Imaging vs. no Testing in Asymptomatic High-risk Diabetic Patients
Imaging vs. no Testing in Asymptomatic High-risk Diabetic Patients
The aim of our study was to evaluate 1- and 3-year outcome of alternative imaging strategies
 in asymptomatic high-risk diabetic patients: functional stress echocardiography combined with
 coronary flow reserve (CFR) and strain imaging, or computed tomography (CT) angiography with
 direct visualization of coronary arteries, and no testing at all.
A meta-analysis of >100 prospective studies, showed that diabetes mellitus (DM) in general
 carries a two-fold excess risk of vascular outcomes (coronary artery disease, ischemic
 stroke, and vascular deaths), independent of other risk factors (1). Although type 2 diabetes
 mellitus (DM) is far more common than type 1 DM, these results confirm adverse prognosis in
 both populations, which is particularly severe in the young in general and young onset female
 individuals with type 1 DM, emphasizing the need for intensive risk-factor management in
 these groups.

 According to new 2019 European Society of Cardiology (ESC) / European Association for the
 study of diabetes (EASD) guidelines for diabetes, pre-diabetes and cardiovascular diseases
 (2) individuals with DM and cardiovascular diseases (CVD), or DM with target organ damage,
 such as proteinuria or renal failure (estimated glomerular filtration rate (eGFR) <30
 mL/min/1.73 m2), are at very high risk (10-year risk of CVD death >10%). Patients with DM
 with three or more major risk factors, or with a DM duration of >20 years, are also at very
 high risk. Type 1 DM at the age of 40 years with early onset (i.e. 1-10 years of age) and
 particularly female are associated with very high CV risk (2). Most others with DM are high
 risk, 10 year risk of cardiovascular diseases death (CVD) 5-10%, with the exception of young
 patients (aged <35 years) with type 1 DM of short duration (<10 years), and patients with
 type 2 DM aged <50 years with a DM duration of <10 years and without major risk factors, who
 are at moderate risk.

 Screening for asymptomatic CAD in patients with DM remains controversial. According to
 current guidelines only resting ECG is recommended in patients with suspected CVD, whereas
 computed tomography (CT) angiography or functional imaging (radionuclide myocardial perfusion
 imaging, magnetic resonance imaging, or physical or pharmacological stress echocardiography)
 may be considered (class IIb) in asymptomatic patients with DM for screening of coronary
 artery disease (CAD) (2). With CT, non-invasive estimation of the atherosclerotic burden
 (based on the coronary artery calcium score) and identification of atherosclerotic plaques
 causing significant coronary stenosis (CT angiography) can be performed. Patients with DM
 have a higher prevalence of coronary artery calcification compared with age- and sex-matched
 subjects without DM (3). While a coronary artery calcium (CAC) score of 0 is associated with
 favorable prognosis in asymptomatic subjects with DM, each increment in CAC score (from 1 -
 99 to 100 - 399 and ≥400) is associated with a 25 - 33% higher relative risk of mortality
 (3). Importantly, CAC is not always associated with ischemia. Therefore, coronary artery
 calcium score may be considered as risk modifier in CV assessment in asymptomatic patients
 with moderate risk (2).

 Stress testing with myocardial perfusion imaging or stress echocardiography allows the
 detection of myocardial ischemia, particularly silent form which is more prevalent in
 patients with DM as demonstrated by observational studies (22%) (4-6). Randomized trials
 evaluating the impact of routine screening for CAD in asymptomatic DM and no history of CAD
 have shown no differences in cardiac death and unstable angina at follow-up in those who
 underwent stress testing, or CT angiography (4,6,7). A meta-analysis of five randomized
 studies with 3299 asymptomatic subjects with DM showed that non-invasive imaging for CAD did
 not significantly reduce event rates of non-fatal myocardial infarction (MI) (relative risk
 0.65; P=0.062) and hospitalization for heart failure (HF) (relative risk 0.61;P=0.1)
 (8).Observed low event rates in these studies and the disparities in patient population and
 the management of screening results (different imaging techniques, invasive coronary
 angiography and revascularization were not performed systematically) may explain the lack of
 benefit of the screening strategy. Accordingly, routine screening of CAD in asymptomatic DM
 is not recommended (2, 8) However, stress testing or CT angiography may be indicated in very
 high-risk asymptomatic individuals (with peripheral arterial disease (PAD), a high CAC score,
 proteinuria, or renal failure) (9).

 The addition of circulating biomarkers for CV risk assessment has limited clinical value
 (10). In patients with DM without known CVD, measurement of C-reactive protein or fibrinogen
 (inflammatory markers) provides minor incremental value to current risk assessment. The
 addition of hs troponin (Tn) T to conventional risk factors has not shown incremental
 discriminative power in this group (11). In individuals with type 1 DM, elevated high
 sensitive troponin T (hsTnT) was an independent predictor of renal decline and CV events
 (12). The prognostic value of N-terminal pro-B-type natriuretic peptide (NT-pro BNP) in an
 unselected cohort of people with DM (including known CVD) showed that patients with low
 levels of NT-pro BNP (<125 pg/mL) have an excellent short-term prognosis (13).

 With emerging role of CT angiography in diagnosis of CAD according to the last 2019 ESC
 guidelines on Chronic coronary syndrome (14), as well as advanced functional imaging
 techniques, there is an obvious gap in evidence on prognostic value of both functional and
 angiographic advanced imaging techniques in patients with diabetes, particularly high risk
 subgroup.

 The investigators hypothesized that a strategy using either functional evaluation with
 advanced stress echocardiography using wall motion abnormalities, coronary flow reserve and
 strain, or CT angiography visualization will lead to better outcome than no testing at all in
 asymptomatic high risk diabetic patients.
Inclusion Criteria:

 Asymptomatic patients (>30 years) with duration of diabetes ≥10 years without target organ
 damage plus any other additional risk factor including age, hypertension, dyslipidemia,
 smoking, and obesity.

 Exclusion Criteria:

 -  Patient categorized as very high or moderate risk for CV diseases

 -  Any symptoms suggestive of angina or heart failure

 -  Patients with baseline ECG or echo abnormalities

 -  Patients with known CV disease, or previous myocardial revascularization

 -  Patients with target organ damage defined as proteinuria, renal impairment defined as
 eGFR <30 mL/min/1.73 m2, left ventricular hypertrophy, or retinopathy