Heart Failure Events and All-cause Death in New Users of SGLT-2 inhibitors vs other glucose-lowering drugs - consistent risk reduction across patient groups in 5 countries and >300,000 patients: The CVD-REAL Study Anna Norhammar1, Matthew Cavender2, Kåre Birkeland3, Kamlesh Khunti4, John Wilding5, Niklas Hammar6, Johan Bodegard7, Marcus Thuresson8, Peter Fenici9, Mikhail Kosiborod10 on behalf of the CVD-REAL Investigators and Study Group 1Karolinska Institute, Department of Medicine, Cardiology Unit, Stockholm, Sweden; 2University of North Carolina Hospitals, Chapel Hill, United States of America; 3University of Oslo and Oslo University Hospital, Oslo, Norway; 4University of Leicester, Leicester, United Kingdom; 5University of Liverpool, Liverpool, United Kingdom; 6AstraZeneca, Gothenburg, Sweden; 7AstraZeneca, Oslo, Norway; 8Statisticon AB, Uppsala, Sweden; 9AstraZeneca, Cambridge, United Kingdom; 10Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, United States of America

Presenter Disclosure Disclosures Consultant and honorarium: AstraZeneca, Boehringer-Ingelheim, Lilly, Novo Nordisk, MSD Sweden Acknowledgements This study was supported by AstraZeneca Researchers from AstraZeneca participated in the CVD-REAL study team and interpretation of data Editorial support was provided by Nicola Truss PhD, inScience Communications, Springer Healthcare, and was funded by AstraZeneca

Background Two large RCTs have shown that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) empagliflozin and canagliflozin reduce the risk of major adverse CV events, in a T2D diabetes population primarily with established CV disease (CVD), suggesting a class effect1,2 Presented at ADA2017 by David R. Matthew http://www.georgeinstitute.org/sites/default/files/canvas-study-results-ada-2017.pdf 1Zinman B et al. N Engl J Med. 2015;373:2117-28; 2Neal B et al. N Engl J Med. 2017; DOI: 10.1056/NEJMoa1611925

Background (2) In CVD-REAL, a multinational, observational study with >1.3 million T2D patients, we demonstrated that SGLT-2i were associated with lower risk of death and heart failure vs other glucose- lowering drugs (GLDs) 1,2 Whether the associated benefits of SGLT-2i differ among patients with various demographic, clinical and treatment characteristics is unknown 1Kosiborod M et al. Circulation 2017;136:249–259; 2Cavender M et al. Diabetes, 2017;66(Suppl 1):A99-100 [abstract 377-OR]

Aim Evaluate if the association between SGLT-2i and heart failure events, all-cause death and the composite of heart failure and death is modified by demographic, clinical and treatment factors

Data Sources: Health records from five countries Truven MarketScan Claims database - United States National full-population registries - Denmark National full- population registries - Norway National full-population registries - Sweden Clinical Practice Research Datalink (CPRD) and The Health Improvement Network (THIN) - United Kingdom

Methods Inclusion criteria New users of SGLT-2i or new users of other GLDs Established T2D ≥18 years old >1 year historical data prior to index date Exclusion criteria Type 1 or gestational diabetes Study period 2012-2016 with a mean follow-up time of 225 days Outcomes Heart failure events All-cause death Composite of heart failure events or death

Methods (2) Subgroups studied: Demographics Co-morbidities Age (<65 years or ≥65 years), sex Co-morbidities chronic kidney disease Concomitant therapies Cardiovascular therapies: Angiotensin receptor blocker (ARB)/angiotensin-converting enzyme inhibitors (ACEi), beta blockers, aldosterone antagonists, diuretics, statins Glucose-lowering therapies: Insulin, sulphonylureas

Statistical methods Non-parsimonious propensity score developed in each country to estimate the likelihood of initiating an SGLT-2i Patients matched 1:1 by propensity score In the matched cohort: Patients stratified by key-subgroups Event rates for heart failure, all-cause death and composite were calculated Cox proportional hazards models used to estimate the hazard ratios (HRs) and 95% confidence intervals (CI) for all outcomes, adjusted for baseline risk factors and treatments Meta-analysis used to pool hazard ratios from each country and obtain summary weighted point estimates

Patient population 1,366,731 new users of SGLT-2 inhibitor or other GLD fulfilling the eligibility criteria 164,501 SGLT-2 inhibitor 1,202,230 Other GLD 7% (11,423) excluded during 1:1 match process 87% (1,049,152) excluded during 1:1 match process 1:1 propensity match 153,078 SGLT-2 inhibitor 153,078 Other GLD Final study population

Baseline Characteristics Characteristics, n (%) SGLT-2i (N=153,078) Other GLD (N=153,078) Age, years, mean (SD) 57.0 (10.0) 57.0 (10.6) Women 67,801 (44.3) 68,158 (44.5) Established CVD 19,529 (12.8) 19,764 (12.9) Acute myocardial infarction 3,651 (2.4) 3,733 (2.4) Unstable angina 2,477 (1.6) 2,513 (1.6) Heart failure 4,635 (3.0) 4,677 (3.1) Atrial fibrillation 5,556 (3.6) 5,619 (3.7) Stroke 6,256 (4.1) 6,309 (4.1) Peripheral artery disease 4,924 (3.2) 4,920 (3.2) Microvascular disease 41,496 (27.1) 41,467 (27.1) Chronic kidney disease 3,702 (2.4) 3,865 (2.5)