Author + information
- Received March 5, 2018
- Accepted March 5, 2018
- Published online March 11, 2018.
- Mikhail Kosiborod, MDa,∗ (, )
- Carolyn S.P. Lam, MBBS PhDb,
- Shun Kohsaka, MDc,
- Dae Jung Kim, MDd,
- Avraham Karasik, MDe,
- Jonathan Shaw, MDf,
- Navdeep Tangri, MD PhDg,
- Su-Yen Goh, MDh,
- Marcus Thuresson, PhDi,
- Hungta Chen, PhDj,
- Filip Surmont, MDk,
- Niklas Hammar, PhDl,m,
- Peter Fenici, MDn,
- on behalf of the CVD-REAL Investigators and Study Group
- aSaint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, Missouri
- bNational Heart Centre, Singapore and SingHealth Duke-NUS, Singapore, and University Medical Centre Groningen, the Netherlands
- cKeio University School of Medicine, Tokyo, Japan
- dDepartment of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
- eTel Aviv University, and Maccabi Healthcare Israel
- fBaker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- gDepartment of Medicine, University of Manitoba, Winnipeg, MB, Canada
- hSingapore General Hospital, Singapore
- iStatisticon AB, Uppsala, Sweden
- jAstraZeneca, Gaithersburg, Maryland
- kAstraZeneca, Luton, United Kingdom
- lKarolinska Institutet, Stockholm, Sweden
- mAstraZeneca, Gothenburg, Sweden
- nAstraZeneca, Cambridge, United Kingdom
- ↵∗Address for correspondence: Mikhail Kosiborod, MD Saint Luke’s Mid America Heart Institute 4401 Wornall Road Kansas City, Missouri, 64111 Tel: +1 8169323445 Fax: +1 8169325798.
Background Randomized trials demonstrated lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with broader risk profile, but focused on heart failure and death, and were limited to US and Europe.
Objectives To examine a broad range of CV outcomes in patients initiated on SGLT-2i vs. other glucose lowering drugs (oGLD) across six countries in Asia Pacific, Middle East and North America (NCT02993614).
Methods New users of SGLT-2i and oGLD were identified via claims, medical records and national registries in South Korea, Japan, Singapore, Israel, Australia and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI and stroke were assessed by country and pooled using weighted meta-analysis.
Results After propensity-matching, there were 235,064 episodes of treatment initiation in each group; ∼27% had established CVD. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3% and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i vs. oGLDs was associated with lower risk of death (HR 0.51, 95%CI 0.37–0.70; P<0.001), HHF (HR 0.64, 95%CI 0.50–0.82; P=0.001), death or HHF (HR 0.60; 95%CI 0.47–0.76; P<0.001), MI (HR 0.81, 95%CI 0.74–0.88; P<0.001) and stroke (HR 0.68, 95%CI 0.55–0.84; P<0.001). Results were directionally consistent both across countries, and patient subgroups, including those with and without CVD.
Conclusions In this large, international study of patients with T2D from the Asia-Pacific, Middle East and North America, initiation of SGLT-2i was associated with a lower risk of CV events, across a broad range of outcomes and patient characteristics.
- diabetes mellitus
- heart failure
- observational studies
- sodium glucose cotransporter-2 inhibitors
- SGLT-2 inhibitor
Funding: This study was funded by AstraZeneca
Disclosures: MK: research grants from AstraZeneca and Boehringer Ingelheim, advisory boards for AstraZeneca, Boehringer Ingelheim, Sanofi, Glytec, Novo Nordisk, ZS Pharma, Janssen, Merck (Diabetes) and Novartis; consultant for AstraZeneca, Boehringer Ingelheim, Sanofi, GSK, Janssen, Intarcia, Merck (Diabetes), Novo Nordisk, Glytec and ZS Pharma.
CSPL: has received research support from Boston Scientific, Bayer, Thermofisher, Medtronic, and Vifor Pharma; and has consulted for Bayer, Novartis, Takeda, Merck, Astra Zeneca, Janssen Research & Development, LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Roche, and Amgen; SK: has received grants from Bayer Yakuhin and Daiichi Sankyo and consulting fees from Bayer Yakuhin, Bristol-Myers Squibb, and Pfizer.; DJK: has received grant support from LG Life Sciences, Chong Kun Dang and AstraZeneca; has been a consultant for AstraZeneca, Novo Nordisk, and Sanofi; has received speaker fees from Novo Nordisk, Takeda, Handok, CJ Healthcare, Chong Kun Dang, MSD, Hanmi, and AstraZeneca.; AK: has received grants and consulting fees from Astra Zeneca, Novo Nordisk, Merck, and Boheringer Ingelheim.; JS: has received honoraria for advisory boards and lectures from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Mylan, Novartis, Novo Nordisk, and Sanofi.; NT: has received consulting fees from Otsuka, Tricida, and AstraZeneca. He has received research support from AstraZeneca, including for this work. His research program is supported by the Canadian Institute for Health Research and Research Manitoba; SYG: has received institutional grants from AstraZeneca, Medtronic, and Sanofi. He has participated in advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Medtronic and Sanofi and has received honoraria for participation; MT: Employee at Statisticon for which AstraZeneca is a client; HC, FS, NH and PF: AstraZeneca employees.
- Received March 5, 2018.
- Accepted March 5, 2018.