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1.
GLP-1 receptor agonists-SGLT-2 inhibitors combination therapy and cardiovascular events after acute myocardial infarction: an observational study in patients with type 2 diabetes.
Marfella, R, Prattichizzo, F, Sardu, C, Rambaldi, PF, Fumagalli, C, Marfella, LV, La Grotta, R, Frigé, C, Pellegrini, V, D'Andrea, D, et al
Cardiovascular diabetology. 2024;(1):10
Abstract
BACKGROUND Few studies explored the effect of the combination of glucose sodium-cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) on the incidence of cardiovascular events in patients with type 2 diabetes (T2D) and acute myocardial infarction (AMI). METHODS We recruited patients with T2D and AMI undergoing percutaneous coronary intervention, treated with either SGLT-2i or GLP-1RA for at least 3 months before hospitalization. Subjects with HbA1c < 7% at admission were considered in good glycemic control and maintained the same glucose-lowering regimen, while those with poor glycemic control (HbA1c ≥ 7%), at admission or during follow-up, were prescribed either a SGLT-2i or a GLP-1RA to obtain a SGLT-2i/GLP-1RA combination therapy. The primary outcome was the incidence of major adverse cardiovascular events (MACE) defined as cardiovascular death, re-acute coronary syndrome, and heart failure related to AMI during a 2-year follow-up. After 3 months, the myocardial salvage index (MSI) was assessed by single-photon emission computed tomography. FINDINGS Of the 537 subjects screened, 443 completed the follow-up. Of these, 99 were treated with SGLT-2i, 130 with GLP-1RA, and 214 with their combination. The incidence of MACE was lower in the combination therapy group compared with both SGLT-2i and GLP-1RA treated patients, as assessed by multivariable Cox regression analysis adjusted for cardiovascular risk factors (HR = 0.154, 95% CI 0.038-0.622, P = 0.009 vs GLP-1RA and HR = 0.170, 95% CI 0.046-0.633, P = 0.008 vs SGLT-2i). The MSI and the proportion of patients with MSI > 50% was higher in the SGLT-2i/GLP-1RA group compared with both SGLT-2i and GLP-1RA groups. INTERPRETATION The combination of SGLT-2i and GLP-1RA is associated with a reduced incidence of cardiovascular events in patients with T2D and AMI compared with either drug used alone, with a significant effect also on peri-infarcted myocardial rescue in patients without a second event. Trial registraition ClinicalTrials.gov ID: NCT06017544.
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2.
Risk factor variability and cardiovascular risk among patients with diabetes: a nationwide observational study.
Ceriello, A, Lucisano, G, Prattichizzo, F, La Grotta, R, Franzén, S, Gudbjörnsdottir, S, Eliasson, B, Nicolucci, A
European journal of preventive cardiology. 2023;(8):719-727
Abstract
AIMS: Cardiovascular risk factor control fluctuates, tends to change over time, and is potentially impacted by multifactorial interactions. Currently, the presence of risk factors, rather than their variability or interplay with one another, is taken into account to define the population at risk. The association between variability of risk factors and cardiovascular morbidity and mortality risk among patients with Type 2 diabetes mellitus (T2DM) remains debatable. METHODS AND RESULTS Using registry-derived data, we identified 29 471 people with T2DM, without cardiovascular disease (CVD) at baseline, and with at least five measurements of risk factors. Variability for each variable was expressed as quartiles of the standard deviation during 3 years (exposure). The incidence of myocardial infarction, stroke, and all-cause mortality was assessed during 4.80 (2.40-6.70) years following the exposure phase. The association between the measures of variability and the risk of developing the outcome was investigated through multivariable Cox proportional-hazards regression analysis with stepwise variable selection. Then, the recursive partitioning and amalgamation (RECPAM) algorithm was used to explore the interaction among the variability of risk factors associated with the outcome. An association between the variability of HbA1c, body weight, systolic blood pressure, and total cholesterol with the outcome considered was found. Among the six classes of risk identified by RECPAM, patients with a high variability of both body weight and blood pressure had the highest risk [Class 6, hazard ratio (HR) = 1.81; 95% confidence interval (CI) 1.61-2.05] compared with patients with low variability of both body weight and total cholesterol (Class 1, reference), despite a progressive reduction in the mean level of risk factors during successive visits. Individuals with high weight variability but low-moderate systolic blood pressure variability (Class 5, HR = 1.57; 95% CI 1.28-1.68), patients with moderate/high weight variability associated with high/very high HbA1c variability (Class 4, HR = 1.33; 95% CI 1.20-1.49), subjects with moderate/high weight variability and with low/moderate HbA1c variability (Class 3, HR = 1.12; 95% CI 1.00-1.25), as well as those with low weight variability associated with high/very high total cholesterol variability (Class 2, HR = 1.14; 95% CI 1.00-1.30) also showed a significant increase in the risk of an event. CONCLUSION Combined high variability of two risk factors, particularly body weight and blood pressure, is associated with cardiovascular risk among patients with T2DM. These findings highlight the importance of continuous balancing of multiple risk factors.
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3.
SGLT-2 inhibitors and in-stent restenosis-related events after acute myocardial infarction: an observational study in patients with type 2 diabetes.
Marfella, R, Sardu, C, D'Onofrio, N, Fumagalli, C, Scisciola, L, Sasso, FC, Siniscalchi, M, Marfella, LV, D'Andrea, D, Minicucci, F, et al
BMC medicine. 2023;(1):71
Abstract
BACKGROUND No study evaluated the incidence of intra-stent restenosis (ISR)-related events in patients with type 2 diabetes (T2DM) and acute myocardial infarction (AMI) treated or not with sodium/glucose cotransporter 2 inhibitors (SGLT2i). METHODS We recruited 377 patients with T2DM and AMI undergoing percutaneous coronary intervention (PCI). Among them, 177 T2DM were treated with SGLT2 inhibitors before PCI. The primary outcome was major adverse cardiovascular events (MACE) defined as cardiac death, re-infarction, and heart failure related to ISR. In patients without ISR, minimal lumen area and minimal lumen diameter were assessed by coronary CT-angiography at 1-year follow-up. RESULTS Glycemic control was similar in SGLT2i-treated patients and never SGLT2i-users. The incidence of ISR-related MACE was higher in never SGLT2i-users compared with SGLT2i-treated patients, an effect independent of glycemic status (HR = 0.418, 95% CI = 0.241-0.725, P = 0.002) and observed also in the subgroup of patients with HbA1c < 7% (HR = 0.393, 95% CI = 0.157-0.984, P = 0.027). In patients without the event, the stent patency was greater in SGLT2i-treated patients compared with never SGLT2i-users at 1-year follow-up. CONCLUSIONS SGLT2i treatment in T2DM is associated with a reduced incidence of ISR-related events, independently of glycemic control.
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4.
Evidence of an anti-inflammatory effect of PCSK9 inhibitors within the human atherosclerotic plaque.
Marfella, R, Prattichizzo, F, Sardu, C, Paolisso, P, D'Onofrio, N, Scisciola, L, La Grotta, R, Frigé, C, Ferraraccio, F, Panarese, I, et al
Atherosclerosis. 2023;:117180
Abstract
BACKGROUND AND AIMS Preclinical evidence suggests that proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors hold anti-inflammatory properties independently of their ability to lower LDL-cholesterol (C). However, whether PCSK9 inhibitors exert anti-inflammatory effects within the atherosclerotic plaque in humans is unknown. We explored the impact of PCSK9 inhibitors, used as monotherapy, compared with other lipid-lowering drugs (oLLD) on the expression of inflammatory markers within the plaque, assessing also the subsequent incidence of cardiovascular events. METHODS In an observational study, we recruited 645 patients on stable therapy for at least six months and undergoing carotid endarterectomy, categorizing patients according to the use of PCSK9 inhibitors only (n = 159) or oLLD (n = 486). We evaluated the expression of NLRP3, caspase-1, IL-1β, TNFα, NF-kB, PCSK9, SIRT3, CD68, MMP-9, and collagen within the plaques in the two groups through immunohistochemistry, ELISA, or immunoblot. A composite outcome including non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality was assessed during a 678 ± 120 days follow-up after the procedure. RESULTS Patients treated with PCSK9 inhibitors had a lower expression of pro-inflammatory proteins and a higher abundance of SIRT3 and collagen within the plaque, a result obtained despite comparable levels of circulating hs-CRP and observed also in LDL-C-matched subgroups with LDL-C levels <100 mg/dL. Patients treated with PCSK9 inhibitors showed a decreased risk of developing the outcome compared with patients on oLLD, also after adjustment for multiple variables including LDL-C (adjusted hazard ratio 0.262; 95% CI 0.131-0.524; p < 0.001). The expression of PCSK9 correlated positively with that of pro-inflammatory proteins, which burden was associated with a higher risk of developing the outcome, independently of the therapeutic regimen. CONCLUSIONS The use of PCSK9 inhibitors is accompanied by a beneficial remodelling of the inflammatory burden within the human atheroma, an effect possibly or partly independent of their LDL-C lowering ability. This phenomenon might provide an additional cardiovascular benefit.
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5.
Overall Quality of Care Predicts the Variability of Key Risk Factors for Complications in Type 2 Diabetes: An Observational, Longitudinal Retrospective Study.
Ceriello, A, Rossi, MC, De Cosmo, S, Lucisano, G, Pontremoli, R, Fioretto, P, Giorda, C, Pacilli, A, Viazzi, F, Russo, G, et al
Diabetes care. 2019;(4):514-519
Abstract
OBJECTIVE An association between variability in clinical parameters (HbA1c, blood pressure, cholesterol, and uric acid) and risk of complications in type 2 diabetes has been reported. In this analysis, we investigated to what extent such variability is associated with overall quality of care. RESEARCH DESIGN AND METHODS The quality of care summary score (Q-score) represents a validated, overall quality of care indicator ranging between 0 and 40; the higher the score, the better the quality of care provided by the diabetes center. We identified patients with five or more measurements of clinical parameters after the assessment of the Q-score. Multiple linear regression analyses assessed the role of the Q-score in predicting the variability of the different parameters. RESULTS Overall, 273,888 patients were analyzed. The variability of all the parameters systematically increased with decreasing Q-score values. At multivariate linear regression analysis, compared with a Q-score >25, a score <15 was associated with a significantly larger variation in HbA1c, blood pressure, uric acid, total cholesterol, and LDL cholesterol and a lower variation in HDL cholesterol. The analysis of standardized β coefficients show that the Q-score has a larger impact on the variability of HbA1c (0.34; P < 0.0001), systolic blood pressure (0.21; P < 0.0001), total cholesterol (0.21; P < 0.0001), and LDL cholesterol (0.20; P < 0.0001). CONCLUSIONS The variability of risk factors for diabetic complications is associated with quality of care. Quality of care improvement initiatives should be targeted to increase the achievement of the recommended target while reducing such variability.
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6.
Circulating microRNA-21 is an early predictor of ROS-mediated damage in subjects with high risk of developing diabetes and in drug-naïve T2D.
La Sala, L, Mrakic-Sposta, S, Tagliabue, E, Prattichizzo, F, Micheloni, S, Sangalli, E, Specchia, C, Uccellatore, AC, Lupini, S, Spinetti, G, et al
Cardiovascular diabetology. 2019;(1):18
Abstract
BACKGROUND Impaired glucose tolerance (IGT) is a risk factor for the development of diabetes and related complications that ensue. Early identification of at-risk individuals might be beneficial to reduce or delay the progression of diabetes and its related complications. Recently, microRNAs emerged as potential biomarkers of diseases. The aim of the present study was to evaluate microRNA-21 as a potential biomarker for the risk of developing diabetes in adults with IGT and to investigate its downstream effects as the generation of reactive oxygen species (ROS), the induction of manganese-superoxide dismutase-2 (SOD2), and the circulating levels of 4-HNE (4-hydroxynonenal). METHODS To evaluate the prognostic and predictive values of plasmatic microRNA-21 in identifying metabolic derangements, we tested a selected cohort (n = 115) of subjects enrolled in the DIAPASON Study, whom were selected on ADA criteria for 2hPG. Statistical analysis was performed using ANOVA or the Kruskal-Wallis test as appropriate. ROC curves were drawn for diagnostic accuracy of the tests; positive and negative predictive values were performed, and Youden's index was used to seek the cut-off optimum truncation point. ROS, SOD2 and 4-HNE were also evaluated. RESULTS We observed significant upregulation of microRNA-21 in IGT and in T2D subjects, and microRNA-21 was positively correlated with glycaemic parameters. Diagnostic performance of microRNA-21 was high and accurate. We detected significant overproduction of ROS by electron paramagnetic resonance (EPR), significant accumulation of the lipid peroxidation marker 4-HNE, and defective SOD2 antioxidant response in IGT and newly diagnosed, drug-naïve T2D subjects. In addition, ROC curves demonstrated the diagnostic accuracy of markers used. CONCLUSIONS our data demonstrate that microRNA-21 is associated with prediabetic status and exhibits predictive value for early detection of glucose imbalances. These data could provide novel clues for miR-based biomarkers to evaluate diabetes.
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7.
A unique plasma microRNA profile defines type 2 diabetes progression.
de Candia, P, Spinetti, G, Specchia, C, Sangalli, E, La Sala, L, Uccellatore, A, Lupini, S, Genovese, S, Matarese, G, Ceriello, A
PloS one. 2017;(12):e0188980
Abstract
A major unmet medical need to better manage Type 2 Diabetes (T2D) is the accurate disease prediction in subjects who show glucose dysmetabolism, but are not yet diagnosed as diabetic. We investigated the possibility to predict/monitor the progression to T2D in these subjects by retrospectively quantifying blood circulating microRNAs in plasma of subjects with i) normal glucose tolerance (NGT, n = 9); ii) impaired glucose tolerance (IGT, n = 9), divided into non-progressors (NP, n = 5) and progressors (P, n = 4) based on subsequent diabetes occurrence, and iii) newly diagnosed T2D (n = 9). We found that impaired glucose tolerance associated with a global increase of plasma circulating microRNAs. While miR-148 and miR-222 were specifically modulated in diabetic subjects and correlated with parameters of glucose tolerance, the most accentuated microRNA dysregulation was found in NP IGT subjects, with increased level of miR-122, miR-99 and decreased level of let-7d, miR-18a, miR-18b, miR-23a, miR-27a, miR-28 and miR-30d in comparison with either NGT or T2D. Interestingly, several of these microRNAs significantly correlated with parameters of cholesterol metabolism. In conclusion, we observed the major perturbation of plasma circulating microRNA in NP pre-diabetic subjects and identified a unique microRNA profile that may become helpful in predicting diabetic development.
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8.
Plasma Triglycerides and HDL-C Levels Predict the Development of Diabetic Kidney Disease in Subjects With Type 2 Diabetes: The AMD Annals Initiative.
Russo, GT, De Cosmo, S, Viazzi, F, Pacilli, A, Ceriello, A, Genovese, S, Guida, P, Giorda, C, Cucinotta, D, Pontremoli, R, et al
Diabetes care. 2016;(12):2278-2287
Abstract
OBJECTIVE Despite the achievement of blood glucose, blood pressure, and LDL cholesterol (LDL-C) targets, the risk for diabetic kidney disease (DKD) remains high among patients with type 2 diabetes. This observational retrospective study investigated whether diabetic dyslipidemia-that is, high triglyceride (TG) and/or low HDL cholesterol (HDL-C) levels-contributes to this high residual risk for DKD. RESEARCH DESIGN AND METHODS Among a total of 47,177 patients attending Italian diabetes centers, 15,362 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, normoalbuminuria, and LDL-C ≤130 mg/dL completing a 4-year follow-up were analyzed. The primary outcome was the incidence of DKD, defined as either low eGFR (<60 mL/min/1.73 m2) or an eGFR reduction >30% and/or albuminuria. RESULTS Overall, 12.8% developed low eGFR, 7.6% an eGFR reduction >30%, 23.2% albuminuria, and 4% albuminuria and either eGFR <60 mL/min/1.73 m2 or an eGFR reduction >30%. TG ≥150 mg/dL increased the risk of low eGFR by 26%, of an eGFR reduction >30% by 29%, of albuminuria by 19%, and of developing one abnormality by 35%. HDL-C <40 mg/dL in men and <50 mg/dL in women were associated with a 27% higher risk of low eGFR and a 28% risk of an eGFR reduction >30%, with a 24% higher risk of developing albuminuria and a 44% risk of developing one abnormality. These associations remained significant when TG and HDL-C concentrations were examined as continuous variables and were only attenuated by multivariate adjustment for numerous confounders. CONCLUSIONS In a large population of outpatients with diabetes, low HDL-C and high TG levels were independent risk factors for the development of DKD over 4 years.