In the current study, SGLT2-I users vs. Non-SGLT2-I users showed, from the 6 months of treatment, a significant reduction of BMI, and the amelioration of glucose homeostasis, BNP values, and inflammatory burden (cells/cytokines). At the follow-up end, we confirmed this ameliorative trend in SGLT2-I users vs. Non-SGLT2-I users. Notably, the SGLT2-I users vs. Non-SGLT2-I users showed a more significant increase of minimum FCT, and reduction of lipid arc degree and macrophage grade at follow-up, just receiving the same tolerated dose of maximal anti-lipids therapy. This was linked to a lower rate of MACEs, which were unfavorably increased in patients with worse glycemic control (Hb1Ac values, HR 1.930), higher macrophage grade (HR 1.188), and significantly reduced by the SGLT2-I therapy (HR 0.342) at 1 year of follow-up. Conversely, we found that at 6 and 12 months of follow-up (T1 and T2), the SGLT2-I users vs. Non-SGLT2-I users had the lowest expression of NLRP3 levels, serum caspase-1 and IL-1β levels (inflammatory markers) and stage of M1/M2 macrophage polarization, as serum levels of CD86 and CD206. In the current study, the SGLT2-I users’ patients differed regards those receiving 10 mg vs. 25 mg daily of empagliflozin, a third group receiving canaglifozin 100 mg daily, and a fourth group of patients under dapaglifozin 10 mg daily. On the other hand, the two-dose groups for empaglifozin, and the group under canaglifozin and dapaglifozin had a similar hazard ratio for cardiovascular outcomes. Thus, we might confirm the cardio-protective effects of the SGLT2-I, in the T2DM with MACEs recurrence.
Therefore, SGLT2-I therapy could exert anti-inflammatory effects and lead to a more stable atherosclerotic coronary plaque phenotype, as reported by the increase of minimum FCT and the reduction of plaque inflammation (macrophage grade) and lipids’ deposit (lipid arc degree) at follow-up end. Previous studies reported the systemic anti-inflammatory effects of SGLT2-I in cohorts of Mv-T2DM, as in those with coronary atherosclerotic plaque rupture and acute myocardial infarction [
2,
3]. These effects caused a significant reduction of MACEs in SGLT2-I users vs. Non-SGLT2-I users [
2,
3]. Authors previously found that the worse glycemic homeostasis could cause over-inflammation and worse prognosis via the increased expression of SGLT2 receptors and atherosclerotic plaque instability in the Mv-patients [
2,
6]. As seen in humans’ ex vivo models, highest levels of inflammatory cytokines linked to the over-expression of the SGLT2 receptors al level of peri-coronary fat [
6], and atherosclerotic plaque [
7]. Conversely, the hypoglycemic drugs could down-regulate the SGLT2 pathways, reducing the over-inflammation (higher serum values of IL-1, IL-6, and TNF-α) in the SGLT2-I users vs. non-SGLT2-I users’ patients, and leading to best clinical outcomes [
6]. In rats’ models, the block of the SGLT2 pathways by empagliflozin (SGLT2-I) reduced the inflammatory/oxidative stress in the non-infarcted myocardium and the mortality, acting by the protective modification of cardiac energy metabolism [
24]. In humans, the canaglifozin (SGLT2-I) caused either a glucose-independent up-regulation of cardiac survival pathways leading to cardioprotective effects in high-risk cardiovascular patients irrespective of diabetic status [
25], and reduced the inflammatory burden and myocardial size in patients with atherosclerotic plaque rupture and acute myocardial infarction [
3]. Indeed, the SGLT2-I could ameliorate glucose homeostasis, lowering blood pressure, weight loss, and improving vascular and coronary function [
3]. Intriguingly, SGLT2-I could exert cardiac protection beyond glucose and lipid-metabolic regulation [
26]. Therefore, SGLT2-I cardioprotective properties could result from both a direct effect on glucose level reduction (glucose-lowering dependent effects) and a glycemic-independent effect, via the inhibition of the NLRP3 inflammasome [
3]. Indeed, the SGLT2-I increased the plasma beta-hydroxybutyrate with a parallel decline in fasting plasma insulin levels due to a considerable improvement in insulin sensitivity via the inhibition of NLRP3 inflammasome activity [
3]. Conversely, SGLT2-I might regulate coronary endothelial function via the modulation of autonomic tone in humans, platelet aggregation, lipoprotein, and glycemic metabolism [
3,
27]. In this setting, the stage of lipids’ contents and inflammation, as assessed here by OCT, could characterize the coronary plaques prone to rupture [
28]. Indeed, atherosclerotic plaques are characterized by larger lipid burden and lipid content, and thin fibrous caps are those unstable, with a higher rate of rupture and consequent clinical events [
28]. In this context, authors found that the addition of the lipids’ lowering agents (PCSK9 inhibitor) to high-intensity statin therapy in patients with acute myocardial infarction, reducing the blood lipids values significantly, resulted in favorable effects on coronary atherosclerosis [
28]. These ameliorative effects on the atherosclerotic plaque included a greater reduction in lipid burden and greater increase in minimal FCT, as assessed by OCT [
28]. Similarly, among patients with stable IHD, those treated with evolocumab (PCSK9 inhibitor) vs. placebo achieved lower LDL-C levels, with a greater decrease in percent atheroma volume [
29]. Thus, among patients with the angiographic coronary disease treated with statins, the addition of evolocumab, compared with placebo, reduced coronary plaque progression by lowering effects on LDL and coronary atheroma volume [
29]. On the other hand, atherosclerotic plaques with large lipid pools, thin fibrous caps, and marked inflammatory cell infiltration are prone to rupture, potentially triggering fatal coronary events [
30]. However, according to these observations, authors proposed the FCT as a marker of plaque stabilization [
5,
28‐
30]. In our study, the worse glycemic control (highest Hb1Ac values), and the atherosclerotic coronary plaque over-inflammation (higher macrophage grade) could increase about 1.9-folds and 1.2-folds respectively the risk of having MACEs in Mv-INOCS patients with T2DM. From a current study, in the T2DM patients with FFR-negative coronary lesion (i.e. FFR > 0.80) that underwent OCT assessment, the TCF lesions are associated with a fivefold higher rate of MACE [
31]. In fact, these lesions in diabetic cohorts could show a significantly higher prevalence of macrophage infiltration and a higher inflammation level that might eventually lead to fibrous cap destabilization and plaque rupture [
31]. Furthermore, in T2DM patients the identification of TCF could be seen more important than ruling out the presence of flow-limiting lesions in predicting future cardiovascular events [
31]. On the contrary, we might suggest that the therapy with SGLT2-I is an inverse predictor of about 65% of the risk of having MACEs in Mv-NOCS patients with T2DM. These study results could confirm the hypothesis of the worse glycemic control (highest Hb1Ac values) as the main cause of atherosclerotic plaque over-inflammation (highest macrophage grade), and rupture with consequent worse clinical outcomes (increased rate of MACEs). Thus, we might speculate that the SGLT2-I ameliorative clinical effects could be due to stabilizing properties on the atherosclerotic plaque. Indeed, SGLT2-I could reduce the lipids’ plaque metabolism (lipid arc degree) and inflammation (macrophage grade) and increase the FCT values. Indeed, from current studies, the increase in minimal FCT values could identify patients with a more stable coronary plaque phenotype [
28‐
31]. Furthermore, our study provides evidence about the effects of SGLT2-I on systemic and local plaque inflammation, added to the reduction of lipids accumulation in the Mv-NOCS lesions and the increase of FCT values. Thus, the SLGT2-I might induce the stabilization of atherosclerotic plaque in Mv-NOCS diabetic patients, leading to the best clinical outcomes (reduction of MACEs). However, the SGLT2-I might exert pleiotropic effects on atherosclerotic cap inflammation, lipids accumulation, and FCT in Mv-NOCS patients. Therefore, we might propose SGLT2-I as drugs with stabilizing effects on the atherosclerotic plaque via anti-inflammatory properties, reduced lipids’ accumulation, and increased FCT. Indeed, we would conclude saying that the most interesting finding of the current study is the increase of FCT after SGLT2-I therapy at 1 year of follow-up. Thus, we could consider SGLT2-I therapy similar effects on coronary plaques as compared to PCSK9 inhibitors. Notably, among patients with acute myocardial infarction, the addition of subcutaneous biweekly alirocumab to high-intensity statin therapy, compared with placebo, resulted in significantly greater coronary plaque regression in non-infarct-related arteries after 52 weeks [
28]. Therefore, the combination of statin and evolocumab after an acute myocardial infarction produces favorable changes in coronary atherosclerosis, via the stabilization and regression of coronary plaque [
29]. This therapy significantly reduces LDL-C levels in patients with acute coronary syndrome and consequently leads to the best clinical outcomes [
29]. Furthermore, the significant lowering of LDL-C levels could be evidenced as a potential therapeutic mechanism for improved clinical outcomes in these patients [
29]. In this scenario, we could hypothesize that the PCSK9i improve FCT by reducing LDL-C, while the SGLT2 probably increased FCT by reducing vascular inflammation and endothelial dysfunction.
The current study evidenced a few limitations. First, the patients were not randomized to the SGLT2-I therapy, which could result in a study bias. On the other hand, the SGLT2-I were not prescribed at the study beginning (2013) and were introduced later in clinical practice as oral anti-T2DM medication. Thus, this could cause the loss of randomization to SGLT-I therapy in the current study. On the other hand, this could represent a clear pic from current real-world clinical practice in the management of T2DM patients and in those with stable IHD and diagnosis of Mv-NOCS. Conversely, this is an observational (real world) study, which is prone to bias. Second, the study follow-up duration of 1 year could limit the generalizability of study results. Third, the number of enrolled patients could reduce the power of the current study and the statistical significance reached for the primary and secondary endpoints of study. Fourth, we cannot identify a clear cut-off value to stage the stable vs. unstable coronary atherosclerotic plaque phenotype in the current study and/or to predict its rupture with the consequent adverse clinical event. On the other hand, this study limitation is under other recent studies conducted on plaque morphology and thickness via OCT evaluation [
28‐
31]. Finally, but not less relevant, in the current study, we found a significant reduction of MACEs at 1 year of follow-up in the SGLT2-I users vs. Non-SGLT2-I users. This result could confirm an ameliorative effect (MACEs reduction), induced by SGLT2-I at 1 year of follow-up. In our study, the MACEs represent a composite endpoint, containing distinct component endpoints, both coronary and non-coronary events, and including soft clinical endpoints. To date, the MACEs endpoint analysis and interpretation could be challenging, and evidence to the potential for widespread distribution of misleading study results [
32]. Moreover, this could be evidenced as the result of an explorative analysis, because the small simple size and short duration of follow-up could represent a limit for this study result. Therefore, we could report that the causality between SGLT2-I use, and future adverse cardiovascular event cannot be concluded by the present study. Furthermore, these effects SGLT2-I induced on FCT and MACEs will be evaluated in a future larger study at a longer follow-up duration.