Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs

The CVD-REAL 2 Study

CVD-REAL Investigators and Study Group

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Background: Randomized trials demonstrated a 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 a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe. Objectives: The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions. Methods: New users of SGLT-2i and oGLDs 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 CV disease. 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 versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval [CI]: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease. Conclusions: In this large, international study of patients with T2D from the Asia Pacific, the 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. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)

Original languageEnglish
Pages (from-to)2628-2639
Number of pages12
JournalJournal of the American College of Cardiology
Volume71
Issue number23
DOIs
Publication statusPublished - 2018 Jun 12

Fingerprint

Sodium-Glucose Transport Proteins
Glucose
Heart Failure
Pharmaceutical Preparations
Confidence Intervals
Hospitalization
Type 2 Diabetes Mellitus
Middle East
Cardiovascular Diseases
Stroke
Propensity Score
Republic of Korea
Singapore
Israel
North America
Canada
Medical Records
Registries
Meta-Analysis
Japan

Keywords

  • death
  • diabetes mellitus
  • heart failure
  • observational studies
  • SGLT-2 inhibitor
  • sodium glucose cotransporter-2 inhibitors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs : The CVD-REAL 2 Study. / CVD-REAL Investigators and Study Group.

In: Journal of the American College of Cardiology, Vol. 71, No. 23, 12.06.2018, p. 2628-2639.

Research output: Contribution to journalArticle

@article{af7d51fd1edd49b4ac546b8f40594019,
title = "Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study",
abstract = "Background: Randomized trials demonstrated a 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 a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe. Objectives: The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions. Methods: New users of SGLT-2i and oGLDs 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 CV disease. 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 versus oGLDs was associated with a lower risk of death (HR: 0.51; 95{\%} confidence interval [CI]: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95{\%} CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95{\%} CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95{\%} CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95{\%} CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease. Conclusions: In this large, international study of patients with T2D from the Asia Pacific, the 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. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)",
keywords = "death, diabetes mellitus, heart failure, observational studies, SGLT-2 inhibitor, sodium glucose cotransporter-2 inhibitors",
author = "{CVD-REAL Investigators and Study Group} and Mikhail Kosiborod and Lam, {Carolyn S.P.} and Shun Kosaka and Kim, {Dae Jung} and Avraham Karasik and Jonathan Shaw and Navdeep Tangri and Goh, {Su Yen} and Marcus Thuresson and Hungta Chen and Filip Surmont and Niklas Hammar and Peter Fenici and Mikhail Kosiborod and Cavender, {Matthew A.} and Fu, {Alex Z.} and Wilding, {John P.} and Kamlesh Khunti and Anna Norhammar and K{\aa}re Birkeland and J{\o}rgensen, {Marit Eika} and Holl, {Reinhard W.} and Lam, {Carolyn SP} and Gulseth, {Hanne L{\o}vdal} and Bendix Carstensen and Esther Bollow and Josep Franch-Nadal and {Garc{\'i}a Rodr{\'i}guez}, {Luis Alberto} and Avraham Karasik and Navdeep Tangri and Shun Kohsaka and Kim, {Dae Jung} and Jonathan Shaw and Suzanne Arnold and Goh, {Su Yen} and Niklas Hammar and Peter Fenici and Johan Bodeg{\aa}rd and Hungta Chen and Filip Surmont and Kyle Nahrebne and Blak, {Betina T.} and Wittbrodt, {Eric T.} and Matthias Saathoff and Yusuke Noguchi and Donna Tan and Maro Williams and Lee, {Hye Won} and Maya Greenbloom and Oksana Kaidanovich-Beilin",
year = "2018",
month = "6",
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doi = "10.1016/j.jacc.2018.03.009",
language = "English",
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TY - JOUR

T1 - Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs

T2 - The CVD-REAL 2 Study

AU - CVD-REAL Investigators and Study Group

AU - Kosiborod, Mikhail

AU - Lam, Carolyn S.P.

AU - Kosaka, Shun

AU - Kim, Dae Jung

AU - Karasik, Avraham

AU - Shaw, Jonathan

AU - Tangri, Navdeep

AU - Goh, Su Yen

AU - Thuresson, Marcus

AU - Chen, Hungta

AU - Surmont, Filip

AU - Hammar, Niklas

AU - Fenici, Peter

AU - Kosiborod, Mikhail

AU - Cavender, Matthew A.

AU - Fu, Alex Z.

AU - Wilding, John P.

AU - Khunti, Kamlesh

AU - Norhammar, Anna

AU - Birkeland, Kåre

AU - Jørgensen, Marit Eika

AU - Holl, Reinhard W.

AU - Lam, Carolyn SP

AU - Gulseth, Hanne Løvdal

AU - Carstensen, Bendix

AU - Bollow, Esther

AU - Franch-Nadal, Josep

AU - García Rodríguez, Luis Alberto

AU - Karasik, Avraham

AU - Tangri, Navdeep

AU - Kohsaka, Shun

AU - Kim, Dae Jung

AU - Shaw, Jonathan

AU - Arnold, Suzanne

AU - Goh, Su Yen

AU - Hammar, Niklas

AU - Fenici, Peter

AU - Bodegård, Johan

AU - Chen, Hungta

AU - Surmont, Filip

AU - Nahrebne, Kyle

AU - Blak, Betina T.

AU - Wittbrodt, Eric T.

AU - Saathoff, Matthias

AU - Noguchi, Yusuke

AU - Tan, Donna

AU - Williams, Maro

AU - Lee, Hye Won

AU - Greenbloom, Maya

AU - Kaidanovich-Beilin, Oksana

PY - 2018/6/12

Y1 - 2018/6/12

N2 - Background: Randomized trials demonstrated a 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 a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe. Objectives: The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions. Methods: New users of SGLT-2i and oGLDs 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 CV disease. 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 versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval [CI]: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease. Conclusions: In this large, international study of patients with T2D from the Asia Pacific, the 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. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)

AB - Background: Randomized trials demonstrated a 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 a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe. Objectives: The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions. Methods: New users of SGLT-2i and oGLDs 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 CV disease. 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 versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval [CI]: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease. Conclusions: In this large, international study of patients with T2D from the Asia Pacific, the 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. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)

KW - death

KW - diabetes mellitus

KW - heart failure

KW - observational studies

KW - SGLT-2 inhibitor

KW - sodium glucose cotransporter-2 inhibitors

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U2 - 10.1016/j.jacc.2018.03.009

DO - 10.1016/j.jacc.2018.03.009

M3 - Article

VL - 71

SP - 2628

EP - 2639

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 23

ER -