Dipeptidyl peptidase-4 inhibitor decreases the risk of atrial fibrillation in patients with type 2 diabetes: a nationwide cohort study in Taiwan

Atrial fibrillation (AF) is the most common cardiac arrhythmia and significantly increases the risk of comorbidity and mortality [1, 2] with a threefold increased risk of heart failure and a fivefold increased risk of stroke [3‐6]. As the world population ages, the prevalence of AF is predicted to increase by 2.5 fold in the next 50 years [7]. Diabetes mellitus (DM) is an important independent risk factor for AF [8‐12]. In a previous study, AF occurred in 14.9% of diabetic patients and 10.3% in non-diabetic patients [8]. Furthermore, diabetes was highly associated with the prevalence of metabolic syndrome, which is also associated with a higher risk for AF [8]. Alogliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i), not only has anti-hyperglycemic effects, but can also inhibit the maintenance of AF induced by tachy-pacing, as shown in a recent animal study [13]. However, Only a few studies investigated if DPP4i has cardiac protective effects including AF [14‐16]. This study had as its underlying hypothesis that DPP4i could potentially reduce the incidence of AF in type-2 diabetic patients. The goal of the present study was to evaluate the risk of AF associated with use of DPP4i in a nationwide cohort study of diabetic patients in Taiwan.

A total of 16,017 DPP4i users and 74,863 non-DPP4i users were eligible for the study. Most patients in the DPP4i group were prescribed sitagliptin (n = 12,180, 76%); while 291, 1501 and 2045 patients were prescribed linagliptin (2%), saxagliptin (9%), and vildagliptin (13%), respectively. Among the non-DPP4i group, most patients were prescribed sulfonylurea (n = 60,606, 81%) as the second-line HA. In addition, 4087, 4783, 2334, 1032, and five patients were prescribed alpha glucosidase inhibitor (5%), meglitinide (6%), thiazolidinedione (3%), insulin (1%), and GLP-1 analogue (0%), respectively. There were 2016 patients (4%) taking more than two second-line HAs concurrently.

Table 1 summarizes the baseline demographic characteristics, comorbidities, and medication differences between the two groups. Before propensity score weighting, the DPP4i group had a higher use of statins and angiotensin-converting enzyme inhibitor/angiotensin receptor blockers than non-DPP4i group, while age, gender, comorbidities and other medications were all similar between two study groups at baseline (all ASMD < 0.1). After propensity-score weighting, the two study groups were well-balanced in all characteristics (all ASMD < 0.1).

DPP4i users were associated with a lower risk of new-onset AF compared with non-DPP4i users, either before or after propensity-score weighting [hazard ratio (HR): 0.65; 95% confidential interval (CI) 0.56–0.76; P < 0.0001]. It was noted that most HAs, with the exception of insulin/GLP1, were associated with a significantly higher risk of new-onset AF when compared with DPP4i (Table 2). Figure 2 and Additional file 2: Figure S1 show a clear separation of event curves for new-onset AF between these two groups either before or after propensity score weighting adjustment. The time interval from the index day to the occurrence of AF in DPP4i user vs non-user is 1.9 ± 2.9 years and 1.7 ± 1.2 years respectively. Some patients did not take DPP4i at the diagnosis of the first AF. Among the 45 AF events in DPP4i users, 10 of them (22.2%) did not take DPP4i within 3 months of the events. Subgroup analysis revealed that DPP4i usage was associated with a lower risk of new-onset AF compared with non-DPP4i usage in most subgroups (Fig. 3).

In Table 3, Cox’s model was performed after propensity score weighting in order to identify the independent risk factors for the new-onset AF for those patients taking HAs. The multivariate analysis indicated that use of DPP4i was associated with lower risk of new-onset AF (HR 0.69; 95% CI 0.59–0.81; P < 0.0001), and age > 65 years (HR 4.75; 95% CI 4.07–5.55; P < 0.0001), presence of hypertension (HR 1.74; 95% CI 1.45–2.06; P < 0.0001), and ischemic heart disease (HR 1.98; 95% CI 1.48–2.66; P < 0.0001) were independent risk factors for new-onset AF.

The nationwide cohort study evaluated the risk of new-onset AF in metformin-based patients with diabetes taking DPP4i versus other second-line hypoglycemic agents. Recently we had presented metformin users were associated with a lower risk of AF in patients with diabetes compared with non-users [20, 21]. In this study, in addition to use of metformin, we observed that patients taking DPP4i had a significantly lower risk of new-onset AF than those treated with other HAs including sulfonylurea, alpha-glucosidase inhibitors, meglitinide, and thiazolidinedione. The risk reduction of new-onset AF for DPP4i users versus other HAs was similar among most subgroups.

Several studies have indicated that diabetes, as well as age, hypertension, and structural heart diseases, are independent risk factors for AF [22]. Atrial fibrosis and chronic inflammation are known to contribute to AF [23, 24]. Diabetes is associated with numerous metabolic defects which could be responsible for AF occurrence. Diabetes could also cause structural, electrical, electromechanical and autonomic remodeling, triggering AF in patients with diabetes [25]. In several animal studies, DPP4i inhibitors increase in threshold of ventricular fibrillation during the ischemic period and stabilized cardiac electrophysiology, protected cardiac mitochondrial function [26]. DPP4i is commonly used for the treatment of patients with diabetes in clinical practice. By inhibiting the degradation of GLP-1, DPP4i has been shown to increase the serum levels of GLP-1, which indirectly stimulate insulin secretion and enhance beta-cell function. DPP-4 is highly expressed in endothelial cells and the GLP-1 receptor is expressed on cardiomyocytes, vascular smooth muscle cells, and endothelial cells. A previous animal study showed that DPP4i had both GLP-1-dependent and GLP-1-independent cardioprotective effects using an ischemic heart model [27]. A recent study also showed that DPP4i may exert antiarrhythmic effects and reduce infarct size during myocardial ischemia and reperfusion [28]. There were several mechanisms to explain the relationship between diabetes and AF and the mechanism of DPP4i in lowering AF risk. Recently Chang et al. showed that in spontaneously hypertensive rats, sitagliptin would modulate the electrical and mechanical properties of pulmonary veins and atria, suggesting that DPP4i may be protective against AF genesis [29]. Furthermore, Yamamoto et al. [13]. demonstrated that alogliptin, a DPP4i, can shorten the AF duration caused by ventricular tachy-pacing in rabbits with fibrotic atria. The underlying mechanisms may include augmentation of atrial remodeling and improvement of mitochondrial function [30]. Further, administration of nitric oxide synthase inhibitor has been shown to block the protective effects of alogliptin via shortening AF duration, capillary density, and atrial fibrosis. Their findings suggest that DPP4i may have an antiarrhythmic effect in the prevention of heart-failure-induced AF [13]. In contrast, Hayami et al. [31]. demonstrated that administration of sulfonylurea and DPP4i both inhibited inflammation and fibrosis of the atria in streptozotocin-induced diabetic rats. However, no significant differences were observed between the two oral HAs. They concluded that reduced atrial fibrosis may derive from the tight control of blood glucose levels rather than a drug-specific anti-inflammatory property.

The monotherapy of metformin is suggested as first-line therapy for glycemic control in newly diagnosed patients with type 2 diabetes according to the current guidelines [32]. If monotherapy does not achieve the therapeutic goal, a second HA would be added [33]. Several studies have indicated that patients with diabetes have an increased risk of developing adverse cardiovascular outcomes [34]. Therefore, prevention of any adverse cardiovascular outcome seems to be an important consideration when choosing second-line HAs. Until now, only empagliflozin, a potent inhibitor of sodium glucose cotransporter 2 (SGLT2), and metformin have provided cardioprotective effects in patients with diabetes beyond the hypoglycemic effects [35, 36]. It is unclear if GLP-1 receptor agonists was associated with AF [37]. At the present time, it is still unclear whether DPP4i would lead to better outcomes with a reduction in incidence of major adverse cardiovascular events [38‐41]. Recent large scale clinical trials, including EXAMINE, SAVOR-TIMI53, and TECOS, all failed to show significant improvement in cardiovascular outcomes in type 2 diabetic patients treated with DPP4i [38, 42, 43]. In contrast, several nationwide cohort studies presented that DPP4i may have cardioprotective properties, including the ability to lower the incidence of heart failure, coronary heart disease, and stroke [15, 39, 44]. In subgroup analysis (Fig. 3), however, we did not find differences in the occurrence of new-onset AF between DPP4 users and non-users in patients > 65 years. It is likely that more AF-precipitating factors coexist in aged diabetic patients, which would remove the protective effect of DPP4i. Until now, no randomized control trials directly compared the risk of new-onset AF in patients with diabetes taking DPP4i compared with patients taking other HAs. Our data revealed that DPP4i was associated with a lower risk of new-onset AF in patients with diabetes, indicating that DPP4i as a feasible second-line oral HA for AF primary prevention. Future prospective studies are necessary, however, to evaluate the potential role of DPP4i on atrial remodeling and AF prevention in the setting of diabetes.

Among patients with diabetes prescribed with metformin, the patients with DPP4i as second HA were associated with a lower risk of AF compared with the patients with other drugs as second HAs in real-world practice.