Diagnostic and therapeutic characteristics of diabetes mellitus and risk of out-of-hospital cardiac arrest

This study aimed to evaluate the risks of diabetes mellitus (DM) on out-of-hospital cardiac arrest (OHCA) and to investigate whether the risks of DM on OHCA varied according to the diagnostic and therapeutic characteristics of diabetes. We conducted a multicenter prospective case–control study in 17 University hospitals in Korea from September 2017 to December 2020. Cases were EMS-treated OHCA patients aged 20 to 79 with a presumed cardiac etiology. Community-based controls were recruited at a 1:2 ratio after matching for age, sex, and urbanization level of residence. A structured questionnaire and laboratory findings were collected from cases and controls. Multivariable conditional logistic regression analyses were conducted to estimate the risk of DM on OHCA by characteristics. A total of 772 OHCA cases and 1544 community-based controls were analyzed. A total of 242 (31.3%) OHCAs and 292 (18.9%) controls were previously diagnosed with DM. The proportions of type I DM (10.7% vs. 2.1%) and insulin therapy (15.3% vs. 6.5%) were higher in OHCAs with DM than in controls with DM. The duration of DM was longer in OHCAs than in controls (median 12 vs. 7 years). DM was associated with an increased risk of OHCA (aOR (95% CI), 2.13 (1.64–2.75)). Compared to the no diabetes group, the risks of OHCA increased in the diabetes patients with type I DM (5.26 (1.72–16.08)) and type II DM group (1.63 (1.18–2.27)), a long duration of DM prevalence (1.04 (1.02–1.06) per 1-year prevalence duration), and a high HbA1c level (1.38 (1.19–1.60) per 1% increase). By treatment modality, the aOR (95% CI) was lowest in the oral hypoglycemic agent (1.47 (1.08–2.01)) and highest in the insulin (6.63 (3.04–14.44)) groups. DM was associated with an increased risk of OHCA, and the risk magnitudes varied according to the diagnostic and therapeutic characteristics.


Scientific Reports
| (2022) 12:1293 | https://doi.org/10.1038/s41598-022-05390-w www.nature.com/scientificreports/ of OHCAs with diabetes are poor 15,16 . A better understanding of the risks of DM on cardiac arrest according to the characteristics of diabetes would be essential to screening high-risk populations among patients with DM and to developing effective preventive strategies for reducing the health burden of fatal cardiovascular complications, such as OHCA.
Diabetes is a chronic disease, and the diagnostic and therapeutic characteristics are not homogenous among patients with the condition. However, the risk variations of DM on OHCA by its characteristics are not well explained, whereas the relationship between DM itself and OHCA is well established. Understanding the risk variations of OHCA for patients with diabetes could contribute to developing prevention strategies for sudden cardiac arrests caused by diabetes. The aims of this study were to evaluate the association between diagnosed DM and OHCA and to investigate whether the risk magnitudes of OHCA were different according to the diagnostic and therapeutic characteristics of diabetes, including the type of DM, duration of prevalence, treatment modality, and HbA1c level.

Methods
Study design, setting, and data source. This study was a multicenter case-control study using the phase II Cardiac Arrest Pursuit Trial with Unique Registration and Epidemiologic Surveillance (CAPTURES-II) project in Korea.
The CAPTURES project was a prospective multicenter project aimed at identifying the risk factors for OHCA incidence and evaluating determinants of good prognosis with long-term follow-up funded by the Korea Disease Prevention and Control Agency. Phase I of the CAPTURES project was a prospective hospital-based OHCA registration study conducted at 27 emergency departments (EDs) from January to December 2014. A detailed description of phase I of the CAPTURE study was previously described 5 .
The CAPTURES-II study was a prospective case-control study conducted at the EDs of 17 university hospitals from September 2017 to December 2020. The project was subjected to OHCA patients transported to the study EDs by emergency medical service (EMS) with resuscitation efforts (EMS-treated OHCA) and patients who had a presumed cardiac etiology as identified by emergency physicians in each ED. The CAPTURES-II project included face-to-face interviews (for patient sociodemographics, health behaviors, stress, and comorbidities), medical record reviews (for Utstein templates, laboratory tests, cardiac examinations, and short-and long-term outcomes), and blood sample registration for biomarker evaluations for OHCA patients. For community-based controls, face-to-face interviews for the same information of OHCA patients and blood sample registration for laboratory tests and biomarker evaluations were conducted. All data collected from participating hospitals were transferred to the Data Quality Management Committee (DQMC), where quality-control checks and statistical analysis were performed. DQMC gave feedback to each center coordinator on the quality management of the CAPTURES data through monthly quality control meetings. This study protocol is registered at ClinicalTrials. gov (NCT03700203).
Cases. For the CAPTURES-II project, EMS-treated OHCA patients aged 20-79 years who had a presumed cardiac etiology were prospectively recruited. The project excluded OHCA patients of noncardiac etiology, including trauma, drowning, poisoning, burn, asphyxia, or hanging, and OHCA cases with a terminal illness, under hospice care, with a 'Do Not Resuscitate' card, with pregnancy, and living alone or experiencing homelessness without reliable information sources. OHCA patients with unknown information on DM were excluded (n = 26).

Controls.
Community-based controls were recruited from 1 metropolitan university hospital and 1 nonmetropolitan university hospital. One center located in a metropolitan area (Seoul) collected metropolitan controls, and the other center located in a nonmetropolitan area (Wonju) collected nonmetropolitan controls. By collaborating with public health centers or various community centers, the CAPTURES-II project and control recruitment were promoted, and voluntary applicants were recruited as the control group. Age (5-year intervals), sex, and urbanization level of residence (metropolitan vs nonmetropolitan) matched controls were recruited at a 1:2 ratio per case.
Variables and measurements. The main exposure was physician-diagnosed DM prior to study enrollment as measured via face-to-face interviews.
The CAPTURES-II project used the same structured questionnaires for case and controls. Emergency physicians at study EDs collected the information during a face-to-face interview with the patients' family for the OHCA case group and study participants for the community-based control group. Information about demographics (age, sex, and residence area) and comorbidities (diabetes, hypertension, myocardial infarction, stroke, dyslipidemia, and arrhythmia) was collected. Only comorbidities that were diagnosed by doctors in hospitals or clinics were documented, and the exact question was determined in the protocol to standardize the survey process. For example, "Have you (or the OHCA patient) ever been diagnosed with an arrhythmia by a doctor?" was used to identify arrhythmia, and if yes, they were classified into the arrhythmia group regardless of specific type of arrhythmia. Health behaviors, including current smoking status, obesity, and regular exercise during the last year, were also noted. Current smoking status was defined as smoking more than 1 cigarette per day within the past month. Regular exercise during the last year was defined as moderate-and vigorous-intensity exercise at least once per week in the last year.
For participants with diabetes, information on the type of DM (Type I or Type II), duration of diabetes prevalence, and DM treatment modality (insulin, oral hypoglycemic agent, lifestyle modification, and no treatment) were collected. Patients receiving combined therapy with insulin and oral hypoglycemic agents were classified www.nature.com/scientificreports/ as the insulin group. The duration of diabetes was categorized into 5 groups: 0-1 years, 2-3 years, 4-10 years, 11-18 years, and 19-years. For cases, blood samples during initial management were collected, and hemoglobin A1c (HbA1c) measurements were conducted at each hospital's laboratory department. For controls, laboratory tests, including HbA1c, were performed with face-to-face interviews at the time of enrollment. HbA1c levels were categorized into three groups: 0-5.6%, 5.7-6.4% and 6.5-%. Statistical analysis. Demographic findings of OHCA cases and community-based controls were described.
We used conditional logistic regression for the matched case-control dataset. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated to estimate the effect of DM on OHCA risk. All variables included in the final model were assessed for multicollinearity. No significant collinearity was detected.
Analyses for risk variations of DM on OHCA according to diagnostic characteristics (type of DM and duration of diabetes prevalence) and therapeutic characteristics (treatment modality and HbA1c level) of diabetes were conducted. For each characteristic of diabetes, 1:2 matched case-control sets were extracted and analyzed where information on the characteristics of DM was not missing for both 1 case and 2 matched controls: type of DM (662 cases and 1324 controls), duration of diabetes (655 patients and 1310 controls), treatment modality (724 cases and 1448 controls), and HbA1c level (382 cases and 764 controls).
Sensitivity analyses without imputation were completed for the main analyses. Statistical analyses were performed using SAS 9.4. We considered a 2-sided P < 0.05 to be statistically significant.
Ethic statements. The study was approved by the ethics committees of all 17 participating university hospitals. All participants, or their proxy, provided written informed consent before taking part in the study. All methods were performed in accordance with relevant guidelines and regulations. All participants, or their proxy, provided written informed consent before taking part in the study. This study is registered at ClinicalTrials.gov (NCT03700203).
To examine the variations in the risk magnitude of DM on OHCA according to the diagnostic and therapeutic characteristics, aORs with 95% CIs were calculated for subgroups where information on the type of DM, duration of illness, type of treatment, and HbA1c level was not missing. In terms of the type of diabetes, the aOR (95% CI) In terms of the treatment modality of diabetes, the aOR (95% CI) was lowest in the oral hypoglycemic agent group (1.47 (1.08-2.01)) and highest in the insulin group (6.63 (3.04-14.44)) compared to the no diabetes group. Regarding HbA1c level, the aOR (95% CI) of a 1% increase in HbA1c level was 1.38 (1.19-1.60). There was a dose-dependent relationship between HbA1c level and OHCA: aORs (95% CIs) were 2.17 (1.45-3.24) for the group whose HbA1c level was over 6.5% and 1.60 (1.12-2.29) for the HbA1c 5.7-6.4% group compared to the HbA1c 0-5.6% group (Table 3).  www.nature.com/scientificreports/ In sensitivity analyses, similar results were observed for the study populations without imputation (Table 4).

Discussion
This study found that diagnosed DM increases the risk of OHCA, and the risk magnitudes varied according to the diagnostic and therapeutic characteristics of DM using the CAPTURES-II project, a multicenter prospective case-control study. Regarding the type of diabetes, the risk of OHCA in the type I DM group was greater than that in the type II DM group compared to the no diabetes group. By treatment modality, the risk was highest in the insulin group, followed by the no treatment and lifestyle modification groups, and lowest in the oral hypoglycemic agent group. A duration of diabetes prevalence longer than 10 years was associated with a high risk of OHCA compared to participants without diabetes. In terms of HbA1c level, there was a dose-dependent relationship between HbA1c level and OHCA risk. Our study emphasizes that DM diagnosis and its characteristics could affect the risk of OHCA, and delaying the onset of diabetes and appropriate glucose control of DM might reduce the risk of OHCA in patients with DM. Understanding the risks of DM on OHCA according to the characteristics of diabetes is essential to develop health policies and public interventions preventing cardiac arrests caused by diabetes. Diabetes is a well-known risk factor for OHCA [5][6][7][8][9]17 , and the prevalence of DM was higher in OHCA cases than in controls in this study (31.3% in cases and 18.9% in controls, aOR (95% CI): 2.13 (1.64-2.75)). Several potential mechanisms were suggested to explain the association between DM and OHCA incidence. Diabetes is associated with coronary artery disease and related cardiovascular risks and is the most common cause of sudden cardiac arrest [18][19][20] . In addition, diabetes is associated with electrocardiographic abnormalities of electrical propagation in the myocardium, which could result in prolongation of the QT and QRS interval 17 . Diabetic autonomic neuropathy reportedly has a critical role in this mechanism 21 . An increased risk of hypoglycemic episodes has also been reported to be associated with arrhythmic events and sudden cardiac arrest 22 . Moreover, diabetes could result in the development of structural changes in the myocardium and interstitium in the diabetic heart, which is called diabetic cardiomyopathy and is associated with sudden cardiac arrest 23 .
In this study, we found that the various diagnostic characteristics (type of DM and prevalence duration) and treatment characteristics (treatment modality and HbA1c level) of DM could modify the magnitude of risks for OHCA. By type of DM, the proportion of type I DM was smaller than that of type II DM, but the risk magnitude Table 4. Sensitivity analyses for the study population without covariate imputation. CI, confidence interval; DM, diabetes mellitus; HbA1c, hemoglobin A1c. Conditional logistic regression adjusted for comorbidities (hypertension, myocardial infarction, stroke, dyslipidemia, and arrhythmia) and health behaviors (current smoking status, obesity, and regular exercise during the last year). † For patients without diabetes, the duration of diabetes was zero. Although few studies about differences in the risks of OHCA incidence between types of DM have been published 10 , a previous study reported that the incidence of sudden cardiac death was higher in type I DM than in type II DM in patients aged 1-49 years 6 . According to the duration of diabetes, patient groups with a diabetes prevalence longer than 10 years had a higher risk of OHCA compared to the no diabetes group. A previous case-control study also reported that the duration of diabetes prevalence was longer in sudden cardiac arrest patients with DM than in age-, gender-, and index year-matched controls with DM 17 . Among the treatment modalities for DM, diabetic patients receiving insulin therapy showed the highest risk of OHCA (aOR (95% CI): 6.63 (3.04-14.44)), whereas diabetic patients receiving oral hypoglycemic agents showed the lowest risk (aOR (95% CI): 1.47 (1.08-2.01)) compared to patients without diabetes. The risk magnitudes on OHCA for patients with no treatment and lifestyle modification were smaller than those of diabetes patients with insulin therapy (aORs (95% CIs): 2.76 (1.01-7.58) and 2.62 (1.14-6.06)); however, there was no significant difference between the effect sizes. This result was not in concordance with the results from a previous phase I CAPTURES study in which the nonpharmacologic therapy group showed the highest risk 5 . DM with nonpharmacologic therapy might be heterogeneous because both the early phase after the diagnosis of diabetes and the advanced phase with poor compliance could belong to this group 24 . In terms of HbA1c level, we found that there was a dose-dependent relationship between HbA1c and the risk of OHCA, similar to previous studies 25,26 . Strict regulation of blood glucose would reduce the risk of OHCA in patients with DM 27 .
Various diagnostic and therapeutic characteristics of DM are interrelated 28 . For example, insulin therapy is more common in patients with type I DM, a long duration of DM prevalence, and high HbA1c levels. Patients with those factors had a greater risk for OHCA. For those high-risk groups, adequate glycemic control and strict risk management could reduce the risk of fatal cardiovascular complications, even in patients with type I DM 6 , a long duration of DM prevalence with microvascular disease 7 , and insulin therapy 29 . A recent study reported that preventive interventions for prolonged diabetes onset mitigate cardiometabolic risks, regardless of genetic risk 30 . Moreover, early cardiovascular risk monitoring and steady management have benefits for alleviation of disease burden among young patients who develop DM in the early period of their life 6 . Public interventions for delaying the onset of diabetes among at-risk populations and monitoring programs for adequate glucose control in patients diagnosed with DM from the early phase immediately after diagnosis will be key strategies to reduce the complications of DM and its risk for cardiac arrest.
This study has several limitations. First, information on the characteristics of diabetes, including diagnosis, type, duration of diabetes, and treatment modality, was collected from family members in most OHCA cases because most OHCA patients were not alert and direct history taking was not feasible. However, this information was obtained directly from subjects in the community-based control group. This difference might lead to information bias and under-or overestimation of diabetes prevalence and its severity among the OHCA case group. Second, the presence of microvascular or macrovascular complications, diabetic autonomic neuropathy, and electrocardiographic abnormalities were not evaluated. These factors may have yielded different effect sizes. Third, because the consent of subjects or family members was necessary for enrollment, OHCA patients who achieved successful resuscitation or were admitted to the hospital were more likely to be enrolled than patients who died in the ED. Fourth, the CAPTURES project enrolled OHCA patients with presumed cardiac etiology. Caution should be taken when interpreting this study results given the significant limitations. Last, the study design was a case-control study, not an intervention trial. There may be significant potential biases that were not controlled for. In addition, there was a possibility of misclassification for matching variables.

Conclusions
In this multicenter prospective case-control study, we found that diabetes was associated with an increased risk of OHCA. The risk for the cardiac arrest varied according to the diagnostic and therapeutic characteristics of diabetes, and a long prevalence duration and high HbA1c level were strongly associated with the OHCA risk compared to patients without diabetes. Our study emphasizes that public interventions for delaying the onset of DM in at-risk populations and adequate glucose control from the early phase for diabetic patients would be key strategies to reduce the risks of fatal cardiovascular complications, including OHCA.