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

Jie Yu; Zien Zhou; Kenneth W Mahaffey; David R Matthews; Brendon L Neuen; Hiddo J L Heerspink; Meg J Jardine; JingWei Li; Vlado Perkovic; Bruce Neal; Clare Arnott

doi:10.1016/j.ijcard.2020.09.050

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

Int J Cardiol. 2021 Feb 1:324:165-172. doi: 10.1016/j.ijcard.2020.09.050. Epub 2020 Sep 24.

Authors

Jie Yu¹, Zien Zhou², Kenneth W Mahaffey³, David R Matthews⁴, Brendon L Neuen⁵, Hiddo J L Heerspink⁶, Meg J Jardine⁷, JingWei Li⁸, Vlado Perkovic⁹, Bruce Neal¹⁰, Clare Arnott¹¹

Affiliations

¹ The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Cardiology, Peking University Third Hospital, Beijing, China.
² The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Oxford Centre for Diabetes, Endocrinology and Metabolism, Harris Manchester College, University of Oxford, Oxford, UK.
⁵ The George Institute for Global Health, UNSW Sydney, Sydney, Australia.
⁶ The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands.
⁷ The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Concord Repatriation General Hospital, Sydney, Australia.
⁸ The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Cardiology, People's Liberation Army General Hospital, Beijing, China; Department of Cardiology, Xinqiao Hospital, Army Military Medical University, Chongqing, China.
⁹ The George Institute for Global Health, UNSW Sydney, Sydney, Australia; The Royal North Shore Hospital, Sydney, Australia.
¹⁰ The George Institute for Global Health, UNSW Sydney, Sydney, Australia; The Charles Perkins Centre, University of Sydney, Sydney, Australia; Imperial College London, London, UK.
¹¹ The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia; Sydney Medical School, University of Sydney, Australia; University of New South Wales, Sydney, Australia. Electronic address: carnott@georgeinstitute.org.au.

PMID: 32979427
DOI: 10.1016/j.ijcard.2020.09.050

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.

Keywords: CANVAS program; Cardiovascular mortality; DECLARE- TIMI 58; EMPA-REG OUTCOME; SGLT2i.

MeSH terms

Cardiovascular Diseases* / diagnosis
Cardiovascular Diseases* / drug therapy
Cardiovascular System*
Diabetes Mellitus, Type 2* / diagnosis
Diabetes Mellitus, Type 2* / drug therapy
Humans
Hypoglycemic Agents / therapeutic use
Sodium-Glucose Transporter 2
Sodium-Glucose Transporter 2 Inhibitors*

Substances

Hypoglycemic Agents
Sodium-Glucose Transporter 2
Sodium-Glucose Transporter 2 Inhibitors