Impact of Cardiovascular Screening Tests in Patients with Type 2 Diabetes Mellitus without Previous Histories of Cardiovascular Disease: 5-year Clinical Outcomes. CURRENT

cardiovascular screening test, Abstract We previously reported that, among the asymptomatic patients with type 2 diabetes mellitus (T2DM) without history of cardiovascular disease (CVD), up to 19% of the patients with myocardial ischemia were detected by cardiovascular screening tests (CVSTs). We concluded that the CVSTs in patients with T2DM may be one of the most effective strategies to find CVD in those patients. Thus, the aim of the study was to assess the long-term clinical outcomes of CVSTs in patients with T2DM without previous histories of CVD.


Conclusions
Thus, it may be important to continue CVSTs in out-patients with T2DM without a previous history of CVD for several years.

Background
The number of patients with type 2 diabetes mellitus (T2DM) continues to increase all over the world [1]. Moreover, cardiovascular (CV) disease (CVD), especially coronary artery disease (CAD), is well-known to be the leading cause of complications and death in the patients with T2DM [2][3][4]. In 2013, the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013 [5] recommended CV screening tests (CVST), and it is desirable that those examinations should be performed in patients with T2DM once a year [5]. Further, we previously reported that, among the asymptomatic patients with T2DM without a history of CVD, up to 19% of the patients with silent myocardial ischemia were detected by CVSTs, and a long disease duration of T2DM and a coexistence of a family history of CVD were independent risk factors in those patients [6]. Finally, we concluded that the CVST for patients with T2DM may be one of the most effective and useful strategies to find CVD in those patients [6]. Thus, the aim of the study was to assess the long-term clinical outcomes of CVSTs in patients with T2DM without previous histories of CVD.

Methods
Study Population and Laboratory Analysis: This study was approved by the institutional review committee and ethics review board of our hospital. Before we started the CVST in March of 2014, there were 657 out-patients (434 males and 223 females with a mean age of 66 ± 11 years and body mass index (BMI) of 24.9 ± 4.5 kg/m 2 ) with T2DM and no previous history of CVD, including cerebral infarctions, carotid artery stenosis, CAD, hemodialysis, renal artery stenosis, arteriosclerosis obliterans, and aortic aneurysms, that visited the Munakata Suikokai General Hospital. Those outpatients with T2DM who received CVSTs at least more than one time or not at all from April in 2014 to March in 2019 were defined as the S group and NS group, respectively. In the S group, the CVSTs were performed after informed consent was obtained at our hospital. The data including the recorded histories, physical examinations, laboratory analyses, and baseline therapies, in 2104 and 2018 were collected from the medical records and compared between the S and NS groups. For the patients who moved to another hospital, an order for the data in 2018 from the family doctor's office was performed. Further, the number of patients who received the CVSTs, internal use of medicine including sodium-glucose cotransporter (SGLT)-2 inhibitors, glucagon-like peptide (GLP)-1 receptor agonists, statins, anti-platelets, and renin-angiotensin system (RAS) inhibitors, all-cause mortality, and cerebro-and cardio-vascular events including acute coronary syndrome (ACS), cerebral infarction, and admissions due to heart failure, were also evaluated from 2014 through 2018. The 4point major adverse cardiovascular events (MACE) [7] including cardiovascular death, non-fetal myocardial and cerebral infarctions, and admissions due to ACS were also evaluated. In the S group, the highly sensitive C-reactive protein (hs-CRP) was measured during each CVST.
Statistical Analysis. The numerical results are expressed in the text as the mean ± standard deviation.
The statistical analyses were performed using a Fisher's exact test and Student t test or two-way Analysis of Variance (ANOVA) for the comparison of the 2 groups. The trend in the proportions and correlation between the frequency of receiving the CVST, internal use of SGLT-2 inhibitors, GLP-1 receptor agonists, statins, anti-platelets, and RAS inhibitors, all-cause mortality, cerebro-and cardiovascular events, admissions due to heart failure, 4-point MACEs, and the years were determined by a Cochran-Armitage analysis. All analyses were performed with SAS version 9.2 software (SAS Institute, Cary, NC). A p < 0.05 was considered to indicate statistical significance.

Discussion
This study revealed that, in the out-patients with T2DM in our hospital over those 5 years, 1) the age of the out-patients who did not receive a CVST was younger than that of those that did receive a CVST (Table 1), 2) the frequency of receiving a CVST significantly increased (bold black line in Fig. 2A), 3) in accordance with that increase, the frequency of the internal use of statins, anti-platelets, and RAS inhibitors for CVD significantly increased (blue, red, and green lines in Fig. 2A, respectively), 4) however, there was only a small increase in the internal use of SGLT-2 inhibitors and GLP-1 receptor agonists for T2DM ( Fig. 2A), 5) dyslipidemia including the LDL-cholesterol and triglyceride significantly improved more in the out-patients who received a CVST than in those who did not (Fig. 1D), 6) the hs-CRP, which is one of the strongest predictors [8] of CVD was significantly suppressed by the CVSTs (Fig. 1F), 7) the progression of renal dysfunction was significantly more suppressed in the out-patients who received CVSTs than in those who did not (Fig. 1E), 8) in an inverse proportion to the CVST increase, the frequency of ACS, cerebral infarctions, 4-point MACEs, and admissions due to heart failure significantly decreased (green, purple, red, and blue lines in Fig. 2B, respectively), and 9) finally, the frequency of all-cause mortality (bold black line in Fig. 2B) was significantly suppressed during those 5 years. Thus, the underling potential mechanism(s) of the suppression of CV events in this study was considered, as described below.
Controls and Treatment of T2DM and the Risk Factors in Patients with T2DM: In this study, as described in our previous study [6] and Table 1, the values in 2014 for these common conditions including T2DM, hypertension, dyslipidemia, and obesity, may seem to be comparably acceptable for treatment. Statins [9,10], anti-platelets [10], and RAS inhibitors [10,11], are well-known as medications not only for hypertension, dyslipidemia, and CAD, but also for OMTs to prevent CVD [12] in patients with T2DM because of their clinical benefit. The increasing frequency of the internal use of those medications significantly increased during those 5 years ( Fig. 2A). Moreover, out of 340 outpatients with T2DM who received CVSTs during those 5 years, myocardial ischemia was detected in 62 patients (18%), and those patients received treatment for CAD with coronary revascularization and/or OMTs using statins, anti-platelets, and/or RAS inhibitors. That may have contributed to suppressing the CV events (Fig. 2B). Further, RAS inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists may also contribute to suppressing the admission due to heart failure.
Suppression of the Progression of Renal dysfunction in Patients with T2DM: It has been reported that the progression of renal dysfunction in patients with T2DM is two times faster than that in those without T2DM [13], and the severity of the renal dysfunction is greater in those patients with T2DM, with an excessive risk of death from any cause and cardiovascular death that increases up to approximately 30-fold as high as the risk among patients without T2DM [14]. In this study, the progression of renal dysfunction in the S group was significantly more suppressed than that in the NS group (Fig. 1E). Because statins [15] and RAS inhibitors [16] are well-known to play a renal protective role in patients with T2DM, the increased use of statins and RAS inhibitors during those 5 years ( Fig. 2A) may have played important roles in suppressing the progression of renal dysfunction leading to the suppression of CV events in patients with T2DM (Fig. 2B).
Anti-inflammatory Therapies in Patients with T2DM: The inflammatory markers, hs-CRP and LDLcholesterol, are well-known to be one of the most important predictors of CV events [17]. A recent study reported that the suppression of the triglyceride level reduces the CV events in patients with T2DM [18]. In this study, the frequency of the internal use of statins [9,17], anti-platelets [19], and RAS inhibitors [20,21], which could play an important role in the suppression of the vascular inflammation contributing to the progression of atherosclerosis [22] had increased during those 5 years ( Fig. 2A).
Further, those 3 markers including the hs-CRP, LDL-cholesterol, and triglyceride levels, could be significantly suppressed in patients with T2DM who received CVSTs (Fig. 1DF). That may contribute to suppressing CV events (Fig. 2B).
New Drugs for T2DM to Suppress the CV events in Patients with T2DM: The SGLT-2 inhibitors [7,[23][24][25] and GLP-1 receptor agonists [24,26,27] are well-known to be new drugs for T2DM, which can suppress CV events in patients with T2DM. In this study, there was a small increase in the internal use of these drugs ( Fig. 2A). Thus, although we could not completely deny that these drugs might have played an important role in the suppression of CV events during those 5 years (Fig. 2B), that effect probably was small.
Theme in the Future: The age of the out-patients who did not receive CVSTs was younger than that in those who did receive CVSTs (Table 1). We previously reported in a Japanese article that because young patients with T2DM in their prime are busy with work, they cannot make the time to undergo CVSTs [28]. Thus, creating systems that can support those young patients with T2DM to help them Consent for publication: All data analysis were performed after informed consent from the patients was obtained at our hospital.
Availability of data and materials: All data and materials are available.