Associations of hypoglycemia, glycemic variability and risk of cardiac arrhythmias in insulin-treated patients with type 2 diabetes: a prospective, observational study

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Abstract

Background

Insulin-treated patients with type 2 diabetes (T2D) are at risk of hypoglycemia, which is associated with an increased risk of cardiovascular disease and mortality. Using a long-term monitoring approach, we investigated the association between episodes of hypoglycemia, glycemic variability and cardiac arrhythmias in a real-life setting.

Methods

Insulin-treated patients with T2D (N = 21, [mean ± SD] age 66.8 ± 9.6 years, BMI 30.1 ± 4.5 kg/m ², HbA1c 6.8 ± 0.4% [51.0 ± 4.8 mmol/mol]) were included for a one-year observational study. Patients were monitored with continuous glucose monitoring ([mean ± SD] 118 ± 6 days) and an implantable cardiac monitor (ICM) during the study period.

Results

Time spend in hypoglycemia was higher during nighttime than during daytime ([median and interquartile range] 0.7% [0.7–2.7] vs. 0.4% [0.2–0.8]). The ICMs detected 724 episodes of potentially clinically significant arrhythmias in 12 (57%) participants, with atrial fibrillation and pauses accounting for 99% of the episodes. No association between hypoglycemia and cardiac arrhythmia was found during daytime. During nighttime, subject-specific hourly incidence of cardiac arrhythmias tended to increase with the occurrence of hypoglycemia (incident rate ratio [IRR] 1.70 [95% CI 0.36–8.01]) but only slightly with increasing time in hypoglycemia (IRR 1.04 [95% CI 0.89–1.22] per 5 min). Subject-specific incidence of cardiac arrhythmias during nighttime increased with increasing glycemic variability as estimated by coefficient of variation whereas it decreased during daytime (IRR 1.33 [95% CI 1.05–1.67] and IRR 0.77 [95% CI 0.59–0.99] per 5% absolute increase, respectively).

Conclusions

Cardiac arrhythmias were common in insulin-treated patients with T2D and were associated with glycemic variability, whereas arrhythmias were not strongly associated with hypoglycemia.

Trial registration: NCT03150030, ClinicalTrials.gov, registered May 11, 2017. https://clinicaltrials.gov/ct2/show/NCT03150030

Supplementary Information

The online version contains supplementary material available at 10.1186/s12933-021-01425-0.

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Most cited references 50

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Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range

Tadej Battelino, Thomas Danne, Richard M. Bergenstal … (2019)

Improvements in sensor accuracy, greater convenience and ease of use, and expanding reimbursement have led to growing adoption of continuous glucose monitoring (CGM). However, successful utilization of CGM technology in routine clinical practice remains relatively low. This may be due in part to the lack of clear and agreed-upon glycemic targets that both diabetes teams and people with diabetes can work toward. Although unified recommendations for use of key CGM metrics have been established in three separate peer-reviewed articles, formal adoption by diabetes professional organizations and guidance in the practical application of these metrics in clinical practice have been lacking. In February 2019, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address this issue. This article summarizes the ATTD consensus recommendations for relevant aspects of CGM data utilization and reporting among the various diabetes populations.

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Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

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Effects of intensive glucose lowering in type 2 diabetes.

J L Probstfield, William T. Friedewald, J Bigger … (2008)

Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001). As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.) 2008 Massachusetts Medical Society

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Author and article information

Contributors

Tina Vilsbøll:

ORCID: http://orcid.org/0000-0002-0456-6787

tina.vilsboell.01@regionh.dk

Journal

Journal ID (nlm-ta): Cardiovasc Diabetol

Journal ID (iso-abbrev): Cardiovasc Diabetol

Title: Cardiovascular Diabetology

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2840

Publication date (Electronic): 24 December 2021

Publication date PMC-release: 24 December 2021

Publication date Collection: 2021

Volume: 20

Electronic Location Identifier: 241

Affiliations

[1 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Clinical Research, , Steno Diabetes Center Copenhagen, University of Copenhagen, ; Borgmester Ib Juuls Vej 83, 2730 Herlev, Denmark

[2 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, , University of Copenhagen, ; Hellerup, Denmark

[3 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Department of Cardiology, Herlev and Gentofte Hospital, , University of Copenhagen, ; Hellerup, Denmark

[4 ]GRID grid.412451.7, ISNI 0000 0001 2181 4941, Department of Medicine and Aging Sciences, , G. d’Annunzio University, ; Chieti, Italy

[5 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Department of Clinical Medicine, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark

[6 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Department of Endocrinology and Nephrology, Nordsjællands Hospital Hillerød, , University of Copenhagen, ; Hillerød, Denmark

[7 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Deparment of Biomedical Sciences, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark

[8 ]GRID grid.453951.f, ISNI 0000 0004 0646 9598, The Danish Heart Foundation, ; Copenhagen, Denmark

[9 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark

Author information

Tina Vilsbøll http://orcid.org/0000-0002-0456-6787

Article

Publisher ID: 1425

DOI: 10.1186/s12933-021-01425-0

PMC ID: 8710000

PubMed ID: 34952579

SO-VID: 67c48dc4-79a6-4d81-afa0-32d926158f1a

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 21 September 2021

Date accepted : 3 December 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100009708, Novo Nordisk Fonden;

Award ID: NNF 16230

Award Recipient : Tina Vilsbøll

Funded by: FundRef http://dx.doi.org/10.13039/501100005275, Region Hovedstaden;

Award ID: E-19280-51-07

Award Recipient : Tina Vilsbøll

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: type 2 diabetes,insulin treatment,hypoglycemia,glycemic variability,cardiac arrhythmias

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: type 2 diabetes, insulin treatment, hypoglycemia, glycemic variability, cardiac arrhythmias

Associations of hypoglycemia, glycemic variability and risk of cardiac arrhythmias in insulin-treated patients with type 2 diabetes: a prospective, observational study

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Most cited references 50

Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Effects of intensive glucose lowering in type 2 diabetes.

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