Arrhythmias and antiarrhythmic therapy in patients with type 2 diabetes mellitus : Swedish registry based studies

<h4>Background</h4><p dir="ltr">Type 2 diabetes mellitus (T2DM) is a well-established risk factor for cardiovascular complications such as coronary heart disease (CHD), heart failure (HF), and stroke. Diabetes mellitus (DM) has also been linked to an increased risk of certain cardiac arrhythmias, particularly atrial fibrillation (AF) and sudden cardiac death (SCD), presumably due to ventricular arrhythmias (VA). However, this association is not as well established as that of other cardiovascular diseases in the context of DM. Moreover, the need for cardiac device therapy among patients with T2DM, and its potential prognostic implications, remains insufficiently explored.</p><h4>Aims</h4><p dir="ltr">The overall aim of this thesis was to broaden the knowledge regarding the association between T2DM and severe arrhythmias in need of treatment with cardiac implantable electronic device (pacemaker, implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy defibrillator/pacemaker (CRT-D/P)) and to study prognosis after device implantation. Specifically, the four studies explored the:</p><ul><li>prevalence of bradyarrhythmias and incidence of pacemaker treatment in individuals with T2DM and without T2DM and potential factors associated with pacemaker implantation (Study I).</li><li>prevalence of tachyarrhythmias and incidence of ICD/CRT-P/D treatment in individuals with T2DM and without T2DM and potential factors associated with ICD/CRT implantation (Study II).</li><li>aetiology for pacemaker and ICD treatment in patients with T2DM and without T2DM (Study III-IV).</li><li>complications and prognosis after a pacemaker and ICD implantation in patients with T2DM and without T2DM (Study III-IV).</li></ul><h4>Material and Methods</h4><p dir="ltr">This thesis consists of four retrospective cohort studies based on data from several Swedish national registries: the Swedish National Diabetes Registry (NDR), the Swedish ICD and Pacemaker Registry, the Swedish Population Registry, the National Patient Registry, the Swedish Prescribed Drug Registry, the Longitudinal Integration Database for Health Insurance and Labor Market Studies and the Swedish Cause of Death Registry.</p><p dir="ltr">Study I included patients with T2DM from the NDR and to each patient, five age-, sex-, and residence- matched controls from the general population based on registration in the population registry. Data on socioeconomic factors, comorbidities, and mortality were obtained from the registries mentioned above apart from the Swedish ICD and Pacemaker Registry and the Prescribed Drug registry. Participants were included from 1998 to 2012 and followed until 2013 with a mean follow-up of seven years after pacemaker implantation. Cox proportional hazards models were used to estimate the risk of needing a pacemaker during follow-up and predictors of pacemaker implantation.</p><p dir="ltr">Study II shared the same study design as Study I, but with the focus on an ICD or CRT-P/D implantation. It included patients with T2DM from the NDR with five matched controls from the general population.</p><p dir="ltr">Study III included patients who underwent de novo pacemaker implantation between 2010 and 2021 from the ICD and Pacemaker registry. The patient cohort was then linked with data from the other registries mentioned above except from the population registry. Information regarding a T2DM diagnosis was retrieved form the NDR. Patients with and without T2DM were compared regarding pacemaker implantation indications, peri- and postoperative complications (up to one year) using chi-square tests. Time to event analyses of major adverse cardiovascular events (MACE), and all-cause mortality were assessed using Cox proportional hazard regression models. The cumulative incidence of MACE and all-cause mortality was visualized using Kaplan-Meier curves and compared between groups with the log-rank test. Study IV share the same study design as Study III but included patients with de novo ICD implantation between 2010 and 2021. Indications, procedural complications, and outcomes were compared between patients with and without T2DM. Additional subgroup analyses regarding ICD implantation for primary or secondary prevention with T2DM and without T2DM were studied by pairwise comparisons using the log-rank test.</p><h4>Results</h4><p dir="ltr">Study I and II included approximately 400,000 patients with T2DM and 2 million controls. Patients with T2DM had a higher prevalence of cardiovascular comorbidities and brady- and tachyarrhythmias than controls. During follow- up, device implantation was more frequent in patients with T2DM (pacemaker 242.2 vs. 152.5 per 100,000 person-years; p<0.01, and ICD 30.3 vs. 14.3 per 100,000 person-years; p<0.01) After adjustment for CHD, HF and demographic factors, the risk remained significantly increased for all devices in patients with T2DM. Female sex was associated with a lesser need of any of the studied devices in patients with T2DM.</p><p dir="ltr">Study III included approximately 95,000 patients with a de novo implanted pacemaker whereof 19% had T2DM. The study showed that sick sinus syndrome and atrio ventricular block III were the most frequent reported ECG findings in patients undergoing a de novo pacemaker implantation regardless of the presence of T2DM at the time of implantation. Cardiac fibrosis and CHD were the most common underlying aetiologies for pacemaker in patients with T2DM and without T2DM. Procedural complications were slightly lower in patients with T2DM, but the all-cause mortality and cardiovascular prognosis was impaired in this group even after adjustments for CHD and HF.</p><p dir="ltr">Study IV included approximately 13,000 patients with a de novo implanted ICD whereof 22% had T2DM. The study showed that patients with T2DM received ICD implantations more often for primary prevention compared with patients without T2DM, and coronary heart disease was the dominant underlying cause in this group. Patients without T2DM more frequently had non-ischemic aetiologies as indications for ICD, such as dilated cardiomyopathy. After ICD implantation, patients with T2DM demonstrated a substantially higher adjusted risk of both all-cause mortality and MACE. Complication rates including infections within the first year after implantation were low and did not differ significantly between the two groups.</p><h4>Conclusions</h4><p dir="ltr">There is a significant association between T2DM and an increased risk of serious cardiac arrhythmias and the need for device treatments. The findings suggest that overall, patients with T2DM carry a heavier burden of arrhythmias and a more dismal prognosis than patients without T2DM, even when device therapy is provided. These associations were partly, however not entirely driven by CHD and HF but other factors that might relate to T2DM, may directly promote arrhythmogenesis and the subsequent need for device therapy in this population. This underscores that while cardiac device implantation remains important for arrhythmic risk reduction in general, additional strategies addressing T2DM specific and comorbidity related risks are essential to optimize outcomes in this high-risk population.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Elina Rautio</b>, Fredrik Gadler, Soffia Gudbjörnsdottir, Stefan Franzén, Lars Rydén, Ann-Marie Svensson, Linda Mellbin. Patients With Type 2 Diabetes Have an Increased Demand for Pacemaker Treatment: A Comparison With Age- and Sex-Matched Control Subjects From the General Population. Diabetes care. 2020;43(11):2853-8. <a href="https://doi.org/10.2337/dc20-0084" rel="noreferrer" target="_blank">https://doi.org/10.2337/dc20-0084</a></p><p dir="ltr">II. <b>Elina Rautio</b>, Fredrik Gadler, Soffia Gudbjörnsdottir, Stefan Franzén, Lars Rydén, Gianluigi Savarese, Ann-Marie Svensson, Linda Mellbin. Implantable Cardioverter Defibrillator and Cardiac Resynchronization Treatment in People with Type 2 Diabetes: a Comparison with Age- and Sex Matched Controls From the General Population. Cardiovasc Diabetol. 2024 Jan 6;23(1):18. <a href="https://doi.org/10.1186/s12933-023-02084-z" rel="noreferrer" target="_blank">https://doi.org/10.1186/s12933-023-02084-z</a></p><p dir="ltr">III. <b>Elina Rautio</b>, Fredrik Gadler, Paolo Gatti, Soffia Gudbjörnsdottir, Lars Rydén, Per Näsman, Anne Wang, Yiran Zhou, Linda Mellbin. Indications for Pacemaker Implantation, Prognosis and Peri/Postoperative Complications in Patients with and without Type 2 Diabetes Mellitus. [Manuscript]</p><p dir="ltr">IV. Yiran Zhou/<b>Elina Rautio</b>, Fredrik Gadler, Soffia Gudbjörnsdottir, Per Näsman, Lars Rydén, Tigist Wodaje, Linda Mellbin. Indications, Prognosis, and Complications of De Novo Implantable Cardioverter Defibrillators in Patients with and without Type 2 Diabetes. [Submitted]</p>