Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial

Sebastian Wiberg, Christian Hassager, Henrik Schmidt, Jakob Hartvig Thomsen, Martin Frydland, Matias Greve Lindholm, Dan Eik Høfsten, Thomas Engstrøm, Lars Køber, Jacob Eifer Møller, Jesper Kjaergaard

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

BACKGROUND: -In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients.

METHODS: -We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 μg exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days.

RESULTS: -The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2-6.7] mmol/L versus 7.3 [6.2-8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups.

CONCLUSIONS: -Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791.

Original languageEnglish
JournalCirculation Research
Volume134
Issue number25
Pages (from-to)2115-2124
ISSN0009-7330
DOIs
Publication statusPublished - 2016

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Neuroprotective Agents
Randomized Controlled Trials
Phosphopyruvate Hydratase
Placebos
exenatide
Patient Admission
Hospital Mortality
Pharmaceutical Preparations
Type 2 Diabetes Mellitus
Intensive Care Units
Cause of Death
Clinical Trials
Wounds and Injuries

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Wiberg, Sebastian ; Hassager, Christian ; Schmidt, Henrik ; Thomsen, Jakob Hartvig ; Frydland, Martin ; Lindholm, Matias Greve ; Høfsten, Dan Eik ; Engstrøm, Thomas ; Køber, Lars ; Møller, Jacob Eifer ; Kjaergaard, Jesper. / Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest : A Randomized Controlled Trial. In: Circulation Research. 2016 ; Vol. 134, No. 25. pp. 2115-2124.
@article{0b04bab4e5d44aa398eb1f2af6e3317f,
title = "Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial",
abstract = "BACKGROUND: -In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50{\%}. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients.METHODS: -We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 μg exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90{\%} patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days.RESULTS: -The study drug was initiated within 240 minutes of return of spontaneous circulation in 96{\%} patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2-6.7] mmol/L versus 7.3 [6.2-8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups.CONCLUSIONS: -Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791.",
author = "Sebastian Wiberg and Christian Hassager and Henrik Schmidt and Thomsen, {Jakob Hartvig} and Martin Frydland and Lindholm, {Matias Greve} and H{\o}fsten, {Dan Eik} and Thomas Engstr{\o}m and Lars K{\o}ber and M{\o}ller, {Jacob Eifer} and Jesper Kjaergaard",
year = "2016",
doi = "10.1161/CIRCULATIONAHA.116.024088",
language = "English",
volume = "134",
pages = "2115--2124",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams & Wilkins",
number = "25",

}

Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest : A Randomized Controlled Trial. / Wiberg, Sebastian; Hassager, Christian; Schmidt, Henrik; Thomsen, Jakob Hartvig; Frydland, Martin; Lindholm, Matias Greve; Høfsten, Dan Eik; Engstrøm, Thomas; Køber, Lars; Møller, Jacob Eifer; Kjaergaard, Jesper.

In: Circulation Research, Vol. 134, No. 25, 2016, p. 2115-2124.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest

T2 - A Randomized Controlled Trial

AU - Wiberg, Sebastian

AU - Hassager, Christian

AU - Schmidt, Henrik

AU - Thomsen, Jakob Hartvig

AU - Frydland, Martin

AU - Lindholm, Matias Greve

AU - Høfsten, Dan Eik

AU - Engstrøm, Thomas

AU - Køber, Lars

AU - Møller, Jacob Eifer

AU - Kjaergaard, Jesper

PY - 2016

Y1 - 2016

N2 - BACKGROUND: -In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients.METHODS: -We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 μg exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days.RESULTS: -The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2-6.7] mmol/L versus 7.3 [6.2-8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups.CONCLUSIONS: -Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791.

AB - BACKGROUND: -In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients.METHODS: -We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 μg exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days.RESULTS: -The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2-6.7] mmol/L versus 7.3 [6.2-8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups.CONCLUSIONS: -Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791.

U2 - 10.1161/CIRCULATIONAHA.116.024088

DO - 10.1161/CIRCULATIONAHA.116.024088

M3 - Journal article

C2 - 27838646

VL - 134

SP - 2115

EP - 2124

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 25

ER -