Coronary artery disease (CAD) is the leading cause of morbidity and mortality in individuals with diabetes. According to the report of the American Diabetes Association (ADA), the estimated cost related to the treatment of cardiovascular event is $37.3 billion annually in individuals with diabetes in the US alone (1). Unfortunately, however, the incidence of diabetes is increasing in epidemic proportions worldwide. It is estimated 170 million individuals are living with diabetes worldwide and its prevalence is estimated to double by 2030 (2). A previous study demonstrated that the risk of mortality from cardiovascular causes in subjects with type 2 diabetes mellitus (T2DM) and no previous history of cardiovascular events is equivalent to that of non-DM subjects with prior myocardial infarction (MI) (3). Asymptomatic atherosclerosis has usually been present for years and even decades prior to the development of clinical evidence of CAD (4,5). Screening for the early detection of patients who are at risk of developing asymptomatic atherosclerosis and monitoring their response to treatment in order to reduce cardiovascular events remains a major challenge in preventive cardiology. Coronary computed tomography angiography (CCTA) is considered a reliable tool with which to detect or rule out the presence, extent and severity of coronary atherosclerosis (6).

Previous studies demonstrated that statin and anti-diabetic therapies may decrease the rate of coronary plaque progression and may participate in plaque stabilization (7–9). Previous experiments performed in our laboratory have shown that the use of aged garlic extract (AGE) is associated with a significant reduction in low attenuation plaque (LAP) progression as compared to the placebo using CCTA in patients with metabolic syndrome (10). Furthermore, AGE has been shown to exert positive effects on several cardiovascular disease risk factors, including endothelial dysfunction, cholesterol and blood pressure (11–14). The aim of the present study was to evaluate the effects of AGE over a period of 1 year on coronary atherosclerotic plaque in individuals with T2DM utilizing CCTA.

From 2016 to 2017, 80 patients were enrolled and randomly assigned to the placebo or AGE groups. In total, 66 patients completed the study with baseline and follow-up CT. The participants had a mean follow-up period of 370±24 days. Of these patients, 28% in the placebo group and 29% in the active group were on statins. Patients in both groups continued to see their primary care physicians and continued their regular medications. All the baseline data at entry into this study in both groups have been previously described (16). No statistically significant differences were found between the groups.

The AGE group compared with the placebo group exhibited a statistically significant regression in normalized LAP [median SD) −0.2 (18.8) vs. 2.5 (69.3), P=0.0415]. By percentage, there was 29% reduction in LAP in the AGE group as opposed to 57% LAP plaque progression in the placebo group. The AGE group exhibited a reduction in FF plaque as compared to the progression of FF in the placebo group; however this did not reach statistically significance (median difference −0.1 vs. +1.6, P-0.287). No marked differences were observed in total plaque (TP), F, or FF plaque volumes between the AGE and placebo group (Table I and Fig. 1).

In this study, 1 year of AGE therapy was associated with a regression of LAP. LAP [non-calcified plaque (NCP) <30 HU] is one of the high-risk plaque features. The results of this study are in concordance with those of previously published studies demonstrating the regression of LAP in participants with metabolic syndrome and general population in studies of AGE (10,17), as well as statin studies (18,19).

According to certain data, LAP represents an intravascular ultrasound (IVUS) equivalent of the necrotic core (19). In contrast to more stable F plaques, plaques with a lipid-rich necrotic core play a significant role in the development of acute coronary syndrome (ACS) (20). Recent advancements in cardiac imaging modalities have provided an accurate and detailed quantitative assessment of plaque composition and burden based on differences in CCTA (21). Previous studies have demonstrated an increased risk of myocardial infarction and cardiovascular death in patients with a larger volume of non-calcified and low-attenuation plaque (22,23).

Motoyama et al (24) demonstrated that patients with ACS exhibited a significantly increased frequency of low attenuation plaque (79 vs. 9%, P<0.001). Balestrieri et al (9) reported that the patients with stable chest pain with adverse plaque features, including LAP, spotty calcification and positive remodeling found an association with a 60% increased risk of future adverse cardiovascular events. Furthermore, LAP along with other vulnerable plaque features have been shown to be associated with rapidly progressive CAD (25). The SCOT-HEART trial, which consisted of mostly intermediate risk patients, demonstrated that low attenuation was associated with a 3-fold increased risk of non-fatal MI or coronary heart disease-associated mortality (26). In this study, there was a 57% increase in low attenuation plaque in the placebo group, representing the natural history of plaque progression. By contrast, a 29% reduction was observed in LAP in the AGE group over a period of 1-year follow-up, strongly suggesting the therapeutic potential of AGE in the diabetic population (Fig. 1).

The present study has several limitations. First, this relatively small sample size and short-term follow-up study did not have enough power to demonstrate the significant differences in TP volume, NCP and DC. Second, patients were under different therapies for hyperlipidemia and T2DM, and some patients used varying medications at different doses. Due to the small sample size, a separate analysis with different hyperlipidemia and T2DM medications was not performed. Further research is thus required to evaluate whether AGE has the ability to stabilize vulnerable plaque and to decrease adverse cardiovascular events.