SGLT2-inhibitors effects on the coronary fibrous cap thickness and MACEs in diabetic patients with inducible myocardial ischemia and multi vessels non-obstructive coronary artery stenosis

Abstract

Background: Sodium-glucose transporter 2 inhibitors (SGLT2-I) could modulate atherosclerotic plaque progression, via down-regulation of inflammatory burden, and lead to reduction of major adverse cardiovascular events (MACEs) in type 2 diabetes mellitus (T2DM) patients with ischemic heart disease (IHD). T2DM patients with multivessel non-obstructive coronary stenosis (Mv-NOCS) have over-inflammation and over-lipids' plaque accumulation. This could reduce fibrous cap thickness (FCT), favoring plaque rupture and MACEs. Despite this, there is not conclusive data about the effects of SGLT2-I on atherosclerotic plaque phenotype and MACEs in Mv-NOCS patients with T2DM. Thus, in the current study, we evaluated SGLT2-I effects on Mv-NOCS patients with T2DM in terms of FCT increase, reduction of systemic and coronary plaque inflammation, and MACEs at 1 year of follow-up.

Methods: In a multi-center study, we evaluated 369 T2DM patients with Mv-NOCS divided in 258 (69.9%) patients that did not receive the SGLT2-I therapy (Non-SGLT2-I users), and 111 (30.1%) patients that were treated with SGLT2-I therapy (SGLT2-I users) after percutaneous coronary intervention (PCI) and optical coherence tomography (OCT) evaluation. As the primary study endpoint, we evaluated the effects of SGLT2-I on FCT changes at 1 year of follow-up. As secondary endpoints, we evaluated at baseline and at 12 months follow-up the inflammatory systemic and plaque burden and rate of MACEs, and predictors of MACE through multivariable analysis.

Results: At 6 and 12 months of follow-up, SGLT2-I users vs. Non-SGLT2-I users showed lower body mass index (BMI), glycemia, glycated hemoglobin, B-type natriuretic peptide, and inflammatory cells/molecules values (p < 0.05). SGLT2-I users vs. Non-SGLT2-I users, as evaluated by OCT, evidenced the highest values of minimum FCT, and lowest values of lipid arc degree and macrophage grade (p < 0.05). At the follow-up end, SGLT2-I users vs. Non-SGLT2-I users had a lower rate of MACEs [n 12 (10.8%) vs. n 57 (22.1%); p < 0.05]. Finally, Hb1Ac values (1.930, [CI 95%: 1.149-2.176]), macrophage grade (1.188, [CI 95%: 1.073-1.315]), and SGLT2-I therapy (0.342, [CI 95%: 0.180-0.651]) were independent predictors of MACEs at 1 year of follow-up.

Conclusions: SGLT2-I therapy may reduce about 65% the risk to have MACEs at 1 year of follow-up, via ameliorative effects on glucose homeostasis, and by the reduction of systemic inflammatory burden, and local effects on the atherosclerotic plaque inflammation, lipids' deposit, and FCT in Mv-NOCS patients with T2DM.

Keywords: FCT; Inflammatory burden; MACEs; Mv-NOCS; SGLT2-I.

Fig. 1

Study flow chart. SGLT2-I sodium glucose transporter 2 inhibitors, MACEs major adverse cardiac events

Fig. 2

In the upper part of panel, representative images of the baseline values of fibrous cap thickness (FCT) and lipid arch in SGLT2-I users (A, left part) vs. Non-SGLT2-I users (B, right part) patients. The lipid length was 8.46 ± 1.87 vs. 8.39 ± 1.89 mm (p > 0.05) in SGLT2-I users vs. Non-SGLT2-I users patients. The macrophage grade was 12.04 ± 2.29 vs. 12.07 ± 2.31 (p > 0.05) in SGLT2-I users vs. Non-SGLT2-I users patients. The representative images of coronary vessels (inferior part) are of the middle segment of left anterior descending artery (LAD), comparing the SGLT2-I users (C, left part) vs. Non-SGLT2-I users’ (D, right part) patients. The red circle evidences the intermediate and non-obstructive coronary stenosis (NOCS) LAD stenosis. In the lower part of the panel, representative images of follow-up end values of fibrous cap thickness (FCT) and lipid arch in SGLT2-I users (E, left upper part) vs. Non-SGLT2-I users patients (F, right upper part). The lipid length was 7.92 ± 1.89 vs. 7.79 ± 1.88 mm (p > 0.05) in SGLT2-I users vs. Non-SGLT2-I users patients. The macrophage grade was 7.24 ± 2.22 vs. 9.27 ± 2.56 (p < 0.05) in SGLT2-I users vs. Non-SGLT2-I users patients. The representative images of coronary vessels (inferior left and right part) is the middle segment of anterior descending artery, comparing the SGLT2-I users (G, left inferior part) vs. Non-SGLT2-I users’ (H, right inferior part) patients. The red circle evidences the intermediate and non obstructive coronary stenosis (NOCS) LAD stenosis. SGLT2-I sodium glucose transporter 2 inhibitors

Fig. 3

Kaplan curves of the cumulative risk to have MACEs at 1 year of follow-up in SGLT2-I users vs. Non-SGLT2-I users. MACEs major adverse cardiac events, SGLT2-I sodium glucose transporter 2 inhibitors

Fig. 4

Plot boxes of serum inflammatory molecules and cells in the study cohorts. Serum levels of NLRP3 inflammasome (pg/mL), Caspase-1 (ng/mL) and Interleukin-1β (pg/mL) in diabetic SGLT2-I users (N = 111) and diabetic Non-SGLT2-I users (N = 258) at baseline (T0), after 24 h (T1), 6 months (T2) and 12 months (T3) of follow-up (A–C). Serum levels of CD86 as a marker of M1 macrophages (U/mL) and CD206 (ng/mL) in diabetic SGLT2-I users (N = 111) and diabetic Non-SGLT2-I users (N = 258) patients at baseline (T0), after 24 h (T1), 6 months (T2) and 12 months (T3) of follow-up (D, E). Values are reported as mean ± SD. NLPR3 NLR family pyrin domain containing 3 (NLRP3) inflammasome, SGLT2-I sodium glucose transporter 2 inhibitors. **P < 0.01 vs SGLT2 users at same T; ^^P < 0.01 vs SGLt2 non-users at baseline