Stefano Genovese

Coronary artery disease (CAD) and its acute manifestation, myocardial infarction (AMI), remain significant global health burdens, with a substantial impact on morbidity and mortality, especially in individuals with Type 2 Diabetes Mellitus (T2DM). The interaction between hyperglycemia, endothelial dysfunction, inflammation, and thrombosis creates a complex pathological environment that contributes to the progression of CAD and its acute complications, including AMI. Over recent years, there has been a shift in the therapeutic approach to CAD, especially in T2DM patients, where pharmacologic agents originally developed for glycemic control have demonstrated notable cardiovascular benefits beyond glucose regulation. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are at the forefront of this paradigm shift. Initially, these agents were designed to improve glycemic control, but their broader cardiovascular protective effects have become increasingly evident, particularly in patients with CAD. This review aims to provide an in-depth exploration of the mechanistic underpinnings of these agents, the clinical data supporting their cardiovascular benefits, and their potential role for patients with CAD.

Innovative lipid-modifying agents are valuable resources to improve the control of atherogenic dyslipidemias and reduce the lipid-related residual cardiovascular risk of patients with intolerance or who are not fully responsive to a consolidated standard of care (statins plus ezetimibe). Moreover, some of the upcoming compounds potently affect lipid targets that are thus far considered “unmodifiable”. The present paper is a viewpoint aimed at presenting the incremental metabolic and cardiovascular benefits of the emerging lipid-modulating agents and real-life barriers, hindering their prescription by physicians and their assumption by patients, which need to be worked out for a more diffuse and appropriate drug utilization.

Background: Continuous glucose monitoring (CGM) shows in more detail the glycaemic pattern of diabetic subjects and provides several new parameters (“glucometrics”) to assess patients’ glycaemia and consensually guide treatment. A better control of glucose levels might result in improvement of clinical outcome and reduce disease complications. This study aimed to gather an expert consensus on the clinical and prognostic use of CGM in diabetic patients at high cardiovascular risk or with heart disease.Methods: A list of 22 statements concerning type of patients who can benefit from CGM, prognostic impact of CGM in diabetic patients with heart disease, CGM use during acute cardiovascular events and educational issues of CGM were developed. Using a two-round Delphi methodology, the survey was distributed online to 42 Italian experts (21 diabetologists and 21 cardiologists) who rated their level of agreement with each statement on a 5-point Likert scale. Consensus was predefined as more than 66% of the panel agreeing/disagreeing with any given statement.Results: Forty experts (95%) answered the survey. Every statement achieved a positive consensus. In particular, the panel expressed the feeling that CGM can be prognostically relevant for every diabetic patient (70%) and that is clinically useful also in the management of those with type 2 diabetes not treated with insulin (87.5%). The assessment of time in range (TIR),glycaemic variability (GV) and hypoglycaemic/hyperglycaemic episodes were considered relevant in the management of diabetic patients with heart disease (92.5% for TIR, 95% for GV, 97.5% for time spent in hypoglycaemia) and can improve the prognosis of those with ischaemic heart disease (100% for hypoglycaemia, 90% for hyperglycaemia) or with heart failure (87.5% for hypoglycaemia, 85% for TIR, 87.5% for GV). The experts retained that CGM can be used and can impact the short- and long-term prognosis during an acute cardiovascular event. Lastly, CGM has a recognized educational role for diabetic subjects.Conclusions: According to this Delphi consensus, the clinical and prognostic use of CGM in diabetic patients at high cardiovascular risk is promising and deserves dedicated studies to confirm the experts’ feelings.

The effects of the oral glucose tolerance test (OGTT) on red blood cells (RBCs) have not been thoroughly investigated, although it is known that the ingestion of 75 g of glucose during OGTT results in a systemic state of inflammation and oxidative stress. Therefore, we evaluated the effect of OGTT on oxidative stress and L-arginine/Nitric Oxide (L-Arg/NO) metabolic pathway in RBCs obtained from patients with prediabetes. Blood samples were collected from all participants before (T0) and at 10 (T1), 20 (T2), 30 (T3), 60 (T4), 90 (T5), 120 (T6), 150 (T7), and 180 (T8) minutes after glucose loading. Results showed a significant increase in oxidative stress status characterized by a rise in the GSSG/GSH ratio at T4 and T6 that increased in parallel with a reduction of NO production in RBCs. In addition, in this time frame, increased exposure of phosphatidylserine on RBCs membrane was observed. These metabolic modifications were rescued at T8, together with an increase in activated RBC NO synthase expression. These findings provide a possible explanation of the phenomena occurring after glucose loading and suggest that, even in the early stages of diabetes, it may be important to avoid acute variations in glycemia in order to prevent diabetic complications.

Background. Continuous glucose monitoring (CGM) shows in more detail the glycaemic pattern of diabetic subjects and provides several new parameters (“glucometrics”) to assess patients’ glycaemia and consensually guide treatment. A better control of glucose levels might result in improvement of clinical outcome and reduce disease complications. This study aimed to gather an expert consensus on the clinical and prognostic use of CGM in diabetic patients at high cardiovascular risk or with heart disease.Methods. A list of 22 statements concerning type of patients who can benefit from CGM, prognostic impact of CGM in diabetic patients with heart disease, CGM use during acute cardiovascular events and educational issues of CGM were developed. Using a two-round Delphi methodology, the survey was distributed online to 42 Italian experts (21 diabetologists and 21 cardiologists) who rated their level of agreement with each statement on a 5-point Likert scale. Consensus was predefined as more than 66% of the panel agreeing/disagreeing with any given statement.Results. Forty experts (95%) answered the survey. Every statement achieved a positive consensus. In particular, the panel expressed the feeling that CGM can be prognostically relevant for every diabetic patient (70%) and that is clinically useful also in the management of those with type 2 diabetes not treated with insulin (87.5%). The assessment of time in range (TIR), glycaemic variability (GV) and hypoglycaemic/hyperglycaemic episodes were considered relevant in the management of diabetic patients with heart disease (92.5% for TIR, 95% for GV, 97.5% for time spent in hypoglycaemia) and can improve the prognosis of those with ischaemic heart disease (100% for hypoglycaemia, 90% for hyperglycaemia) or with heart failure (87.5% for hypoglycaemia, 85% for TIR, 87.5% for GV). The experts retained that CGM can be used and can impact the short- and long-term prognosis during an acute cardiovascular event. Lastly, CGM has a recognized educational role for diabetic subjects.Conclusions. According to this Delphi consensus, the clinical and prognostic use of CGM in diabetic patients at high cardiovascular risk is promising and deserves dedicated studies to confirm the experts’ feelings.

Circulating microRNAs are potential biomarkers of type 2 diabetes mellitus (T2DM) and related complications. Here, we investigated the association of microRNA-15a with early retinal damage in T2DM. A cohort of untreated subjects screened for intermediate/high risk of T2DM, according to a score assessment questionnaire, and then recognized to have a normal (NGT) or impaired (IGT) glucose tolerance or T2DM was studied. The thickness of the ganglion cell complex (GCC), an early marker of retinal degeneration anteceding overt retinopathy was assessed by Optical Coherence Tomography. Total and extracellular vesicles (EV)-associated microRNA-15a quantity was measured in plasma by real time PCR. MicroRNA-15a level was significantly higher in subjects with IGT and T2DM compared with NGT. MicroRNA-15a abundance was correlated to body mass index and classical diabetes biomarkers, including fasting glucose, HbA1c, insulinemia, and HOMA-IR. Moreover, GCC thickness was significantly reduced in IGT and T2DM subjects compared with NGT controls. Importantly, total microRNA-15a correlated with GCC in IGT subjects, while in T2DM subjects, EV-microRNA-15a negatively correlated with GCC, suggesting that microRNA-15a may monitor initial retinal damage. The assessment of plasma microRNA-15a may help refining risk assessment and secondary prevention in patients with preclinical T2DM.

Background: CD 34 ⁺ stem/progenitor cells are involved in vascular homeostasis and in neovascularization of ischemic tissues. The number of circulating CD 34 ⁺ stem cells is a predictive biomarker of adverse cardiovascular outcomes in diabetic patients. Here, we provide evidence that hyperglycemia can be “memorized” by the stem cells through epigenetic changes that contribute to onset and maintenance of their dysfunction in diabetes mellitus. Methods and Results: Cord‐blood–derived CD 34 ⁺ stem cells exposed to high glucose displayed increased reactive oxygen species production, overexpression of p66 ^shc gene, and downregulation of antioxidant genes catalase and manganese superoxide dismutase when compared with normoglycemic cells. This altered oxidative state was associated with impaired migration ability toward stromal‐cell–derived factor 1 alpha and reduced protein and mRNA expression of the C‐X‐C chemokine receptor type 4 ( CXCR 4) receptor. The methylation analysis by bisulfite Sanger sequencing of the CXCR 4 promoter revealed a significant increase in DNA methylation density in high‐glucose CD 34 ⁺ stem cells that negatively correlated with mRNA expression (Pearson r =−0.76; P =0.004). Consistently, we found, by chromatin immunoprecipitation assay, a more transcriptionally inactive chromatin conformation and reduced RNA polymerase II engagement on the CXCR 4 promoter. Notably, alteration of CXCR 4 DNA methylation, as well as transcriptional and functional defects, persisted in high‐glucose CD 34 ⁺ stem cells despite recovery in normoglycemic conditions. Importantly, such an epigenetic modification was thoroughly confirmed in bone marrow CD 34 ⁺ stem cells isolated from sternal biopsies of diabetic patients undergoing coronary bypass surgery. Conclusions: CD 34 ⁺ stem cells “memorize” the hyperglycemic environment in the form of epigenetic modifications that collude to alter CXCR 4 receptor expression and migration.

Diabetes is a common comorbidity in patients hospitalized for an acute coronary syndrome event, and prevalence is increasing. Among patients hospitalized with acute myocardial infarction, diabetes can be an independent predictor of mortality and new cardiovascular events; both short- and long-term outcomes are worse for patients with diabetes relative to those without, and undiagnosed diabetes is associated with greater mortality. The impact of glycemic control on cardiovascular outcomes and the best approach to treat hyperglycemia upon hospital admission for acute coronary syndrome in patients with or without known diabetes remain open questions. This review assesses available evidence for hyperglycemia management at the time of admission for acute coronary syndrome and, thereafter, finds that (1) admission plasma glucose plays a role in predicting adverse events, especially in patients with unknown diabetes; (2) glycated haemoglobin is a likely predictor of events in patients with unknown diabetes; and (3) hypoglycemia at the time of acute myocardial infarction hospital admission is an important predictor for mortality in patients with and without diabetes. Whether glucose-targeted insulin and glucose infusion have advantages over glucose–insulin–potassium infusion remains controversial. Evidence for the effect of novel glucose-lowering agents used at the time of an acute cardiovascular event is limited and requires more dedicated studies.

OBJECTIVE ST-segment elevation myocardial infarction (STEMI) patients with type 2 diabetes mellitus (DM) have higher in-hospital mortality than those without. Since cardiac and renal functions are the main variables associated with outcome in STEMI, we hypothesized that this prognostic disparity may depend on a higher rate of cardiac and renal dysfunction in DM patients. RESEARCH DESIGN AND METHODS We retrospectively analyzed 5,152 STEMI patients treated with primary angioplasty. Left ventricular ejection fraction (LVEF) and estimated glomerular filtration rate (eGFR) were evaluated at hospital admission. The primary end point was in-hospital mortality. A composite of in-hospital mortality, cardiogenic shock, and acute kidney injury was the secondary end point. RESULTS There were 879 patients (17%) with DM. The incidence of LVEF ≤40% (30% vs. 22%), eGFR ≤60 mL/min/1.73 m² (27% vs. 18%), or both (12% vs. 6%) was higher (P < 0.001 for all comparisons) in DM patients. In-hospital mortality was higher in DM patients than in non-DM patients (6.1% vs. 3.5%; P = 0.002), with an unadjusted odds ratio (OR) of 1.81 (95% CI 1.31–2.49; P < 0.001). However, DM was no longer associated with an increased mortality risk after adjustment for cardiac and renal function (OR 1.03, 95% CI 0.68–1.56; P = 0.89). A similar behavior was observed for the secondary end point, with an unadjusted OR for DM of 1.52 (95% CI 1.25–1.85; P < 0.001) and an OR after adjustment for cardiac and renal function of 1.07 (95% CI 0.85–1.36; P = 0.53). CONCLUSIONS The study indicates that the increased in-hospital mortality and morbidity of DM patients with STEMI is mainly driven by their underlying cardio-renal dysfunction.

Aims There is an unmet need among healthcare providers to identify subgroups of patients with type 2 diabetes who are most likely to respond to treatment. Methods Data were taken from electronic medical records of participants of an observational, retrospective study in Italy. We used logistic regression models to assess the odds of achieving glycated haemoglobin (HbA_1c) reduction ≥ 1.0% point after 12-month treatment with liraglutide (primary endpoint), according to various patient-related factors. RECursive Partitioning and AMalgamation (RECPAM) analysis was used to identify distinct homogeneous patient subgroups with different odds of achieving the primary endpoint. Results Data from 1325 patients were included, of which 577 (43.5%) achieved HbA_1c reduction ≥ 1.0% point (10.9 mmol/mol) after 12 months. Logistic regression showed that for each additional 1% HbA_1c at baseline, the odds of reaching this endpoint were increased 3.5 times (95% CI: 2.90–4.32). By use of RECPAM analysis, five distinct responder subgroups were identified, with baseline HbA_1c and diabetes duration as the two splitting variables. Patients in the most poorly controlled subgroup (RECPAM Class 1, mean baseline HbA_1c > 9.1% [76 mmol/mol]) had a 28-fold higher odds of reaching the endpoint versus patients in the best-controlled group (mean baseline HbA_1c ≤ 7.5% [58 mmol/mol]). Mean HbA_1c reduction from baseline was as large as − 2.2% (24 mol/mol) in the former versus − 0.1% (1.1 mmol/mol) in the latter. Mean weight reduction ranged from 2.5 to 4.3 kg across RECPAM subgroups. Conclusions Glycaemic response to liraglutide is largely driven by baseline HbA_1c levels and, to a lesser extent, by diabetes duration.