Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Oct 22;18(1):138.
doi: 10.1186/s12933-019-0942-x.

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

Lindsay E Clegg  1 , Robert C Penland  2 , Srinivas Bachina  2 , David W Boulton  3 , Marcus Thuresson  4 , Hiddo J L Heerspink  5 , Stephanie Gustavson  6 , C David Sjöström  7 , James A Ruggles  8 , Adrian F Hernandez  9 , John B Buse  10 , Robert J Mentz  9 , Rury R Holman  11
Affiliations

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

Lindsay E Clegg et al. Cardiovasc Diabetol. .

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.

Keywords: Cardiovascular outcomes; Combination therapy; Exenatide; GLP-1 receptor agonist; Propensity score matching; SGLT2 inhibitor; Type 2 diabetes mellitus; eGFR slope.

PubMed Disclaimer

Conflict of interest statement

LEC, RCP, SB, DWB, SG, CDS, and JR are employees and/or shareholders of AstraZeneca. SG’s spouse is also an employee of AstraZeneca. HJLH serves on advisory panels for Boehringer Ingelheim GmbH and Merck & Co., Inc, and is a consultant for AbbVie Inc., AstraZeneca, Fresenius SE & Co. KGaA, Janssen Research & Development, and Mitsubishi Tanabe Pharma Corporation. RCP is a stockholder of Novartis Pharmaceuticals Corporation. DWB is a stockholder of Bristol-Myers Squibb Company. MT is a consultant for AstraZeneca. RJM has received research support and honoraria from AstraZeneca, GlaxoSmithKline plc., and Merck & Co., Inc. AFH is a consultant for Bayer AG & Boehringer Ingelheim Pharmaceuticals, Inc., and receives research support from AstraZeneca, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., and Novartis Pharmaceuticals Corporation. RRH has attended advisory boards at Elcelyx Therapeutics, Inc., Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Amylin, and Eli Lilly. RRH has given lectures supported by Bayer AG, Eli Lilly, Merck & Co., Inc, and Novo Nordisk A/S, and received research support and honoraria from AstraZeneca, Bayer AG, and Merck & Co., Inc. RRH is an Emeritus NIHR Senior Investigator. JBB’s contracted consulting fees are paid to the University of North Carolina by Adocia, AstraZeneca, Dance Biopharm, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, vTv Therapeutics, and Zafgen; grant support from Novo Nordisk, Sanofi, and vTv Therapeutics. He is a consultant to Cirius Therapeutics Inc, CSL Behring, Neurimmune AG, and Whole Biome Inc. He holds stock options in Mellitus Health, PhaseBio, Stability Health, and Whole Biome Inc. He is supported by a grant from the National Institutes of Health (UL1TR002489).

Figures

Fig. 1
Fig. 1
SGLT2i usage in EXSCEL. a Percentage of exenatide arm participants taking SGLT2i at some point, by drug and by region. “Multiple” indicates use of more than one SGLT2i during the trial. b Histogram of time from first to last known SGLT2i use in the EXSCEL exenatide QW (light gray) and placebo (dark gray) arms. Note that, given lack of precise start/stop dates, this estimate of length of SGLT2i exposure represents a lower bound. c, d Time of SGLT2i initiation or matching relative to discontinuation of EQW or placebo in the propensity-matched cohorts. Blue: combination EQW+SGLT2i cohort; green: placebo cohort; red: EQW cohort
Fig. 2
Fig. 2
Cardiovascular, mortality, and safety outcomes with combination exenatide QW+SGLT2i in the propensity-matched cohorts. Additional details are found in Additional file 1: Tables S3, S4, and Kaplan–Meier curves in Additional file 1: Figures S5–S9. Hazard ratio adjusted for age, duration of diabetes, prior cardiovascular disease, heart failure, sex, microalbuminuria, macroalbuminuria, eGFR, and HbA1c, all evaluated at first known SGLT2i usage or equivalent visit in comparator groups. MACE: major adverse cardiovascular events; CV: cardiovascular; pt-yrs: participant-years
Fig. 3
Fig. 3
Geometric mean (+/− standard error) eGFR in the propensity-matched cohorts. a Placebo comparison. b Exenatide comparison. Time zero is the time of first visit with known SGLT2i use/matching. The small differences in eGFR at matching (t=0) also reflect restrictions on SGLT2i use in moderate renal impairment. eGFR slopes prior to matching are shown in Additional file 1: Figure S11. Blue: combination exenatide + SGLT2i cohorts; green: placebo cohort; red: exenatide cohort. eGFR, estimated glomerular filtration rate; SGLT2i, sodium-glucose co-transporter-2 inhibitor
See this image and copyright information in PMC

References

    1. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019 doi: 10.1016/s0140-6736(18)32590-x. - DOI - PubMed
    1. Zelniker Thomas A, Wiviott Stephen D, Raz I, Im K, Goodrich Erica L, Furtado Remo HM, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose co-transporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus: a systematic review and meta-analysis of cardiovascular outcomes trials. Circulation. 2019 doi: 10.1161/circulationaha.118.038868. - DOI - PubMed
    1. Hussein H, Zaccardi F, Khunti K, Seidu S, Davies MJ, Gray LJ. Cardiovascular efficacy and safety of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: a systematic review and network meta-analysis. Diabetic Med. 2019;36(4):444–452. doi: 10.1111/dme.13898. - DOI - PubMed
    1. Giugliano D, Maiorino MI, Bellastella G, Longo M, Chiodini P, Esposito K. GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: an updated meta-analysis including the REWIND and PIONEER 6 trials. Diabetes Obes Metab. 2019 doi: 10.1111/dom.13847. - DOI - PubMed
    1. DeFronzo RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab. 2017;19(10):1353–1362. doi: 10.1111/dom.12982. - DOI - PMC - PubMed

Publication types

MeSH terms

Associated data