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Open Access 01-12-2019 | Exenatide | Original investigation

Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial

Authors: Lindsay E. Clegg, Robert C. Penland, Srinivas Bachina, David W. Boulton, Marcus Thuresson, Hiddo J. L. Heerspink, Stephanie Gustavson, C. David Sjöström, James A. Ruggles, Adrian F. Hernandez, John B. Buse, Robert J. Mentz, Rury R. Holman

Published in: Cardiovascular Diabetology | Issue 1/2019

Abstract

Background

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes.

Methods

In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses.

Results

In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39–1.17) and EQW alone (0.85, 0.48–1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16–0.90) and compared with EQW (0.41, 0.17–0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94–2.94 mL/min/1.73 m²/year) and EQW alone (+ 2.38, 1.40–3.35 mL/min/1.73 m²/year).

Conclusions

This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality.

Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.

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Title: Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial
Authors: Lindsay E. Clegg
Robert C. Penland
Srinivas Bachina
David W. Boulton
Marcus Thuresson
Hiddo J. L. Heerspink
Stephanie Gustavson
C. David Sjöström
James A. Ruggles
Adrian F. Hernandez
John B. Buse
Robert J. Mentz
Rury R. Holman
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Exenatide
Type 2 Diabetes
Published in: Cardiovascular Diabetology / Issue 1/2019
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-019-0942-x

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