An exploration of the heterogeneity in effects of SGLT2 inhibition on cardiovascular and all-cause mortality in the EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI 58, and CREDENCE trials
Author(s)
Type
Journal Article
Abstract
BACKGROUND: Large-scale outcome trials of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have identified consistent effects on major adverse cardiovascular events, heart failure, and progression of kidney disease. However, the magnitude of effects on cardiovascular and all-cause death appeared to vary between some of the studies. METHODS: We explored the impact of differences in trial methodologies, participant characteristics, types of deaths, follow-up duration, effects on intermediate markers of risk, and drug selectivity for SGLT2 on the magnitude of the protective effect against fatal events achieved in the 4 trials. RESULTS: The trial populations differed substantively in the proportions with baseline atherosclerotic cardiovascular disease history (99.2% in EMPA-REG OUTCOME to 40.6% in DECLARE-TIMI 58), and macroalbuminuria (88.0% in CREDENCE to 7.6% in the CANVAS Program). Meta-regression analyses identified no clear effect of these (both P > 0.09) or other participant characteristics on mortality benefits (all P > 0.55). Other differences between the trials (duration, selectivity of the SGLT2 inhibitor, or effects on intermediate markers of risk) also did not explain the heterogeneity in effects on mortality observed (all P > 0.30). CONCLUSION: No clear explanation for the statistical evidence of heterogeneity in effects of SGLT2 inhibition on fatal outcomes between the trials could be identified. While the analyses had limited statistical power, these results raise the possibility that the observed variations in treatment effects on fatal outcomes between trials may be at least partly due to chance.
Date Issued
2021-02-01
Date Acceptance
2020-09-20
ISSN
0167-5273
Publisher
Elsevier
Start Page
165
End Page
172
Journal / Book Title
International Journal of Cardiology
Volume
324
Copyright Statement
© 2020 Elsevier B.V. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Identifier
https://www.sciencedirect.com/science/article/pii/S0167527320338316?via%3Dihub
https://www.ncbi.nlm.nih.gov/pubmed/32979427
S0167-5273(20)33831-6
Subjects
CANVAS program
Cardiovascular mortality
DECLARE- TIMI 58
EMPA-REG OUTCOME
SGLT2i
CANVAS program
Cardiovascular mortality
DECLARE- TIMI 58
EMPA-REG OUTCOME
SGLT2i
Cardiovascular System & Hematology
1102 Cardiorespiratory Medicine and Haematology
1117 Public Health and Health Services
Publication Status
Published
Coverage Spatial
Netherlands
Date Publish Online
2020-09-24