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Subcutaneous infusion of exenatide and cardiovascular outcomes in type 2 diabetes: a non-inferiority randomized controlled trial

Nature Medicine volume 28, pages 89–95 (2022)Cite this article

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Abstract

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) injected periodically have been shown to not increase and, for some members of this class, decrease the risk of cardiovascular events. The cardiovascular safety of delivering a continuous subcutaneous infusion of the GLP-1RA exenatide (ITCA 650) is unknown. Here, we randomly assigned patients with type 2 diabetes with, or at risk for, atherosclerotic cardiovascular disease (ASCVD) to receive ITCA 650 or placebo to assess cardiovascular safety in a pre-approval trial (NCT01455896). The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina. On the basis of 2008 guidance from the US Food and Drug Administration, a non-inferiority margin of 1.8 for the upper bound of the 95% confidence interval (CI) of the hazard ratio (HR) was used. We randomized 4,156 patients (2,075 assigned to receive ITCA 650 and 2,081 assigned to receive placebo) who were followed for a median of 16 months. The primary outcome occurred in 4.6% (95/2,075) of patients in the ITCA 650 group and 3.8% (79/2,081) of patients in the placebo group, meeting the pre-specified non-inferiority criterion (HR = 1.21, 95% CI, 0.90–1.63, Pnon-inferiority = 0.004). Serious adverse events were similar between the two groups. Adverse events were more frequent in the ITCA 650 group (72%, 1,491/2,074) than in the placebo group (63.9%, 1,325/2,070), mainly due to an increase in gastrointestinal events and disorders while on ITCA 650. In patients with type 2 diabetes with, or at risk for, ASCVD, ITCA 650 was non-inferior to placebo. A larger and longer-duration cardiovascular outcomes trial is needed to define more precisely the cardiovascular effects of ITCA 650 in this population.

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Fig. 1: CONSORT flow diagram.
Fig. 2: Cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina.
Fig. 3: Glycated hemoglobin and body weight.

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Data availability

Data from these analyses cannot be made publicly available owing to contractual obligations with the sponsor. We encourage parties interested in collaboration and data sharing to submit an application for non-commercial use to the corresponding author (C.T.R.). Applications should outline specifically what data they are interested in receiving and how the data will be used. Any data that can be shared will need approval from the sponsor and require a material transfer agreement. All data shared will be de-identified.

Code availability

Detailed descriptions of analyses and methods are provided in the Trial Protocol and the Statistical Analysis Plan, which have been provided as separate documents. All statistical computations were performed with SAS software, version 9.4 (SAS Institute).

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Acknowledgements

Intarcia Therapeutics was the sponsor of this trial and was responsible for data collection.

Author information

Authors and Affiliations

  1. TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Christian T. Ruff, KyungAh Im, Michelle L. O’Donoghue & Marc S. Sabatine

  2. Intarcia Therapeutics, Hayward, CA, USA

    Michelle Baron & Fred T. Fiedorek

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  1. Christian T. Ruff
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Contributions

All authors had full access to the data. C.T.R. wrote the first draft of the manuscript. All co-authors (C.T.R., M.B., K.I., M.L.O., F.T.T. and M.S.S.) participated in subsequent revisions of the manuscript. C.T.R. and M.S.S. had final responsibility for the decision to submit the manuscript for publication, and they assume responsibility for the accuracy and completeness of the data and analyses.

Corresponding author

Correspondence to Christian T. Ruff.

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Competing interests

C.T.R. reports grant support from Boehringer Ingelheim, Daiichi Sankyo, MedImmune and the National Institutes of Health and has received consulting fees from Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, MedImmune, Pfizer, Portola and Anthos. M.B. and F.T.T. are employees of Intarcia Therapeutics, and M.B. owns stock in Intarcia Therapeutics. M.L.O. reports grants from Eisai, AstraZeneca, GlaxoSmithKline, Merck, Amgen, Janssen and The Medicines Company and has received consulting fees from Novartis, Janssen, Amgen and AstraZeneca. M.S.S. reports research grant support from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia Therapeutics, IONIS, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Quark Pharmaceuticals, Roche Diagnostics and Takeda and has received consulting fees from Alnylam, Amgen, AstraZeneca, Bristol Myers Squibb, CVS Caremark, Dyrnamix, Esperion, IFM Pharmaceuticals, Intarcia Therapeutics, Ionis, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Moderna, MyoKardia, Novartis and Novo Nordisk. C.T.R., M.L.O., K.I. and M.S.S. are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, BRAHMS, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia Therapeutics, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company and Zora Biosciences.

Additional information

Peer review information Nature Medicine thanks Luke Ouma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Jennifer Sargent and Michael Basson were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 ITCA 650.

ITCA 650 delivers a continuous subcutaneous infusion of exenatide by an osmotic mini-pump, which releases the drug at a predetermined rate based on the principle of osmosis.

Extended Data Fig. 2 Subgroup Analysis for Cardiovascular Death, Non-Fatal Myocardial Infarction, Non-Fatal Stroke, or Hospitalization for Unstable Angina.

Shown are hazard ratios, 95% confidence intervals, and two-sided p-values derived from a stratified Cox proportional-hazards model for the primary efficacy outcome of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina. There was no adjustment for multiple testing.

Extended Data Fig. 3 Additional Trials Included in Meta-Analysis.

Primary outcome: CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina. Key secondary outcome: CV death, non-fatal myocardial infarction, or non-fatal stroke.

Extended Data Fig. 4 IPD Meta-Analysis: Cardiovascular Death, Non-Fatal Myocardial Infarction, Non-Fatal Stroke, or Hospitalization for Unstable Angina.

Shown is the cumulative incidence of the primary efficacy outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina.

Extended Data Fig. 5 IPD Meta-Analysis: Cardiovascular Death, Non-Fatal Myocardial Infarction, or Non-Fatal Stroke.

Shown is the cumulative incidence of the key secondary outcome of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.

Extended Data Fig. 6 Initiation of New Antihyperglycemic Medication.

Shown is cumulative incidence of initiation of new antihyperglycemic medication.

Supplementary information

Supplementary Information

Supplementary Notes 1 (Site Investigator List), 2 (Inclusion and Exclusion Criteria) and 3 (Clinical Event Definition)

Reporting Summary

Supplementary Data

Statistical Analysis Plan

Supplementary Data

Trial Protocol

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Ruff, C.T., Baron, M., Im, K. et al. Subcutaneous infusion of exenatide and cardiovascular outcomes in type 2 diabetes: a non-inferiority randomized controlled trial. Nat Med 28, 89–95 (2022). https://doi.org/10.1038/s41591-021-01584-3

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