Sulfonylurea antidiabetics are associated with lower risk of out-of-hospital cardiac arrest: Real-world data from a population-based study
Eroglu, Talip E.; Jia, Lixia; Blom, Marieke T.; Verkerk, Arie O.; Devalla, Harsha D.; Boink, Gerard J.J.; Souverein, Patrick C.; de Boer, Anthonius; Tan, Hanno L.
(2021) British Journal of Clinical Pharmacology, volume 87, issue 9, pp. 3588 - 3598
(Article)
Abstract
Aims: Out-of-hospital cardiac arrest (OHCA) mostly results from ventricular tachycardia/ventricular fibrillation (VT/VF), often triggered by acute myocardial infarction (AMI). Sulfonylurea (SU) antidiabetics can block myocardial ATP-regulated K+ channels (KATP channels), activated during AMI, thereby modulating action potential duration (APD). We studied whether SU drugs impact on OHCA risk, and whether
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these effects are related to APD changes. Methods: We conducted a population-based case–control study in 219 VT/VF-documented OHCA cases with diabetes and 697 non-OHCA controls with diabetes. We studied the association of SU drugs (alone or in combination with metformin) with OHCA risk compared to metformin monotherapy, and of individual SU drugs compared to glimepiride, using multivariable logistic regression analysis. We studied the effects of these drugs on APD during simulated ischaemia using patch-clamp studies in human induced pluripotent stem cell-derived cardiomyocytes. Results: Compared to metformin, use of SU drugs alone or in combination with metformin was associated with reduced OHCA risk (ORSUdrugs-alone 0.6 [95% CI 0.4–0.9], ORSUdrugs + metformin 0.6 [95% CI 0.4–0.9]). We found no differences in OHCA risk between SU drug users who suffered OHCA inside or outside the context of AMI. Reduction of OHCA risk compared to glimepiride was found with gliclazide (ORadj 0.5 [95% CI 0.3–0.9]), but not glibenclamide (ORadj 1.3 [95% CI 0.6–2.7]); for tolbutamide, the association with reduced OHCA risk just failed to reach statistical significance (ORadj 0.6 [95% CI 0.3–1.002]). Glibenclamide attenuated simulated ischaemia-induced APD shortening, while the other SU drugs had no effect. Conclusions: SU drugs were associated with reduced OHCA risk compared to metformin monotherapy, with gliclazide having a lower risk than glimepiride. The differential effects of SU drugs are not explained by differential effects on APD.
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Keywords: ESCAPE-NET, K channelssulfonylurea, sudden cardiac arrest, Pharmacology, Pharmacology (medical)
ISSN: 0306-5251
Publisher: NLM (Medline)
Note: Funding Information: This work was supported by the European Union's Horizon 2020 research and innovation programme under the acronym ESCAPE‐NET, registered under grant agreement No. 733381 (T.E.E., M.T.B., H.L.T.), and the COST Action PARQ (grant agreement No. CA19137) supported by COST (European Cooperation in Science and Technology), and the Netherlands CardioVascular Research Initiative (Dutch Heart Foundation, Dutch Federation of University Medical Centers, Netherlands Organization for Health Research and Development, and Royal Netherlands Academy of Sciences) grants CVON‐2017‐15 RESCUED (H.L.T.) and CVON‐2018‐30 Predict‐2 (M.T.B., H.L.T.). The ARREST registry is supported by an unconditional grant from Physio‐Control Inc., part of Stryker, Redmond, WA, USA. The funders were not involved in designing the study, collecting and analysing the data, preparing the manuscript, or the decision to publish. Funding Information: COST Action PARQ, Grant/Award Number: CA19137; European Union's Horizon 2020, Grant/Award Number: 733381; Netherlands CardioVascular Research Initiative, Grant/Award Numbers: CVON‐2017‐15 RESCUED, CVON‐2018‐30 Predict‐2; Physio‐Control Inc., part of Stryker Funding information Funding Information: The authors greatly appreciate the contributions of Paulien Homma, Remy Stieglis and Sandra de Haas for data management of the ARREST registry, and are greatly indebted to all participating EMS dispatch centres (Amsterdam, Haarlem and Alkmaar), regional ambulance services (Ambulance Amsterdam, GGD Kennemerland, Witte Kruis and Veiligheidsregio Noord-Holland Noord Ambulancezorg), fire brigades, and police departments in the study region for their contribution and support. The authors would also like to thank Leontien Bosch for providing the hiPSC-CMs, and all the healthcare providers contributing information to the PHARMO Database Network. The authors would also like to thank Stichting Farmaceutische Kerngetallen and the pharmacists for their participation in this study. This work was supported by the European Union's Horizon 2020 research and innovation programme under the acronym ESCAPE-NET, registered under grant agreement No. 733381 (T.E.E., M.T.B., H.L.T.), and the COST Action PARQ (grant agreement No. CA19137) supported by COST (European Cooperation in Science and Technology), and the Netherlands CardioVascular Research Initiative (Dutch Heart Foundation, Dutch Federation of University Medical Centers, Netherlands Organization for Health Research and Development, and Royal Netherlands Academy of Sciences) grants CVON-2017-15 RESCUED (H.L.T.) and CVON-2018-30 Predict-2 (M.T.B., H.L.T.). The ARREST registry is supported by an unconditional grant from Physio-Control Inc., part of Stryker, Redmond, WA, USA. The funders were not involved in designing the study, collecting and analysing the data, preparing the manuscript, or the decision to publish. Publisher Copyright: © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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