1546 (18.9) <0.001‡ Nephropathy 238 (21.4) 199 (23.6) 437 (22.3) 756 (16.1) 581 (16.6) 1337 (16.3) <0.001‡ Neuropathy 481 (43.2) 344 (40.7) 825 (42.1) 1306 (27.9) 979 (28.0) 2285 (27.9) <0.001‡ Atherosclerotic vascular disease — no. (%)|| Coronary 595 (53.5) 445 (52.7) 1040 (53.1) 2639 (56.4) 2042 (58.3) 4681 (57.2) 0.001‡ Peripheral 341 (30.6) 237 (28.0) 578 (29.5) 835 (17.8) 700 (20.0) 1535 (18.8) <0.001‡ Any 1113 (100.0) 845 (100.0) 1958(100.0) 3014 (64.4) 2352 (67.2) 5366 (65.6) <0.001‡

Cardiovascular disease# 1010 (90.7) 744 (88.0) 1754 (89.6) 2746 (58.7) 2156 (61.6) 4902 (59.9) <0.001‡ Amputation — no. (%) 21 (1.9) 14 (1.7) 35 (1.8) 115 (2.5) 88 (2.5) 203 (2.5) 0.07‡ Body mass index 32.1±5.8 31.8±5.6 32.0±5.7 31.9±5.9 32.0±6.0 32.0±6.0 0.83† Blood pressure — mmHg (N=1111) (N=844) (N=1955) (N=4676) (N=3497) (N=8173) Systolic 136.7±15.4 137.2±15.6 136.9±15.5 136.4±15.9 136.8±15.8 136.6±15.8 0.43† Diastolic 78.1±9.6 78.2±9.7 78.1±9.6 77.5±9.6 77.7±9.7 77.6±9.7 0.04† HbA1c — % 8.3±1.0 8.2±0.9 8.2±0.9 8.2±0.9 8.3±0.9 8.3±0.9 0.69† Cholesterol — mmol/L Total 4.5±1.3 4.5±1.3 4.5±1.3 4.3±1.1 4.3±1.1 4.3±1.1 <0.001† † HDL (N=1099)1.2±0.3 (N=829)1.2±0.3 (N=1928)1.2±0.3 (N=4635)1.2±0.3 (N=3459)1.2±0.3 (N=8094)1.2±0.3 <0.001 † LDL (N=1099)2.4±1.0 (N=829)2.4±1.0 (N=1928)2.4±1.0 (N=4635)2.3±0.9 (N=3459)2.3±0.9 (N=8094)2.3±0.9 <0.001 † Ratio of LDL to HDL (N=1098)2.1±1.0 (N=829)2.1±1.0 (N=1927)2.1±1.0 (N=4633)2.0±0.9 (N=3458)2.0±0.9 (N=8091)2.0±0.9 0.01 † Triglycerides — mmol/L (N=1098)2.0±1.5 (N=829)2.0±1.6 (N=1927)2.0±1.6 (N=4633)2.0±1.3 (N=3458)2.0±1.5 (N=8091)2.0±1.4 0.90 † eGFR — mL/min/1.73 m² (N=1099)75.0±20.1 (N=829)74.0±20.9 (N=1928)74.6±20.4 (N=4634)77.1±20.3 (N=3459)76.7±20.8 (N=8093)76.9±20.5 <0.001 UACR — mg/g, median (IQR) (N=1113)14.2 (7.0- 44.4) (N=844)12.8 (7.0 -52.6) (N=1957)13.5 (7.0- 46.4) (N=4681)12.0 (6.6- 40.4) (N=3502)11.9 (6.5- 42.2) (N=8183)12.0 (6.6- 40.9) 0.001** †† ratioNormoalbuminuria (interquartile range) — no. (%) (7.0748 -(67.9)44.4) (7.0571 -(68.2)52.6) (7.01319-46.4) (68.0) (6.63264-40.4) (70.4) (6.52424-42.2) (70.1) (6.65688-40.9) (70.3) 0.03 Microalbuminuria — no. (%) 271 (24.6) 177 (21.1) 448 (23.1) 1051 (22.7) 767 (22.2) 1818 (22.5) —no./total no. (%) (N=1102)(67.9) (N=837)(68.2) (N=1939)(68.0) (N=4638)(70.4) (N=3456)(70.1) (N=8094)(70.3) —Macroalbuminuriano./total no. (%) — no. (%) (24.6)83 (7.5) (21.1)89 (10.6) (23.1)172 (8.9) (22.7)323 (7.0) (22.2)265 (7.7) (22.5)588 (7.3) Drug—no./total therapy no.— no.(%) (%) (7.5) (10.6) (8.9) (7.0) (7.7) (7.3) Insulin 553 (49.7) 440 (52.1) 993 (50.7) 2337 (49.9) 1765 (50.4) 4102 (50.1) 0.64‡ Sulfonylurea 496 (44.6) 348 (41.2) 844 (43.1) 2032 (43.4) 1485 (42.4) 3517 (43.0) 0.92‡ Metformin 818 (73.5) 593 (70.2) 1411 (72.1) 3629 (77.5) 2785 (79.5) 6414 (78.4) <0.001‡ GLP-1 receptor agonist 29 (2.6) 33 (3.9) 62 (3.2) 193 (4.1) 152 (4.3) 345 (4.2) 0.03‡ Statin 831 (74.7) 607 (71.8) 1438 (73.4) 3499 (74.7) 2663 (76.0) 6162 (75.3) 0.09‡ Antithrombotic‡‡ 934 (83.9) 698 (82.6) 1632 (83.4) 3302 (70.5) 2537 (72.4) 5839 (71.3) <0.001‡ RAAS inhibitor 910 (81.8) 678 (80.2) 1588 (81.1) 3735 (79.8) 2793 (79.8) 6528 (79.8) 0.18‡ β-blocker 599 (53.8) 435 (51.5) 1034 (52.8) 2440 (52.1) 1947 (55.6) 4387 (53.6) 0.53‡ Diuretic 541 (48.6) 436 (51.6) 977 (49.9) 1995 (42.6) 1518 (43.3) 3513 (42.9) <0.001‡ DPP-4 inhibitor 120 (10.8) 104 (12.3) 224 (11.4) 577 (12.3) 460 (13.1) 1037 (12.7) 0.14‡ Calcium channel blocker 436 (39.2) 364 (43.1) 800 (40.9) 1494 (31.9) 1149 (32.8) 2643 (32.3) <0.001‡

CANVAS, CANagliflozin cardioVascular Assessment Study; CANVAS-R, CANagliflozin cardioVascular Assessment Study–Renal; DPP-4, dipeptidyl peptidase-

4; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; RAAS, renin–angiotensin–aldosterone system; SD, standard deviation, UACR, urinary albumin-to-creatinine ratio.

*One participant was randomized at two different sites, and only the first randomization is included in the intention-to-treat analysis set.

†P value corresponds to the test for no difference between with and without stroke history cohorts from analysis of variance (ANCOVA) model.

‡P value corresponds to generalized Cochran-Mantel-Haenszel test for no general association.

§Includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple, other, and unknown.

||Some patients had more than one type of atherosclerotic vascular disease.

#A history of cardiovascular disease was defined as a history of symptomatic atherosclerotic vascular disease (coronary, cerebrovascular, or peripheral).

**P value corresponds to Wilcoxon rank sum test of equal medians.

††P value corresponds to Van Elteren test for no association.

‡‡Includes antiplatelets and anticoagulants.

§§P value for comparison between total participants with cerebrovascular disease at baseline and total participants without.

Figure I. CANVAS Program: trial flow chart.

ITT, intent-to-treat. *One patient was randomised at 2 different sites and therefore the second randomised ID was excluded from the ITT analysis set. † Percentages calculated based on the ITT analysis set. ‡A patient is considered as having completed the study, regardless of whether the patient is on or off study drug, if the patient is followed until a time point between the notification of the trial end date (November 1, 2016) and the trial end date (February 23, 2017), or until § the time of death for those who died prior to the trial end date. Including results from the search of public records.

Reprinted from New England Journal of Medicine, Neal B, et al., Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes, Volume 377, Pages 644-647 © Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure II. Effects of canagliflozin on stroke risk according to the interval between stroke and last dose of randomized treatment*

HR, hazard ratio; CI, confidence interval. *On-treatment is usually defined as within 30 days of treatment.