Diabetes as a Risk Factor for Cardiovascular Events in Patients Receiving Permanent Pacemaker – A Propensity Score-Matched Cohort Study

Background: Type 2 diabetes was associated with higher risk for permanent pacemaker (PPM) implantation. We aimed to compare the clinical outcomes between diabetic and non-diabetic patients receiving PPM treatment. Methods: Between January 2003 and December 2017, 1742 patients receiving naïve PPM treatment comprised this retrospective cohort study and were categorized into two groups by the presence or absence of diagnosis of diabetes: diabetic group (n=632, 36.3%) and non-diabetic group (n=1110, 63.7%). The primary outcome was cardiovascular events including heart failure (HF) hospitalization and acute myocardial infarction (AMI). Propensity score matching (PSM) was applied to reduce selection bias between the study groups. Results: During a mean follow-up of 7.8 ± 4.8 years, there were 264 cardiovascular events. A total of 746 patients with a 1:1 paired ratio between diabetic and non-diabetic groups were analyzed in the propensity score-matched series. After PSM, the incidence of cardiovascular events was higher in the diabetic group compared to the non-diabetic group (18.8% vs. 12.3%, P=0.015). Moreover, the incidence of HF hospitalization was higher in the diabetic patients compared to the non-diabetic patients (15.3% vs. 10.2%, P=0.037), whereas the incidence of AMI did not differ between the diabetic and non-diabetic groups (3.5% vs. 2.1%, P=0.268). After adjustments for covariates in multiple Cox regression analysis, diabetes remained as an independent predictor for cardiovascular events [hazard ratio, 1.54; 95% condence interval, 1.04-2.29; P=0.031]. Conclusions: this


Introduction
Diabetes mellitus is a serious chronic disease with an imperative in uence on health of human being in the worldwide. Owing to ageing population, economic development and change of lifestyle, the growth in global and regional prevalence of type 2 diabetes markedly increased [1][2][3][4]. The number of patients with type 2 diabetes had doubled during the past two decades, and half of people with diabetes are not even aware that they have diabetes [1,4]. Diabetes is a well-known risk factor for cardiovascular events, such as acute myocardial infarction (AMI) and heart failure (HF) [5,6]. Previous studies demonstrated that lethal tachyarrhythmia occurs commonly in diabetic patients, possibly related to myocardial ischemia and sympathoadrenal activation in response to hypoglycemia [7][8]. On the other hand, an association between bradyarrhythmia and diabetes has also been reported, which is possibly caused by microangiopathy and increased cholinergic sensitivity [9][10][11]. From a national diabetes registry study, Rautio et al. reported that type 2 diabetes was associated with 1.6-fold higher risk for permanent pacemaker (PPM) treatment after adjustments for age, sex, and other factors [12]. However, the difference in cardiovascular outcomes between type 2 diabetic patients and non-diabetic patients receiving PPM treatment remains unexplored. Moreover, type 2 diabetes as an independent risk factor for cardiovascular events in pacemaker recipients remains unexplored. Accordingly, we conducted this retrospective cohort study to investigate and compare the clinical outcomes between diabetic and non-diabetic patients receiving PPM treatment after propensity score matching (PSM). Moreover, this study also aimed to identify whether type 2 diabetes was a risk factor for cardiovascular events in PPM recipients.

Study population
This retrospective cohort study enrolled 2706 consecutive patients receiving cardiac implantable electronic devices implantation in our hospital between January, 2003 and December, 2017. A total of 964 patients, including 191 patients with implantable intracardiac de brillators, 78 patients with cardiac resynchronization therapy and 695 patients with replacement of generator, were excluded ( Figure 1). Finally, 1742 patients receiving single ventricular or dual chamber PPMs comprised this retrospective cohort study population and were categorized into two groups by the presence or absence of diagnosis of type 2 diabetes at the time of PPM implantation: diabetic group (n=632, 36.3%), and non-diabetic group (n=1110, 63.7%) ( Figure 1). The standard protocol for PPM implantation in our center had been described in our previous study [15], mainly right ventricular lead placed at right ventricular out ow tract or high septum.

De nitions
Based on recommendations from the American Diabetes Association [16], diabetes was de ned as prescription for oral antidiabetic drugs or insulin, or HbA1c ≥6.5% (48 mmol/mol), or fasting plasma glucose level ≥126 mg/dl (7.0 mmol/L), or a random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of hyperglycemia or hyperglycemic crisis during hospitalization for PPM implantation. According to the guidelines of Kidney Disease: Improving Global Outcomes [17], microalbuminuria was de ned as at least two positive results obtained within 1 year and was de ned as an albumin-to-creatinine ratio of 30-300 mg/g (3-30 mg/mmol); macroalbuminuria was de ned as an albumin-to-creatinine ratio ≥300 mg/g (>30mg/mmol).
Estimated glomerular ltration rate (eGFR) was estimated from the creatinine value and calculated using the Chronic Kidney Disease Epidemiology Collaboration equation [18]. Chronic kidney disease (CKD) was de ned as eGFR lower than 60 mL/min/1.73m2 without renal replacement therapy, and end-stage renal disease as the need for peritoneal dialysis, hemodialysis, or renal transplantation. Hyperlipidemia was de ned as total cholesterol ≥240 mg/dL, low density lipoprotein ≥150 mg/dL, or triglyceride ≥200 mg/dL, or on lipid lowering medications [19]. Valvular heart disease was de ned as moderate to severe regurgitation or stenosis of aortic, mitral or tricuspid valves. Cardiovascular surgery included coronary artery bypass graft and valvular surgery. Chronic lung disease was de ned as a history of asthma, chronic obstructive pulmonary disease, or pulmonary brosis.

Clinical outcomes
The primary outcome of this study was cardiovascular events of patients after PPM implantation. Cardiovascular events included hospitalization related to HF event of New York Heart Association functional class of III-IV, or AMI. The secondary outcomes of this study included pacing-induced cardiomyopathy, cerebrovascular accident, cardiovascular mortality and all-cause mortality. Pacing-induced cardiomyopathy was de ned as a ≥10% decrease of the baseline left ventricular ejection fraction (LVEF) with a resultant LVEF <50%. Cerebrovascular accident was de ned as an episode of transient ischemic attack, ischemic stroke, intracranial hemorrhage, or any incident nding by images, including brain computed tomography or magnetic resonance imaging after PPM implantation. Cardiovascular mortality was de ned as death from AMI, HF, refractory ventricular arrhythmias, or cardiac arrest. After PPM implantation, patients were followed up monthly for the rst three months and then every three to six months until clinical outcomes of interest, death, loss to follow up, or the latest date in the dataset (31 December, 2020), whichever came rst.

Study covariates
Baseline variables considered in the analyses included patient's age, sex, body mass index and comorbidities associated with clinical outcomes including hypertension, hyperlipidemia, coronary artery disease, HF, atrial brillation, valvular heart disease, chronic kidney disease, history of cardiovascular surgery, cancer, and chronic lung disease. The prescription for medication, such as beta-blocker, anti-hypertensive drugs, diuretic agents and lipid-lowering agents, laboratory data including hemoglobin and serum creatinine, the indication and lead number of PPM, baseline and pacing QRS duration were also obtained.

Statistical analysis
Continuous variables are expressed as a mean ± standard deviation or percentages. The clinical characteristics of the study groups were compared using the independent t-test for continuous variables and Chi-square test or Fisher's exact test for categorical variables. PSM was applied to reduce selection bias between the study groups. Using NCSS 10 Statistical Software (LLC, Kaysville, Utah, USA), the greedy method was used for matching at a 1:1 ratio between the study groups with a caliper width 0.2-fold the standard deviation of the propensity score between the study groups. The standardized mean difference was used to evaluate covariate balance after PSM, and a value of >0.1 indicated meaningful imbalance after PSM [20].

Results
Baseline characteristics of the study patients with and without type 2 diabetes Table 1 lists the clinical characteristics of the study patients before and after PSM. Before PSM, the mean age of the patient population was 73 ± 11 years and 48.6% of the study patients were male. There were 632 (36.3%) diabetic patients, which were under diet control alone (12.8%), oral antidiabetic drugs (74.7%) or insulin-based therapy (12.5%), and 1110 (63.7%) non-diabetic patients ( Figure 1). The diabetic group had more patients with overweight and higher prevalence of hypertension, hyperlipidemia, coronary artery disease, CKD and end-stage renal disease (all P<0.001) compared to the non-diabetic group. The diabetic group also had a higher prevalence of history of HF (P=0.033), atrial brillation (P=0.007), and cerebrovascular accident (P=0.028) compared to the non-diabetic group. The diabetic group had more prescription for beta-blocker (P=0.001), angiotensin converting enzyme inhibitors/angiotensin receptor blocker (ACEi/ARB), diuretic agents, and statin (all P<0.001). The diabetic group had higher serum creatinine, hemoglobin A1c and triglyceride, and higher prevalence of albuminuria including microalbuminuria and macroalbuminuria (all P<0.001) compared to the non-diabetic group. The diabetic group had lower levels of hemoglobin, eGFR, low-density lipoprotein and high-density lipoprotein (all P<0.001) compared to the non-diabetic group. The diabetic group had higher prevalence of atrioventricular block (P=0.001), larger number of PPM leads (P=0.025) and wider baseline and pacing QRS durations (P=0.037 and P=0.019, respectively) compared to the non-diabetic group. The diabetic group had larger pre-procedural left atrial size (P=0.010) and LV end-diastolic volume (P=0.049), and lower preprocedural LVEF (P=0.042) compared to the non-diabetic group (Table 1).
In the cohort after 1:1 PSM, 373 diabetic and non-diabetic pairs were analyzed. The baseline characteristics were balanced in the matched groups (Table 1). After PSM, the matched diabetic group still had lower lowdensity lipoprotein (P=0.001) and high-density lipoprotein (P=0.005) and higher triglyceride (P=0.049) levels as well as higher prevalence of albuminuria (P<0.001) compared to the matched non-diabetic group (Table 1).

Clinical outcomes of the study patients before and after PSM
During a mean follow-up period of 7.8 ± 4.8 years, before PSM, the incidence of cardiovascular events was higher in the diabetic group compared to the non-diabetic group (19.8% vs. 12.5%, P<0.001) ( Table 2), and the incidences of pacing-induced cardiomyopathy, cardiovascular mortality, and all-cause mortality were all higher in the diabetic group compared to the non-diabetic group ( Table 2). After PSM, the incidence of cardiovascular events was still higher in the diabetic group compared to the non-diabetic group (18.8% vs. 12.3%, P=0.015) ( Table 2). The diabetic patients had a higher incidence of HF hospitalization compared to the non-diabetic patients (15.3% vs. 10.2%, P=0.037), whereas the incidence of AMI did not differ between the two groups ( Table 2). After PSM, the incidences of secondary outcomes, including pacing-induced cardiomyopathy, cerebrovascular accident, cardiovascular mortality and all-cause mortality, did not differ between the two groups ( Table 2). The Kaplan-Meier curve analysis for cardiovascular events showed that diabetic patients had a higher cumulative incidence of cardiovascular events compared to non-diabetic patients before and after PSM (log-rank test, P<0.001 and P=0.001, respectively) ( Figure 2a and Figure 2d). Moreover, the diabetic group had a higher cumulative incidence of HF hospitalization compared to the non-diabetic group before and after PSM (log-rank test, P<0.001 and P=0.005, respectively) ( Figure 2b and Figure 2e). However, the cumulative incidence of AMI did not differ between the two groups before and after PSM (Figure 2c and 2f).
Clinical predictors of cardiovascular events in the propensity score-matched patients receiving pacemakers In this study, there were 264 cardiovascular events during follow-up (  Table 3).

Discussion
In this cohort study, the prevalence of diabetes was 36.3%, over one-third of naïve PPM recipients. During a mean follow-up of 7.8 ± 4.8 years, after PSM, the incidences of cardiovascular events and HF hospitalization were signi cantly higher in the diabetic group compared to the non-diabetic group. Moreover, the cumulative incidences of cardiovascular events and HF hospitalization were signi cantly higher in the diabetic matched group compared to the non-diabetic matched group. Furthermore, by multiple Cox regression analysis, diabetes remained as an independent predictor for cardiovascular events in patients after naïve PPM implantation.

The prevalence of diabetes in patients receiving pacemakers
The global prevalence of diabetes is rising from 8% in 1980 to 9.3% in 2019, and is estimated to be 10.9% by 2045, which may be attributable to population growth and ageing [1,2]. In the Taiwanese population, the annual prevalence of diabetes increased signi cantly from 5.8% in 2000 to 8.3% in 2007, especially in the subgroup of men, age ≥80 years, and individuals residing in aging society areas [3]. In the elderly ≥65 years, around 15%-20% of people live with diabetes [1,21]. In this study, PPM recipients were aged and the prevalence of diabetes was 36.3%, which was higher than general population [1][2][3]21] and was compatible with previous data of PPM recipients [13,14]. Moreover, similar to other reports [1][2][3]21], the trend in the prevalence of diabetes in this study, also increased from 28.8% (between 2003 and 2007) and 36.0% (between 2008 and 2012) to 41.4% (between 2013 and 2017).
Prior study reported that diabetes was possibly associated with sinus nodal dysfunction and cardiac conduction abnormalities [9][10][11]22]. Movahed et al. reported that the incidence of complete atrioventricular block in the diabetic patients was 1.1%, which was 3-fold increased risk compared to the non-diabetic patients [11]. Diabetic patients of this study had a higher prevalence of atrioventricular block compared to non-diabetic patients (44.0% vs. 35.8%, P=0.001) ( Table 1), similar to other reports [10][11][12]. From a national diabetes registry study, Rautio et al. reported that diabetes increased 1.6-fold risk for implantation of PPM after adjustments for age, sex, and other factors [12]. Therefore, type 2 diabetes is a risk factor for PPM implantation and vigilant follow-up for bradyarrhythmia in diabetic patients is necessary.
Heart failure hospitalization in diabetic patients after pacemaker implantation The prevalence of diabetes in HF patients is around 20%, and diabetes increased 1.74-fold risk and 1.95-fold risk of HF in men and women, respectively [6,23]. The reasons for increasing risk of HF in diabetic patients included combined comorbidities such as hypertension, acceleration of the development of coronary atherosclerosis, and diabetic cardiomyopathy, which was related to microangiopathy, metabolic factors or myocardial brosis [23]. Moreover, a study using the National Readmission Database showed that the most common cause for readmission in PPM recipients was HF hospitalization [24]. In this study, we showed that the incidence of HF hospitalization was signi cantly higher in the diabetic group compared to the non-diabetic group before and after PSM. Diabetic cardiomyopathy is characterized by diastolic relaxation abnormalities in its early stage and later systolic dysfunction [25]. The pathophysiological mechanisms of diabetic cardiomyopathy include systemic metabolic disorders, inappropriate activation of the renin-angiotensinaldosterone system, subcellular component abnormalities, oxidative stress, in ammation and dysfunctional immune modulation and nally, interstitial brosis of cardiac tissue, which contributed to substantial cardiac stiffness with diastolic dysfunction and later, systolic dysfunction [25]. Furthermore, diabetes is an important phenotype for HF with preserved LVEF, and is also an independent predictor for HF hospitalization, despite under treatments of ACEi/ARB [26]. Interestingly, the study population in this study had preserved LVEF and the administration of ACEi/ARB was higher in the diabetic group compared to the non-diabetic group before PSM (Table 1). In this study, prescription for ACEi/ARB was an independent risk for cardiovascular events (Table 3). Of note, patients prescribed with ACEi/ARB were older and had higher prevalence of hypertension, hyperlipidemia and CKD, and had larger LV end-systolic volume and lower LVEF (even within the normal range) compared to those without prescribed with ACEi/ARB (supplementary Table 1

Other predictors for cardiovascular events in patients after pacemaker implantation
Previous studies reported that type 2 diabetes was associated with higher risk of HF in women than men [6,23]. There are several potential explanations including poorer glycemic control in women, under-treatment for diabetic women contributing to the development of diabetic cardiomyopathy, prolonged exposure to hyperglycemia during the prediabetic state in women, diastolic dysfunction of LV more common in women and deteriorations in major cardiovascular risk factors in women than in men [6]. In this study, women, compared with men, had a 1.72-fold increased risk for cardiovascular events (Table 3), which was compatible with other studies [6,23]. In diabetic patients with diabetic nephropathy, the risk of cardiovascular events increased by the decline of eGFR and the presentation of macroalbuminuria [31]. This study showed that CKD and presentation of albuminuria were independent risk factors for cardiovascular events (Table 3). Therefore, regular follow-up of renal function and serial measurement for albuminuria for PPM recipients, especially in women, is necessary.

Limitation
In this study, some potential limitations existed. First, although this was a retrospective single-center study, the sample size was large. Still, the potential bias inherent to nonrandomized investigations cannot be excluded. However, we performed PSM to minimize the bias between diabetic and non-diabetic groups. Second, the compliance period and dosage of prescription for beta-blocker, ACEi/ARB, diuretic agents, and statin during follow-up period were not available in this study. Third, the duration of diagnosed diabetes before PPM implant was unknown. Finally, the pre-procedural echocardiographic parameters of diastolic function by tissue Doppler or speckle-tracking imaging were not performed.

Conclusions
In this cohort study of patients with naïve PPMs implantation, the incidences of cardiovascular events and HF hospitalization were signi cantly higher in the diabetic group compared to the non-diabetic group. Moreover, diabetes increased 1.54-fold risk of cardiovascular events in PPM recipients, especially for HF hospitalization. 2 . Breakthrough results for empagli ozin con rm EMPEROR-Preserved as rst and only successful trial for heart failure with preserved ejection fraction. 2021. https://www.boehringer-ingelheim.com/pressrelease/emperor-preserved-heart-failure-toplineresults. Accessed 6 July 2021.   ACEi/ARB = angiotensin converting enzyme inhibitors/angiotensin receptor blocker. CI = con dence interval; HR: hazard ratio; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction. Figure 1 Flow chart of enrollment of patients receiving cardiac implantable electronic devices. CIED, cardiac implantable electronic devices; ICD, implantable cardioverter-de brillator; CRT, cardiac resynchronization therapy