Study selection process
In this systematic review, a total of 220 studies were retrieved from a literature search; of which, 211 were entered after duplication removal. Subsequently, 186 records were excluded based on the title and abstract screening, and 25 studies were included. Of them, 23 articles were further excluded as irrelevant (n = 16); retracted articles (n = 3); review/systematic review and meta-analysis of animal studies (n = 2); non-English written article (n = 1); and in-vitro/animal experiments (n = 1). In the end, the systematic review included two observational studies, as shown in the PRISMA flow diagram illustrated in Fig. 1.
Risk of bias assessment results
The risk of bias assessment for observational studies was conducted using the ROBINS-E tool. The visual presentation of the assessment results was then accomplished with the robvis tool as shown in Fig. 2.
Study characteristics
In this systematic review, a total of 1229 participants from 2 studies were taken into account, with 209 received SGLT-2 inhibitors and 1020 not received. The majority of participants were males (73.1%), with a mean age of 70.25 years old. All of the participants were diabetic patients admitted with AMI, both STEMI and non-STEMI, undergoing PCI. The studies did not enumerate the specific type of SGLT-2 inhibitors utilized and had a multicenter approach (Belgium, Bulgaria, Italy). The detailed characteristics of each study can be found in Table 2.
Table 2
Characteristics of the studies included in the systematic review
Study, Year | Paolisso et al., 2023 | Paolisso et al., 2022 |
Location | Belgium, Bulgaria, Italy, | NR |
Setting | Retrospective, cohort, observational study | Retrospective, cohort, observational study |
Patients | Patients with diabetes and AMI who underwent PCI | Patients with diabetes and AMI who underwent PCI |
Age; mean ± SD (years) | 70 ± 5.2 | 70.5 ± 5.18 |
Male (%) | 70 | 76.2 |
SGLT-2 inhibitor groups (N) | SGLT-2 inhibitors users (111) | SGLT-2 inhibitors users (98) |
Non-SGLT-2 inhibitor groups (N) | Non- SGLT-2 inhibitors users (535) | Non- SGLT-2 inhibitors users (485) |
Other treatments | ACEi / ARB, MRA, diuretics, statin, ezetimibe CCB, antiplatelet, anticoagulant, metformin, DPP-4 inhibitor, sulfonylurea, GLP1-RA, insulin | ACEi / ARB, MRA, diuretics, statin, ezetimibe CCB, antiplatelet, anticoagulant, metformin, DPP-4 inhibitor, sulfonylurea, GLP1-RA |
Hypertension (%) | 83.7 | 83.2 |
Dyslipidemia (%) | 78.6 | 78.9 |
Previous AMI (%) | 26.2 | 26.1 |
Duration | 24 ± 13 months | NR |
Outcome | Troponin levels: SGLT-2 inhibitors’ group significantly lower than non- SGLT-2 inhibitors’ group (P ≤ 0.003) Resolution of ST-segment: SGLT-2 inhibitors’ group more often seen (P = 0.001) LVEF: SGLT-2 inhibitors’ group significantly higher at discharge (P < 0.001) RWMA: SGLT-2 inhibitors’ group significantly reduced (P = 0.003) Moderate-to-severe mitral regurgitation: SGLT-2 inhibitors’ group lower rate of discharge compared to hospital admission (P = 0.133) In-hospital mortality: significantly greater in SGLT-2 inhibitors individuals (P = 0.041) Arrhythmias: significantly lower in SGLT-2 inhibitors’ group ( P = 0.010) Mechanical circulatory support with an intra-aortic balloon pump, re-AMI, and days of hospital stay: no significant differences Contrast-induced AKI: significantly lower in SGLT-2 inhibitors’ group (P = 0.022 ) MACE: significantly lower in SGLT-2 inhibitors’ group (P < 0.001) Cardiovascular mortality and HF hospitalization: significantly lower in SGLT-2 inhibitors’ group (P < 0.04) MACE occurrence: significantly lower in SGLT-2 inhibitors’ group (HR = 0.57; 95%CI 0.33–0.99; P = 0.039) HF hospitalization: significantly lower in SGLT-2 inhibitors’ group (HR = 0.46; 95%CI 0.21–0.98; P = 0.041) | Troponin sequence and peak troponin values: significantly lower in SGLT-2 inhibitors’ group (P ≤ 0.003) ST-segment recovery post-PCI: more common in SGLT-2 inhibitors group (P = 0.001) Infarct size: significantly lower in SGLT-2 inhibitors’ group (P = 0.001) Total WBC count, neutrophils, and CRP Levels: significantly greater in non- SGLT-2 inhibitors individuals (P < 0.006) NLR, PLR, and NPR: significantly lower among SGLT-2 inhibitors users (P < 0.03) Neutrophils, NLR, and CRP after 24 h: Lower in SGLT-2 inhibitors’ group (P = 0.03, P < 0.001, and P = 0.04 respectively) CRP levels at discharge: remained higher among non-SGLT-2 inhibitors users (P = 0.01) |
AMI, acute myocardial infarction; ACEi, angiotensin-converting enzyme inhibitors ; AKI, acute kidney injury; ARB, angiotensin ii receptor antagonist; ARNI, angiotensin receptor neprilysin inhibitor; CCBs, calcium channel blockers; CRP, C-reactive protein; DPP-4, dipeptidyl peptidase-4; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; HF, heart failure, LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; MRA, mineralocorticoid receptor antagonists; NLR, neutrophil-to-lymphocyte ratio; NPR, neutrophil-to-platelet ratio; PCI, percutaneous coronary intervention; PLR, platelet-to-lymphocyte ratio; RWMA, regional wall motion abnormalities; WBC, white blood cells |
SGLT-2 inhibitors as a therapeutic agent in IRI
In Paolisso et al. diabetic individuals with AMI treated with SGLT-2 inhibitors between January 2018 and September 2021 were enrolled and infarct sizes, and inflammatory biomarkers, were evaluated among them. On admission left ventricular size and function; along with regional wall motion abnormalities (RWMA) were similar in both study groups. However, the people who had taken SGLT-2 inhibitors than those who had not had significantly lower troponin, and peak troponin values (P ≤ 0.003). Furthermore, the rate of ST resolution was significantly higher in the SGLT-2 inhibitors group (P = 0.001). During discharge RMWA and left ventricular function that representing the infarct size were significantly lower in those who had taken SGLT-2 inhibitors compared to those who had not (P = 0.001 for both). On admission, total white blood cell (WBC) count, neutrophils, and C-reactive protein (CRP) levels were significantly greater in non-SGLT-2 inhibitors individuals when compared to SGLT-2 inhibitors users (P < 0.001 for all). Consequently, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and neutrophil-to-platelet ratio (NPR) were significantly lower among those taking SGLT-2 inhibitors. The results also revealed that the levels of neutrophils, NLR, and CRP were still significantly lower in those taking the SGLT-2 inhibitors after 24 hours. Furthermore, at discharge among non-SGLT-2 inhibitors patients CRP levels remained higher (P = 0.01). [15]
In the second study conducted in 2023, diabetic AMI patients undergoing PCI were enrolled. The levels of troponin were significantly lower in those who used SGLT-2 inhibitors compared to those who did not (P ≤ 0.003). Subsequently, resolution of ST following PCI was more often seen in the SGLT-2 inhibitors group (P = 0.001). Upon admission, left ventricular (LV) volume, left ventricular ejection fraction (LVEF), and RWMA were similar between the two cohorts. However, post-revascularization LVEF was significantly higher in the SGLT-2 inhibitors group at discharge (P < 0.001). Moreover, at discharge RWMA was significantly reduced among individuals used SGLT-2 inhibitors users (P = 0.003), but not in the non-SGLT-2 inhibitors’ group (83.6% versus 79.8%, P = 0.133). As a result, those who used SGLT-2 inhibitors had a lower rate of discharge with moderate-to-severe mitral regurgitation compared to those who did not [15].
Ongoing clinical trials
The ClinicalTrials.gov was searched from the database inception until August 7th, 2023, was conducted to gather ongoing trials of SGLT-2 inhibitors. Eligible studies included those that focused on IRI-related outcomes and included patients with AMI. Results showed 1185 trials as follows: dapagliflozin (482), empagliflozin (393), canagliflozin (160), ipragliflozin (58), ertugliflozin (43), sotagliflozin (38), tofogliflozin (6), luseogliflozin (3), and remogliflozin (2). Of which four studies investigated effects of SGLT-2 inhibitors on IRI. Cumulative estimated population size of the studies was 1228 and sample sizes ranged from 100 to 800. The used SGLT2 inhibitors and the daily doses varied. The first trial (NCT05261867) is an observational study recruiting 800 patients to assess the effects of SGLT-2 inhibitors on reduction of the infarct size and the inflammatory response. The second trial (NCT05020704) is an interventional study enrolling 100 patients to investigate the effects of empagliflozin on troponin I. The third trial (NCT03591991) is an interventional study enrolling 128 patients to evaluate the effects of empagliflozin on infarct size and the fourth trial (NCT04899479) is an interventional study recruiting 200 patients to assess the effects of SGLT-2 inhibitors on myocardial infarct size, and target lesion revascularization. The detailed outcomes and results are shown in Table 3.
Table 3
Summary of the ongoing clinical trials investigating the therapeutic effects of SGLT-2 inhibitors in IRI
ID, (Acronym) | Status | Study type | Initiation date | Administered SGLT-2 inhibitors | Estimated sample size | Study population | Desired outcomes | Other outcomes |
NCT05261867, (SGLT2-I AMI) | Recruiting | Observational | January 2017 | NR | 800 | Patients with T2DM and AMI | Reduction of the infarct size, reduction of the inflammatory response | Intra-hospital CV death and arrhythmias, all-cause and CV mortality, length of hospital stay, recurrent AMI, HHF, any coronary revascularization, MACE |
NCT05020704, (EMPRESS MI) | Not yet recruiting | Interventional | November 1, 2021 | Empagliflozin | 100 | Patients with AMI and LV systolic dysfunction | troponin I, infarct size | Change in LVEDV, LVESV, LVEF, LAVI, LVMI, NT-proBNP, |
NCT03591991 | Unknown | Interventional | October 1, 2018 | Empagliflozin | 128 | Patients with STEMI | Infarct size | CIAKI |
NCT04899479, (PRESTIGE-AMI) | Recruiting | Interventional | July 5, 2021 | NR | 200 | Patients with AMI and high risk of HF | Myocardial Infarct size , target lesion revascularization | AKI, MSI, MVO, HI, LVEDV, LVEF, LV adverse remodeling, LV reverse remodeling, eGFR, NT-proBNP, CV death or HHF, LVESV, target vessel MI, all-cause death |
AMI, acute myocardial infarction; AKI, acute kidney injury; CIAKI, contrast induced acute kidney injury; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HHF, hospitalized heart failure; HI, hemorrhagic infarction; IRI, ischemic reperfusion injury; LAVI, left atrial volume index; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end systolic volume; LVMI, left ventricular mass index; MSI, myocardial salvage index; MVO, microvascular obstruction; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; STEMI, ST elevation myocardial infarction; T2DM, type 2 diabetes mellitus |