SGLT2 inhibitors have become increasingly used due to their effectiveness in improving not only type 2 diabetes but also cardiovascular, renal and hepatic diseases, as well as the obesity found in metabolic syndrome. Starting from the structure of gliflozins, modifications of the carbohydrate part, aglycone, and also the glycosidic bond between them can determine variations in pharmacokinetic and pharmacodynamic properties. SGLT2 inhibitors, in addition to reducing blood glucose levels, improve alterations in lipid metabolism by diverting excessively accumulated lipids in tissues towards mobilization, lipolysis, β-oxidation, ketogenesis and the utilization of ketone bodies. This enhances anti-inflammatory properties by decreasing the levels of some proinflammatory mediators and by modulating some cell signaling pathways. Thus, in this review, the intimate mechanisms by which SGLT2 inhibitors achieve these therapeutic effects in the various conditions belonging to metabolic syndrome and beyond were described, along with the structure–effect relationship with some specific features of each gliflozin. Starting from these findings, further modeling of these molecules may lead to the creation of new therapeutic uses. Further research is needed to broaden the range of indications and also eliminate adverse effects, such as phenomena leading to lower limb amputations.

Background/Objectives: Sodium-glucose cotransporter 2 (SGLT2) inhibitors provide well-established cardiovascular and renal benefits in heart failure (HF), type 2 diabetes (T2DM), and chronic kidney disease (CKD). Although emerging trials suggest potential value after acute myocardial infarction (AMI), SGLT2 inhibitors currently have no formal indication for AMI, and real-world prescribing patterns in this setting remain uncharacterized. This study aimed to evaluate in-hospital and post-discharge prescribing patterns and clinical predictors of SGLT2 inhibitor initiation among AMI patients eligible for therapy based on guideline-supported indications. Methods: We conducted a retrospective cohort study including 244 consecutive AMI patients hospitalized between January 2023 and July 2024. A total of 180 (73.7%) met guideline-based eligibility criteria for SGLT2 inhibitors. Four multivariable logistic regression models were developed to identify independent predictors of SGLT2 inhibitor prescription. Results: A total of 117 patients (65%) received SGLT2 inhibitors and 63 (35%) remained untreated. Receivers were more frequently male (81% vs. 65%) and exhibited lower left ventricular ejection fraction (LVEF) (38.2 ± 6.7% vs. 42.4 ± 8.3%), larger ventricular volumes, and higher Killip class at presentation. HF patients with preserved ejection fraction (HFpEF) were markedly undertreated (25.9%) compared with mid-range (HFmrEF) (69.8%) or reduced (HFrEF) (73.7%). Across all models, HFpEF was a strong negative predictor of prescribing (OR 0.071–0.081, p < 0.001), while male sex and markers of clinical severity were associated with higher likelihood of initiation. Many untreated patients had T2DM or CKD despite guideline-based eligibility. No serious adverse events attributable to SGLT2 inhibitors were reported. Conclusions: In this real-world AMI cohort, SGLT2 inhibitors were prescribed primarily in relation to established indications for HF, T2DM, and CKD, yet their use remained highly variable in the absence of a dedicated recommendation for AMI. Significant therapeutic gaps were observed in HFpEF and high-risk cardiometabolic profiles, underscoring the need for clearer guidance and standardized pathways to support consistent initiation in eligible patients after MI.

Background and Objectives: SGLT2 inhibitors are foundational in heart failure therapy, yet their impact on left ventricular (LV) remodeling immediately following acute coronary syndrome (ACS) remains less defined. This study evaluated the association between early SGLT2 inhibitor initiation and structural recovery in a real-world post-ACS cohort. Materials and Methods: We conducted a retrospective observational study including 238 revascularized ACS patients, stratified into an SGLT2 inhibitor group (n = 71) and a control group (n = 167). Changes in LV ejection fraction (LVEF) and indexed LV mass (LVMi) were assessed by echocardiography at baseline and follow-up (mean 286 days). Multivariable regression models were adjusted for baseline imbalances and tested for interactions with diabetes status. Results: A significant “confounding by indication” was observed; the SGLT2 group presented a high-risk phenotype with higher diabetes prevalence (56.3% vs. 25.7%, p < 0.001), lower baseline LVEF (38.3% vs. 43.3%), and greater hypertrophy. After adjustment, statistical independence was attenuated by baseline severity, yet the SGLT2 group achieved follow-up structural outcomes comparable to lower-risk controls. Interaction analysis indicated these trends were consistent regardless of diabetes status (p > 0.05). Conclusions: In this high-risk ACS population, early SGLT2 inhibitor therapy was associated with stabilization of cardiac structure. Despite a profound baseline disadvantage, the recovery trajectory effectively aligned with that of a lower-risk population, highlighting a clinically relevant pattern of structural stabilization consistent across metabolic subgroups.

Background: Guideline-directed medical therapy (GDMT) is recommended after acute myocardial infarction (AMI), particularly in patients with left ventricular systolic dysfunction, yet real-world implementation remains suboptimal. Whether greater early GDMT intensity is associated with post-infarction ventricular remodeling has not been fully established. We aimed to quantify the guideline-to-practice gap and evaluate the association between GDMT intensity, cardiac remodeling, and clinical outcomes after AMI. Methods: In this single-center retrospective cohort study, 186 consecutive patients hospitalized for AMI who underwent successful percutaneous coronary intervention and had baseline plus follow-up transthoracic echocardiography were included. GDMT intensity was defined as the number of prescribed foundational therapy classes at discharge (renin–angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium–glucose cotransporter 2 inhibitors; range 0–4). The primary endpoint was change in left ventricular end-diastolic diameter (ΔLVEDD). Secondary endpoints included changes in left ventricular ejection fraction, left ventricular end-diastolic volume, left ventricular mass, and heart failure rehospitalization. Multivariable models adjusted for relevant clinical covariates were applied. Results: Only 18.8% of the overall cohort and 26.2% of patients with baseline left ventricular ejection fraction ≤ 40% received all four GDMT pillars. A graded association was observed between higher GDMT intensity and more favorable remodeling. In adjusted analyses, each additional GDMT pillar was associated with a greater reduction in LVEDD (β = 0.120 cm, p = 0.004). In the prespecified reduced-ejection-fraction subgroup, the association was stronger (β = 0.204 cm, p < 0.001). Higher GDMT intensity was also associated with lower odds of heart failure rehospitalization (odds ratio 0.384, 95% CI 0.195–0.754; p = 0.006). Conclusions: In this real-world post-AMI cohort, broader implementation of foundational GDMT at discharge was associated with more favorable early ventricular reverse remodeling and lower odds of heart failure rehospitalization. These findings highlight a persistent implementation gap and support prospective studies evaluating rapid comprehensive GDMT initiation after AMI.

Background/Objectives: Sodium–glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular benefits beyond glycemic control, yet the specific biological pathways potentially linking SGLT2 inhibitor exposure to cardiovascular outcomes after acute myocardial infarction (AMI) remain incompletely characterized. Two biologically plausible pathways, serum uric acid (SUA) reduction and renal functional preservation, have been proposed, but not directly compared in a unified analytical framework. This study aimed to explore whether associations between SGLT2 inhibitor exposure and recurrent post-AMI outcomes may be more strongly linked to SUA reduction and to renal functional changes, using a hypothesis-generating causal mediation analysis. Methods: This retrospective observational cohort study included 142 consecutive patients hospitalized for AMI who underwent percutaneous coronary intervention (PCI) during the index hospitalization, reflecting standard-of-care management for AMI in this tertiary center. Patients were categorized by SGLT2 inhibitor exposure (n = 57) vs. controls (n = 85). Both diabetic (47.2%) and non-diabetic (52.8%) patients were included. The primary endpoint was change in SUA (ΔUA); the secondary endpoint was myocardial infarction (MI) recurrence. Causal mediation analysis with nonparametric bootstrap simulation tested both mechanistic pathways. Results: SGLT2 inhibitor therapy was associated with significant SUA reduction (ΔUA = −0.99 mg/dL vs. +0.56 mg/dL in controls; p < 0.001), consistent across diabetic and non-diabetic subgroups and independent of AMI recurrence. Each 1 mg/dL decrease in SUA was associated with lower odds of recurrent MI in the initial model (β = −0.25; p = 0.041). However, after incorporation of renal functional change, the uric acid-mediated pathway lost significance (ACME p = 0.462), whereas the renal-mediated pathway remained significant (ACME p = 0.038). Serum creatinine change emerged as the strongest independent predictor of MI recurrence (β = 2.22; p = 0.015). Conclusions: The findings are more consistent with a renal-mediated pathway than with an independent uric acid-mediated pathway in explaining the observed associations between SGLT2 inhibitor exposure and recurrent post-AMI outcomes. These hypothesis-generating results from a retrospective design warrant prospective validation.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally developed as glucose-lowering agents for type 2 diabetes mellitus, have been shown in large, randomized trials to improve clinical outcomes in heart failure (HF) across the ejection fraction (EF) spectrum. The imaging-derived and hemodynamic changes that accompany these benefits remain incompletely characterized, and it is not known whether the patterns of cardiac remodeling observed differ between HF with reduced ejection fraction (HFrEF, left ventricular ejection fraction [LVEF] ≤ 40%) and HF with preserved ejection fraction (HFpEF, LVEF ≥ 50%). This systematic review synthesized randomized evidence on the effects of SGLT2 inhibitors on cardiac remodeling parameters and described the patterns observed in each phenotype. Methods: PubMed/MEDLINE, Scopus and Embase were searched for randomized controlled trials (RCTs) published between February 2016 and March 2026. Eligible studies enrolled adults with chronic HF receiving an SGLT2 inhibitor, included a non-SGLT2-inhibitor comparator and assessed cardiac structure, function or loading by echocardiography, cardiac magnetic resonance (CMR) or cardiac catheterization over at least three months. Risk of bias was assessed with Cochrane RoB 2, separately for each outcome domain and targeting the effect of assignment to intervention, and certainty of evidence with GRADE, separately by phenotype and imaging modality. A structured narrative synthesis following Synthesis Without Meta-analysis (SWiM) guidance that prioritized the direction, magnitude and precision of randomized between-group treatment effects was performed. Results: Fourteen publications from thirteen unique RCTs (1232 participants) were included: four trials enrolled HFrEF (LVEF ≤ 40%), five enrolled mixed reduced and mildly reduced EF cohorts (LVEF < 50% or 35–49%), four enrolled HFpEF (LVEF ≥ 50%) and one enrolled a mixed ejection-fraction population. No trial enrolled an exclusively HFmrEF population. In reduced EF, the direction of effect on LV volumes favored SGLT2 inhibition in four of eight trials reporting volumes, but the estimates were not compatible in magnitude, and the one adequately powered trial at low risk of bias (EFFORT) was neutral; the largest volumetric estimates came from EMPA-TROPISM, which published no adjusted between-group estimate. The only prespecified, adjusted and confidence-interval-bearing volumetric estimates were those of SUGAR-DM-HF (left ventricular end-systolic volume index −6.0 mL/m², 95% CI −10.8 to −1.2; end-diastolic volume index −8.2 mL/m², 95% CI −13.7 to −2.6). The global longitudinal strain improved in the trial with blinded core-laboratory reading (EFFORT −1.44%, 95% CI −2.42 to −0.46), but effect sizes in the open-label trials without stated reader blinding were two to three times larger, and the CMR-derived strain was unchanged. In HFpEF, volumes, EF, mass and strain were unchanged throughout. The most secure finding of the review was invasive: in CAMEO-DAPA, dapagliflozin reduced pulmonary capillary wedge pressure at rest by 3.5 mmHg (95% CI −6.6 to −0.4) and at peak exercise by 5.7 mmHg (95% CI −10.8 to −0.7). NT-proBNP results were directionally inconsistent, and the trials in which NT-proBNP was a prespecified primary endpoint (Empire HF, CANDLE) were neutral. Certainty of evidence was very low for 18 of 20 evidence profiles and low for the remaining two. Conclusions: Randomized imaging and hemodynamic studies suggest phenotype-related differences in the cardiac remodeling associated with SGLT2 inhibitor therapy. In studies enrolling patients with reduced EF, treatment was associated predominantly with reverse remodeling of left ventricular volumes and modest improvements in myocardial function, whereas in preserved EF, the observed changes were mainly confined to filling pressures and diastolic function, with no consistent evidence of left ventricular volumetric remodeling. Given the limited number of studies, substantial heterogeneity, and the overall low certainty of evidence, these findings should be considered hypothesis-generating and warrant confirmation in adequately powered phenotype-specific mechanistic trials.