SGLT-2 inhibitors and in-stent restenosis-related events after acute myocardial infarction: an observational study in patients with type 2 diabetes

This was an observational, prospective study evaluating the association between SGLT2i therapy and ISR in T2DM patients with AMI (ST-segment-elevation myocardial infarction-STEMI- and NSTEMI patients). Patients underwent successful stent implantation according to ACC/AHA/SCAI Guideline for Coronary Artery Revascularization [2]. Diabetes was categorized according to the American Diabetes Association criteria [9]. Furthermore, patients answered a specific questionnaire about medicines used for diabetes treatment before the beginning of the study, the date of the beginning and end of therapy, the route of administration, and the duration of use. Information from the medicine inventory during the research and this specific questionnaire was used to classify patients as “never SGLT2i-users” and “current SGLT2i-users.” Never SGLT2i-users were patients who never received SGLT2i before AMI nor during follow-up. The current SGLT2i-users were patients with ongoing SGLT2i therapy without discontinuation for at least 6 months before AMI and continued SGLT2i therapy without discontinuation during the follow-up. All patients completed the 12-month clinical follow-up through face-to-face interviews, phone calls, or medical chart review. Patients with heart failure, impaired renal function (eGFR < 60 ml/min, estimated through the CKD-EPI equation), coronary bypass indications, absence of coronary lesions, and malignancies were excluded from the study. The investigation conforms to the principles outlined in the Declaration of Helsinki for using human tissue or patients. The Institutional Review Board approved the protocol.

Routine analyses were obtained on admission before coronary angiography and before full medical therapy was started. Before PCI, all patients were administered loading doses of aspirin 200–300 mg and clopidogrel 300–600 mg; alternatively, ticagrelor 180 mg or prasugrel 60 mg was administered. PCI was performed via the femoral or radial approach after an intravenous bolus dose of heparin (50–100 U/kg) to achieve an activated clotting time of > 250 s. DAPT (a combination of aspirin 100 mg/day with clopidogrel 75 mg/day or ticagrelor 90 mg twice daily or prasugrel 5–10 mg/day) was recommended for > 12 months for patients who underwent PCI. Triple antiplatelet therapy (TAPT: cilostazol 100 mg twice daily in addition to DAPT) was left to the discretion of the individual operators. To stabilize glycemic control in the emergency setting, all patients underwent continuous insulin infusion: the infusion lasted until a stable glycemic goal (140–180 mg/dl) for at least 24 h. After that glycemic goal was maintained for 24 h, the infusion was stopped, and subcutaneous insulin was initiated. After discharge from the hospital, all patients were managed and followed for 12 months after PCI, as outpatients, to maintain an HbA1c level at < 7%. Diagnostic coronary angiography and PCI were performed using standard guidelines [2]. A successful PCI was defined as residual stenosis of < 30% and more than grade 3 flow in Thrombolysis In Myocardial Infarction flow for the infarct-related artery (IRA) after the procedure.

Coronary CT angiography (CCTA) was performed in all patients at 1-year follow-up. All CCTA was performed with a 320 lines-wide detector row scanner capable of whole-heart coverage in 1 beat (Aquilion ONE, Genesis Edition, Canon Medical Systems, Tokyo, Japan) and combining 0.17-mm spatial resolution, 0.275 s gantry rotation time, FIRST®, and AiCE® reconstruction algorithm. Interpolation algorithm was used to obtain 640 0.5 axial sections with 50% overlap. A Z-axis coverage of 16 cm was used for coronary CTA in all patients. CCTA was conducted according to the recommendations of the Society of Cardiovascular Computed Tomography [10]. All patients received a 40–55 ml bolus of Iomeprolo 400 (Iomeron® 400 mg/ml, Bracco, Milan, Italy) at an infusion rate of 5.5/6.5 ml/s followed by 50 ml of saline solution. The scan window was based on HR. A body mass index–adapted scanning protocol was used, as previously described [5]. Datasets of each coronary CCTA examination were transferred to an image-processing workstation (VitreaTM Advanced Visualization, Canon Medical Europe) and analyzed by 2 readers, both with > 10 years of clinical experience in coronary CTA performance and analysis, blinded to the clinical findings. For any disagreement in data analysis between the 2 readers, a consensus agreement was achieved. The visualizing coronary segments were classified as interpretable when of adequate, good, or excellent image quality (scores 2 to 4). ISR > 50% were considered significant when assessing anatomy by CCTA. The location and extent of the region of interest were manually defined using proximal and distal markers as the coronary vessel region where the lumen diameter was reduced by ≥ 30% compared with the normal vessel. Planimetry of the inner lumen and outer vessel areas was performed following a stepwise approach. In summary, a centerline originating from the ostium was first automatically extracted and successively reacquired also manually to avoid potential misregistration errors; then, straightened and stretched multiplanar reformatted images were generated, and the lumen and vessel borders were detected longitudinally on 24 different vessel views by the software; based on these longitudinal contours, cross-sectional images at 0.25 mm intervals were calculated to create transversal lumen and vessel wall contours, which were examined and, if necessary, adjusted by a single experienced observer. Based on the detected contours proximal and distal from the lesion region, a reference area function was derived modeling the tapering of a healthy vessel. From these data, the following cross-sectional CTCA-derived parameters were automatically provided by operators: minimum lumen area (MLA), and % area stenosis (%AS) at the level of the MLA defined by [1-MLA/corresponding reference lumen area) × 100]. Minimum lumen diameter (MLD), less accurate parameter, was not considered.

The primary outcome was major adverse cardiovascular events (MACE) defined as cardiac death, acute coronary syndrome, and development of heart failure related to ISR. The relationship between cardiovascular events and restenosis was attributed by coronary angiography without evidence of other culprit lesions.

Among 522 T2DM patients with AMI who underwent successful stent implantation from November 2017 to March 2022, 377 were eligible for the study and had complete data at 12 months follow-up (Fig. 1). All patients underwent primary PCI within 3 h. Among the 377 patients enrolled in the study, 200 were never SGLT2i-users, and 177 were current SGLT2i-users. The duration of SGLT2i treatment was 18 ± 7 months (mean ± SD). During follow-up, there were no changes in the dose of SGLT2i. Twenty-one patients among never SGLT2i-users (10.5%) and 18 patients among current SGLT2i-users (10.2%) were treated with TAPT (P = 0.167). There were no differences in the mean age, BMI, sex distribution, smoking habits, HbA1c, admission glucose level, plasma cholesterol, and triglyceride levels among the groups. Angiographic data indicated that the treated lesion types were similar in the two groups. The stent type was also comparable between the two groups (Table 1). Using a mean of 2.2 matched angiographic projections per lesion, the reference diameter of the target vessel, the mean minimal luminal diameter (MLD), and the mean length of the lesion at baseline were similar in the two groups. After PCI, the MLD increased similarly in both groups. Moreover, the post-PCI stenosis was similar in both groups (Table 1).

There were no differences in the 1-year HbA1c mean levels among the groups (Fig. 2A). The incidence of ISR-related MACE was significantly higher in never SGLT2i-users (22.1%, n = 44) compared with current SGLT2i-users (10.2%, n = 18; P < 0.001) (Fig. 2B). The CT angiography, performed at follow-up in patients without ISR-related events, evidenced that the lesions treated with the stents deteriorated, resulting in a smaller MLA and MLD at follow-up in never SGLT2i-user compared with current SGLT2i-user (Fig. 2C, D). Multiple logistic regression was then performed to evaluate the relationship between the use of SGLT-2i and ISR-related MACE, adjusted for glycemic control (admission HbA1c and 1-year HbA1c mean), age, BMI, and sex. The probability of ISR-related MACE in patients treated with SGLT2i was reduced by 58 % regardless of glycemic control, age, BMI, and sex (OR, 0.42; 95% CI, 0.23–0.76). After 1 year following AMI, a multivariable Cox regression analysis, adjusted for admission HbA1c, 1-year HbA1c levels, age, hypertension, cigarette smoking, BMI, HDL, LDL-cholesterol levels, triglycerides, antithrombotic, and lipid-lowering and glucose-lowering therapies, showed a significantly higher 1-year risk of ISR-related events in never-SGLT2i-users compared to current-SGLT2i-users (Fig. 3A). In addition, to evaluate whether SGLT2i therapy was effective in patients with good glycemic control (1-year HbA1c mean < 7%), we performed a Cox regression analysis in this subgroup of patients, adjusted for admission age, hypertension, cigarette smoking, BMI, HDL, LDL-cholesterol levels, triglycerides, antithrombotic, and lipid-lowering and glucose-lowering therapies. The Cox analysis showed that also in patients with good glycemic control, SGLT2i therapy significantly reduced the risk of ISR-related MACE (Fig. 3B). After 1 year following AMI, a multivariable Cox regression analysis, adjusted for admission HbA1c, 1-year HbA1c levels, age, hypertension, cigarette smoking, BMI, HDL, LDL-cholesterol levels, triglycerides, antithrombotic, and lipid-lowering and glucose-lowering therapies, showed a significantly higher 1-year risk of ISR-related cardiovascular death (Fig. 4A), acute coronary syndrome (Fig. 4B), and heart failure (Fig. 4C) in never-SGLT2i-users compared to current-SGLT2i-users. The same trend for all the three outcomes considered was observed in the subgroup of patients with good glycemic control (1-year HbA1c mean < 7%) (Fig. 4D–F).

Subgroup analysis exploring the effect of single SGLT2i on the main composite outcome revealed there were no differences in the risk of ISR-related MACE among users of empagliflozin, canagliflozin, or dapagliflozin, while each of these groups has a significant lower rate compared with never-SGLT2i-users (Supplementary Fig. 1).

Residual confounders are inherently linked to all observational studies. Despite our effort to control for all the most relevant risk factors, we did not monitor the dietary habits nor the amount of physical activity performed by the patients, two aspects that might have influenced the results. In addition, the comparator drugs were not a specific class, thus we could not perform a possible head-to-head comparison with drugs having known cardioprotective benefit, e.g., the GLP-1 receptor agonists [19]. In addition, the study was adequately powered to detect differences among different SGLT2i, albeit current literature suggests a generally homogenous class effect for these drugs [20].