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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftCirculation Research
Vol/bind134
Udgave nummer25
Sider (fra-til)2115-2124
ISSN0009-7330
DOI
StatusUdgivet - 2016

Fingeraftryk

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

Citer dette

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. I: Circulation Research. 2016 ; Bind 134, Nr. 25. s. 2115-2124.
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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.

I: Circulation Research, Bind 134, Nr. 25, 2016, s. 2115-2124.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer 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 -