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Cited by 247Diabetes Management and ResearchDiabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and Lipoproteins

Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial

The ORIGIN Trial Investigators, Mellbin, Linda G., Rydén, Lars, Riddle, Matthew C., Probstfield, Jeffrey, Rosenstock, Julio, Díaz, Rafael, Yusuf, Salim +1 more·2013·European Heart Journal
DOI 10.1093/eurheartj/eht332
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Abstract

AIMS: Hypoglycaemia caused by glucose-lowering therapy has been linked to cardiovascular (CV) events. The ORIGIN trial provides an opportunity to further assess this relationship. METHODS AND RESULTS: A total of 12 537 participants with dysglycaemia and high CV-risk were randomized to basal insulin glargine titrated to a fasting glucose of ≤ 5.3 mmol/L (95 mg/dL) or standard glycaemic care. Non-severe hypoglycaemia was defined as symptoms confirmed by glucose ≤ 54 mg/dL and severe hypoglycaemia as a requirement for assistance or glucose ≤ 36 mg/dL. Outcomes were: (i) the composite of CV death, non-fatal myocardial infarction or stroke; (ii) mortality; (iii) CV mortality; and (iv) arrhythmic death. Hazards were estimated before and after adjustment for a hypoglycaemia propensity score. During a median of 6.2 years (IQR: 5.8-6.7), non-severe hypoglycaemic episodes occurred in 41.7 and 14.4% glargine and standard group participants, respectively, while severe episodes occurred in 5.7 and 1.8%, respectively. Non-severe hypoglycaemia was not associated with any outcome following adjustment. Conversely, severe hypoglycaemia was associated with a greater risk for the primary outcome (HR: 1.58; 95% CI: 1.24-2.02, P < 0.001), mortality (HR: 1.74; 95% CI: 1.39-2.19, P < 0.001), CV death (HR: 1.71; 95% CI: 1.27-2.30, P < 0.001) and arrhythmic death (HR: 1.77; 95% CI: 1.17-2.67, P = 0.007). Similar findings were noted for severe nocturnal hypoglycaemia for the primary outcome and mortality. The severe hypoglycaemia hazard for all four outcomes was higher with standard care than with insulin glargine. CONCLUSION: Severe hypoglycaemia is associated with an increased risk for CV outcomes in people at high CV risk and dysglycaemia. Although allocation to insulin glargine vs. standard care was associated with an increased risk of severe and non-severe hypoglycaemia, the relative risk of CV outcomes with hypoglycaemia was lower with insulin glargine-based glucose-lowering therapy than with the standard glycaemic control. Trial Registration (ORIGIN ClinicalTrials.gov number NCT00069784).

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  • Cardiac arrhythmia is thought to be a key mechanism underlying hypoglycemia-associated death.

    “Cardiac arrhythmia is thought to be a key mechanism underlying hypoglycemia-associated death (4).”

    From Effect of Hypoglycemia on QT Interval in Individuals With and Without Type 2 Diabetes: A Randomized Crossover Trial (2025) · cites this paper as [4]

    The Introduction (page unavailable) identifies ventricular arrhythmias as a possible effect of hypoglycaemia that may contribute to cardiovascular events. The Discussion (page unavailable) also considers other mechanisms and says hypoglycaemia may be a marker, rather than a cause, of adverse outcomes. The paper does not establish or single out arrhythmia as a key mechanism of hypoglycaemia-associated death. (LLM, conf=0.84)

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  • Similar results were confirmed in other trials.

    “Similar results were confirmed in other trials.140,187,188”

    From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [187]

  • Insulin-induced hypoglycaemia has been associated with nocturnal death (dead-in-bed syndrome) in type 1 diabetes.

    “Insulin-induced hypoglycaemia has been associated with nocturnal death (also called 'dead-in-bed syndrome') in T1DM, and arrhythmic deaths were reported in several T2DM trials.187,576,[650][651][652][653][654]”

    From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [187]

  • Arrhythmic deaths were reported in several type 2 diabetes trials.

    “Insulin-induced hypoglycaemia has been associated with nocturnal death (also called 'dead-in-bed syndrome') in T1DM, and arrhythmic deaths were reported in several T2DM trials.187,576,[650][651][652][653][654]”

    From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [187]

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Authors
The ORIGIN Trial Investigators, Mellbin, L. G., Rydén, L., Riddle, M. C., Probstfield, J., Rosenstock, J., Díaz, R., Yusuf, S., & Gerstein, H. C.
Affiliations
  • Karolinska Institutet (SE)
  • Karolinska University Hospital (SE)
  • Oregon Health & Science University (US)
  • University of Washington (US)
  • The University of Texas Southwestern Medical Center (US)
  • Estudios Clínicos Latinoamérica (AR)
  • McMaster University (CA)
ORCID
Venue
European Heart Journal
Publisher
Oxford University Press (OUP)
Published
2013-09-02
Volume
34
Issue
40
Pages
3137-3144
ISSN
  • 0195-668X (ISSN-L)
  • 1522-9645
DOI
10.1093/eurheartj/eht332
OpenAlex
W2090816085
Cited by
247
References
17
Citations by year
2026: 8 · 2025: 6 · 2024: 13 · 2023: 8 · 2022: 18 · 2021: 22 · 2020: 25 · 2019: 21 · 2018: 22 · 2017: 21 · 2016: 32 · 2015: 26 · 2014: 21 · 2013: 4
FWCI
21.76
Type
journal article
Language
en
Open access
closed
Locations
  • European Heart Journal (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • Sanofi
  • Intarcia Therapeutics
  • MannKind Corporation
  • Halozyme
  • AFA Försäkring
  • Hjärt-Lungfonden
  • Novo Nordisk
  • Daiichi Sankyo Europe
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
hypoglycemia, severe hypoglycemia, cardiovascular events, insulin glargine, basal insulin, glucose-lowering therapy, ORIGIN trial, dysglycemia, cardiovascular mortality, myocardial infarction, stroke, arrhythmic death, nocturnal hypoglycemia, high cardiovascular risk, hypoglycemia risk
MeSH terms
Insulin Glargine, Arrhythmias, Cardiac, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Female, Glycated Hemoglobin, Humans, Hypoglycemia, Hypoglycemic Agents, Male, Middle Aged, Myocardial Infarction, Prognosis, Risk Factors, Stroke, Insulin, Long-Acting

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