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Original Research
Confirming the Bidirectional Nature of the Association Between Severe Hypoglycemic and Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL
Eberhard Standl, Susanna R. Stevens, Yuliya Lokhnygina, M. Angelyn Bethel, John B. Buse, Stephanie M. Gustavson, Aldo P. Maggioni, Robert J. Mentz, Adrian F. Hernandez, Rury R. Holman for the EXSCEL Study Group
Diabetes Care 2019 Dec; dc191079. https://doi.org/10.2337/dc19-1079
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Abstract

OBJECTIVE We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk.

RESEARCH DESIGN AND METHODS In a post hoc analysis of 14,752 Exenatide Study of Cardiovascular Event Lowering (EXSCEL) participants, we examined time-dependent associations between SHEs and subsequent major adverse cardiac events (CV death, nonfatal myocardial infarction [MI] or stroke), fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for acute coronary syndrome (hACS), hospitalization for heart failure (hHF), and all-cause mortality (ACM), as well as time-dependent associations between nonfatal CV events and subsequent SHEs.

RESULTS SHEs were uncommon and not associated with once-weekly exenatide therapy (hazard ratio 1.13 [95% CI 0.94–1.36], P = 0.179). In fully adjusted models, SHEs were associated with an increased risk of subsequent ACM (1.83 [1.38–2.42], P < 0.001), CV death (1.60 [1.11–2.30], P = 0.012), and hHF (2.09 [1.37–3.17], P = 0.001), while nonfatal MI (2.02 [1.35–3.01], P = 0.001), nonfatal stroke (2.30 [1.25–4.23], P = 0.007), hACS (2.00 [1.39–2.90], P < 0.001), and hHF (3.24 [1.98–5.30], P < 0.001) were all associated with a subsequent increased risk of SHEs. The elevated bidirectional time-dependent hazards linking SHEs and a composite of all CV events were approximately constant over time, with those individuals at dual risk showing higher comorbidity scores compared with those without.

CONCLUSIONS These findings, showing greater risk of SHEs after CV events as well as greater risk of CV events after SHEs, validate a bidirectional relationship between CV events and SHEs in patients with high comorbidity scores.

Footnotes

  • This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-1079/-/DC1.

  • Received May 29, 2019.
  • Accepted October 21, 2019.
  • © 2020 by the American Diabetes Association.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Confirming the Bidirectional Nature of the Association Between Severe Hypoglycemic and Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL
Eberhard Standl, Susanna R. Stevens, Yuliya Lokhnygina, M. Angelyn Bethel, John B. Buse, Stephanie M. Gustavson, Aldo P. Maggioni, Robert J. Mentz, Adrian F. Hernandez, Rury R. Holman
Diabetes Care Dec 2019, dc191079; DOI: 10.2337/dc19-1079

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Confirming the Bidirectional Nature of the Association Between Severe Hypoglycemic and Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL
Eberhard Standl, Susanna R. Stevens, Yuliya Lokhnygina, M. Angelyn Bethel, John B. Buse, Stephanie M. Gustavson, Aldo P. Maggioni, Robert J. Mentz, Adrian F. Hernandez, Rury R. Holman
Diabetes Care Dec 2019, dc191079; DOI: 10.2337/dc19-1079
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