Introduction

Dipeptidyl peptidase-4 (DPP-4) inhibitors have several advantages over other glucose-lowering agents [1]. DPP-4 inhibitors improve glycemic control in monotherapy or combined therapy with other medications without many adverse effects [2]. DPP-4 inhibitors improve blood glucose control, reduce blood pressure, show neutral to modest beneficial effects on body weight, improve postprandial lipemia, reduce inflammatory markers, diminish oxidative stress, and improve endothelial function in diabetic patients [3,4,5,6,7,8,9,10]. Thus, DPP-4 inhibitors could reduce cardiovascular events through the improvement in risk factors. However, most studies and meta-analyses have shown that DPP-4 inhibitors do not significantly reduce cardiovascular events in Westerners [11,12,13,14,15,16,17]. These study populations mainly consisted of diabetic patients with a history of cardiovascular events. Furthermore, it is known that there is a difference in insulin secretory function between Japanese or east Asian and Westerners [18, 19].

Therefore, we sought to evaluate whether DPP-4 inhibitors alter the incidence of cardiovascular events in Japanese diabetic patients without a history of cardiovascular events.

Materials and methods

JPAD2 study

We undertook the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial to examine the efficacy of low-dose aspirin therapy for the primary prevention of cardiovascular events in type 2 diabetic patients [20]. The study protocol for the JPAD trial is registered at clinicaltrials.gov with the identifier NCT00110448. The study protocol is in agreement with the guidelines of the ethics committees at Kumamoto University (Rinri 956) and Nara Medical University (No. 263), and the study complied with the Declaration of Helsinki. Briefly, this multicenter, prospective, randomized, open, clinical trial was conducted at 163 institutions throughout Japan, and 2536 type 2 diabetic patients who had no history of cardiovascular disease were enrolled. The institutional review board at each participating hospital approved this trial, and written informed consent was obtained from each patient. The inclusion criteria of the JPAD trial were a diagnosis of type 2 diabetes mellitus, 30–85 years of age, and the ability to provide informed consent. The exclusion criteria were electrocardiographic ischemic changes, a history of coronary heart disease, cerebrovascular disease, arteriosclerotic disease, atrial fibrillation, use of antiplatelet or antithrombotic therapy, a history of severe gastric or duodenal ulcer, severe liver dysfunction, severe renal dysfunction, or allergy to aspirin [20].

After completion of the JPAD trial in 2008, all patients were followed up biennially. The JPAD trial and its follow-up period together constitute the JPAD2 study (Fig. 1). We reported the results of the JPAD2 study using data obtained until 2015 [21]. In the present study, the JPAD patients were followed up until 2019.

Fig. 1
figure 1

JPAD trial, JPAD2 study and present study population. The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a randomized controlled trial. All patients were biennially followed up after completion of the JPAD trial in 2008. The JPAD trial and its follow-up period together constitute the JPAD2 study. The present study consisting of the DPP-4 group and the non-DPP-4 group began in 2013

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At the time of follow-up of JPAD patients in 2011, few patients were taking DPP-4 inhibitors. JPAD patients were divided into a DPP-4 group and a non-DPP-4 group based on whether they were taking DPP-4 inhibitors at the 2013 follow-up. None of the non-DPP-4 group had received DPP-4 by 2013. Patients who had had a cardiovascular event by the 2013 follow-up were excluded from the study. Finally, we investigated the incidence of cardiovascular events in 1099 JPAD patients who had had at least one follow-up by 2019. In the present study, cardiovascular events were defined as the following: sudden death; death resulting from coronary, cerebrovascular, and aortic causes; nonfatal acute myocardial infarction; unstable angina; newly developed exertional angina; heart failure requiring hospitalization; nonfatal ischemic and hemorrhagic stroke; transient ischemic attack; and nonfatal aortic and peripheral vascular disease.

Statistical analyses

Patient characteristics are presented as the mean ± standard deviation, median (interquartile range) or number (%). Comparisons of variables between the DPP-4 and non-DPP-4 groups were conducted using t-tests or Wilcoxon rank sum tests for continuous variables or Chi-square tests for categorical variables. We followed up the patients until the day of the first cardiovascular event or July 2019, if patients did not have a cardiovascular event. If the patients were not followed up until July 2019, they were censored on the day of their last visit. Comparisons of cardiovascular events were performed on the basis of time to the first event. The follow-up time was computed from baseline until death, or the date of last known contact. Cumulative incidences of primary end points were estimated using the Kaplan–Meier method and differences between groups were then assessed with the log-rank test. We constructed Cox proportional hazard models to estimate the hazards ratio of the DPP-4 group relative to the non-DPP-4 group, with a 95% confidence interval. We adjusted for several clinically relevant factors such as age ≥ 65 years, hypertension, use of statins, and use of insulin as confounders in the multivariable Cox proportional hazard models. Patients with missing values for any selected variable were excluded from the analyses that used this variable. All statistical analyses were conducted by a statistician (TM) from an independent data center (Institute for Clinical Effectiveness) using JMP version 15.2 (SAS Institute Inc, Cary, NS, USA). Two-tailed P-values of less than 0.05 were considered statistically significant.

Results

Baseline clinical characteristics

In the JPAD study in 2013 (Fig. 1), 1099 patients had no previous history of cardiovascular events, 518 patients were taking DPP-4 inhibitors (DPP-4 group), and 581 patients were not taking DPP-4 inhibitors (non-DPP-4 group).

The baseline clinical characteristics are shown in Table 1. There were significant differences in age, hemoglobin A1c and triglyceride levels, and in the frequency of dyslipidemia and diabetic retinopathy between the DPP-4 and non-DPP-4 groups. The use of insulin was significantly higher in the non-DPP-4 group than in the DPP-4 group. Furthermore, the use of statins was significantly higher in the DPP-4 group than in the non-DPP-4 group. Clinical characteristics such as sex, blood pressure, body mass index, estimated glomerular filtration rate, total cholesterol, high-density lipoprotein levels, duration of diabetes, the frequency of smoking and proteinuria, and the use of each antihypertensive drug were similar between the two groups.

Table 1 Baseline characteristics (2013)
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Comparison of cardiovascular events between the DPP-4 and non-DPP-4 groups

During the observation period from 2013 to 2019, there were 37 (7%) cardiovascular events in the DPP-4 group and 66 (11%) in the non-DPP-4 group (Table 2). Fewer cardiovascular events occurred in the DPP-4 group than in the non-DPP-4 group. The frequency of coronary events, transient ischemic attack, vascular events, and sudden death were similar between the DPP-4 group and non-DPP-4 group. By contrast, the frequency of heart failure requiring hospitalization and cerebrovascular events were significantly lower in DPP-4 group than in the non-DPP-4 group: 8 (1.5%) and 10 (1.9%) events, respectively, in the DPP-4 group compared with 19 (3.3%) and 22 (3.8%) events, respectively, in the non-DPP-4 group.

Table 2 Comparison of cardiovascular events between the DPP-4 group and non-DPP-4 group
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Effects of administration of DPP-4 inhibitors on the incidence of cardiovascular events

The incidence of cardiovascular events was significantly lower in the DPP-4 group than in the non-DPP-4 group (Log-Rank P = 0.0065, Fig. 2). Cox proportional hazards model analysis revealed that the use of DPP-4 inhibitors (hazard ratio, 0.65; 95% confidence interval 0.43–0.98; P = 0.0377) independently reduced the incidence of cardiovascular events after adjustment for age ≥ 65 years, hypertension, statin usage, and, insulin usage (Table 3).

Fig. 2
figure 2

Comparison of cardiovascular events between the DPP-4 group and the non-DPP-4 group. The incidence of cardiovascular events was significantly reduced in the DPP-4 group compared to the non-DPP-4 group

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Table 3 Multivariable Cox proportional hazard models
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Discussion

Our 6-year follow-up study has shown that administration of DPP-4 inhibitors may reduce the incidence of cardiovascular events in type 2 diabetic patients. This new evidence in Japanese diabetic patients reveals that the DPP-4 inhibitors might inhibit first cardiovascular events in diabetic patients without a history of cardiovascular events.

Numerous recent studies in Westerners, however, have reported that DPP-4 inhibitors do not significantly reduce cardiovascular events [11,12,13,14,15,16,17]. Differences in insulin secretory function exist between Japanese or east Asian and Westerners [18, 19]; therefore, there may be differences in the effects of DPP-4 inhibitors on the suppression of cardiovascular events. To the best of our knowledge, this is the first report to investigate the effect of DPP-4 inhibitors on suppression of cardiovascular events in Japanese diabetic patients.

Furthermore, the recent trials did not assess the cardiovascular benefits of DPP-4 inhibitors in the general population with type 2 diabetes mellitus, but assessed the cardiovascular safety of DPP-4 inhibitors in patients with very high-risk type 2 diabetes mellitus [22]. One possible cause of the negative result in the recent studies is the progress of preventive medicines such as the development and clinical prescription of intense-dose statins. The cardiovascular risk factors of patients with a history of cardiovascular events have become more tightly controlled, which may obscure the additional effect of DPP-4 inhibitors on reducing cardiovascular events. Therefore, recent studies in patients with a history of cardiovascular events may have low power to detect event-suppressing effects of DPP-4 inhibitors. Primary prevention studies, like our study, may facilitate the detection of cardiovascular event-suppressing effects of DPP-4 inhibitors.

Median follow-up in the recent studies on DPP-4 inhibitors was limited to 1.5 to 3 years [11,12,13,14,15,16,17], which may not represent sufficient time to assess the potential long-term benefits. The guidance document by the US Food and Drug Administration states that all new glucose-lowering agents must prove cardiovascular safety [23]. Therefore, many randomized controlled trials were primarily designed as noninferiority trials compared with placebo to exclude an unacceptable risk of cardiovascular events associated with DPP-4 inhibitors in the shortest possible time period [24]. The duration of these trials was rather short; therefore, the difference in hyperglycemia exposure between the two arms was probably too low to show any difference in cardiovascular events, especially in type 2 diabetic patients with advanced cardiovascular diseases [25].

Most of the recent studies used a composite, triple major adverse cardiac event as a primary outcome, which combined cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke [11,12,13,14,15,16,17]. On the other hand, our study used a different composite, major adverse cardiac event, which included unstable angina, newly developed exertional angina, heart failure requiring hospitalization, and nonfatal aortic and peripheral vascular disease. The inhibition of cardiovascular events, especially heart failure requiring hospitalization and cerebrovascular events, was observed in our study. There are several possible mechanisms by which DPP-4 inhibitors may reduce cardiovascular events, including improved glycemic control and endothelial function and decreased lipids and blood pressure [3,4,5,6,7,8,9,10]. In the primary prevention setting, Mita et al. and Tanaka et al. showed significant inhibitory effects of aloglptin and sitagliptin on mean and maximum internal carotid artery intima-media thickness [26, 27]. An experimental study showed that linagliptin inhibited plaque growth in the brachiocephalic artery and stabilized plaque in Watanabe heritable hyperlipidemic rabbits [28]. This evidence may support the inhibition of stroke events by DPP-4 inhibitor in our data. Furthermore, in diabetic patients with acute coronary syndrome, DPP-4 inhibitors did not significantly reduce the percentage change in coronary plaque volume, but significantly reduced the percentage change in lipid plaque volume [29].

DPP-4 inhibitors decrease heart failure requiring hospitalization in diabetic patients with heart failure [30]. This finding supports our results. Moreover, DPP-4 inhibitors attenuate the severity of left ventricular fibrosis, and, thus, left ventricular diastolic dysfunction in rats [31]. Furthermore, DPP-4 inhibitors improve myocardial energy metabolism in a murine model of pressure-overloaded heart [32]. The association of DPP-4 inhibitors and better outcomes of heart failure might be partially because of these effects. Thus, DPP-4 inhibitors may still have the potential to suppress cardiovascular events in primary prevention studies even in Westerners.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are associated with a significant reduction in cardiovascular events [33, 34]. In the present study, no patients had received SGLT2 inhibitors in 2013. In the DPP-4 group, SGLT2 inhibitors had been prescribed in 23 and 54 patients at the 2015 and 2017 follow-ups, respectively. In the non-DPP-4 group, SGLT2 inhibitors had been prescribed in 11 and 25 patients at the 2015 and 2017 follow-ups, respectively. Since the number of the study subject taking SGLT2 inhibitors was low and there was no significant difference in the prescription rate between the two groups, the effect of SGLT2 inhibitors on the study results is likely to be small.

Our study was a follow-up study of a randomized controlled trial. To confirm the effects of DPP-4 inhibitors on cardiovascular events, randomized controlled trials are needed. Given the current situation of type 2 diabetes, however, it may be hard to perform a new randomized clinical trial to assess the clinical benefits of DPP-4 inhibitors on cardiovascular events.

In our cohort study, we showed that DPP-4 inhibitors may have a primary preventive effect against cardiovascular events in Japanese diabetic patients. We believe that DPP-4 inhibitors are still necessary drugs for diabetes treatment even in terms of prevention of cardiovascular disease.

Our study had some limitations. First, this study was a follow-up study of the JPAD trial that was designed as a randomized controlled trial to evaluate the efficacy of low-dose aspirin, but not DPP-4 inhibitors, in preventing cardiovascular events. Second, there were some imbalances in clinical factors between the DPP-4 group and the non-DPP-4 group, and although we adjusted these, the they may have affected the results.

Conclusions

Our study suggests that the use of DPP-4 inhibitors is associated with a reduced incidence of first cardiovascular events in Japanese diabetic patients without a history of cardiovascular events. Randomized controlled trials are necessary to confirm the findings.