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Despite the risk of atherosclerosis has progressively declined over the past few decades, subjects with type 2 diabetes mellitus (T2DM) continue to experience substantial excess of atherosclerotic cardiovascular disease (ASCVD)-related events. Therefore, there is urgent need to treat ASCVD disease in T2DM earlier, more intensively, and with greater precision. Many factors concur to increase the risk of atherosclerosis, and multifactorial intervention remains the basis for effective prevention or reduction of atherosclerotic events. The role of anti-hyperglycemic medications in reducing the risk of ASCVD in subjects with T2DM has evolved over the past few years. Multiple cardiovascular outcome trials (CVOTs) with new and emerging glucose-lowering agents, namely SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RA), have demonstrated significant reductions of major cardiovascular events and additional benefits. This robust evidence has changed the landscape for managing people with T2DM. In addition to glycemic and ancillary extra-glycemic properties, SGLT2i and GLP1-RA might exert favorable effects on subclinical and clinical atherosclerosis. Therefore, the objective of this review is to discuss the available evidence supporting anti-atherosclerotic properties of SGLT2i and GLP1-RA, with a quick nod to sotagliflozin and tirzepatide., Competing Interests: Declaration of competing interest Angela Dardano (AD) reported no duality of interest. Cristina Bianchi (CB) reported consulting fees and grants from Lilly, Novo Nordisk, Merck Sharp & Dohme Corp. Monia Garofolo (MG) reported consulting fees from Novo Nordisk, Eli Lilly, Merck Sharp & Dohme Corp. and Bayer Inc. Stefano Del Prato (SDP) has served as president of EASD/European Foundation for the Study of Diabetes (EFSD) (2020–2022); has received research grants to the institution from AstraZeneca and Boehringer Ingelheim; has served as advisor for Abbott, Amarin Corporation, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., EvaPharma, Jiangsu Hengrui Pharmaceuticals Co., Menarini International, Merck Sharpe & Dohme, Novartis Pharmaceutical Co., Novo Nordisk, Sanofi and Sun Pharmaceuticals; and has received fees for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Laboratori Guidotti, Menarini International, Merck Sharpe & Dohme, and Novo Nordisk. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD), identified by the Fatty Liver Index (FLI), is associated with increased mortality and cardiovascular (CV) outcomes. Whether this also applies to type 1 diabetes (T1D) has not been yet reported., Methods: We prospectively observed 774 subjects with type 1 diabetes (males 52%, 30.3 ± 11.1 years old, diabetes duration (DD) 18.5 ± 11.6 years, HbA1c 7.8 ± 1.2%) to assess the associations between FLI (based on BMI, waist circumference, gamma-glutamyl transferase and triglycerides) and all-cause death and first CV events., Results: Over a median 11-year follow-up, 57 subjects died (7.4%) and 49 CV events (6.7%) occurred among 736 individuals with retrievable incidence data. At baseline, FLI was < 30 in 515 subjects (66.5%), 30-59 in 169 (21.8%), and ≥ 60 in 90 (11.6%). Mortality increased steeply with FLI: 3.9, 10.1, 22.2% (p < 0.0001). In unadjusted Cox analysis, compared to FLI < 30, risk of death increased in FLI 30-59 (HR 2.85, 95% CI 1.49-5.45, p = 0.002) and FLI ≥ 60 (6.07, 3.27-11.29, p < 0.0001). Adjusting for Steno Type 1 Risk Engine (ST1-RE; based on age, sex, DD, systolic BP, LDL cholesterol, HbA1c, albuminuria, eGFR, smoking and exercise), HR was 1.52 (0.78-2.97) for FLI 30-59 and 3.04 (1.59-5.82, p = 0.001) for FLI ≥ 60. Inclusion of prior CV events slightly modified HRs. FLI impact was confirmed upon adjustment for EURODIAB Risk Engine (EURO-RE; based on age, HbA1c, waist-to-hip ratio, albuminuria and HDL cholesterol): FLI 30-59: HR 1.24, 0.62-2.48; FLI ≥ 60: 2.54, 1.30-4.95, p = 0.007), even after inclusion of prior CVD. CV events incidence increased with FLI: 3.5, 10.5, 17.2% (p < 0.0001). In unadjusted Cox, HR was 3.24 (1.65-6.34, p = 0.001) for FLI 30-59 and 5.41 (2.70-10.83, p < 0.0001) for FLI ≥ 60. After adjustment for ST1-RE or EURO-RE, FLI ≥ 60 remained statistically associated with risk of incident CV events, with trivial modification with prior CVD inclusion., Conclusions: This observational prospective study shows that FLI is associated with higher all-cause mortality and increased risk of incident CV events in type 1 diabetes., (© 2024. The Author(s).)

Aims: Subjects with type 2 diabetes (T2D) are characterized by a high cardiovascular morbidity and mortality. MG53, a marker of peripheral insulin resistance, has been linked with impaired β-cell function and decreased β-cell survival, and its circulating levels are increased in T2D. Its relationship with the cardiovascular risk profile and mortality in T2D is currently unknown., Methods: In this longitudinal study, MG53 was measured in serum samples collected at baseline for 296 Caucasian participants in the MIND.IT study, relating its circulating levels with the cardiovascular risk profile and all-cause mortality over a 17-years follow up., Results: As compared to a reference cohort of 234 healthy subjects, MG53 levels were higher in T2D individuals (p < 0.001), and higher in T2D women than in men (p = 0.001). In the whole study cohort, MG53 levels were directly related to HbA1c (r 2 0.029; p = 0.006) and systolic blood pressure (r 2 0.032; p = 0.004). There was no difference in baseline MG53 levels between deceased and alive participants, neither predict all-cause mortality., Conclusions: MG53 does not mark the cardiovascular risk profile neither predict long-term mortality in Caucasian T2D individuals., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Authors declare no competing interests. The MIND.IT study was supported by Foundation of the Italian Society of Diabetology (Fo.Ri.SID for the research on diabetes and metabolic diseases)., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Large cardiovascular outcome trials (CVOTs) have lent support to a cardiovascular protection with the use of SGLT2-inhibitors (SGLT2is) and GLP1-Receptor Agonists (GLP1-RAs) in subjects with type 2 diabetes. These two classes of novel glucose lowering agents have been shown to have a similar effect on the risk reduction of Major Adverse Cardiovascular Events (MACE: nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality). Nonetheless, they may not be simply interchangeable. Rather, careful evaluation of all the results of CVOTs leads identification of different effects that may allow profiling of the ideal individuals with T2DM who may benefit most from the use of one or the other class of agents. These differences include effect on heart failure, stroke and diabetic kidney disease that have prompt recent guidelines and recommendation for the treatment of type 2 diabetes to suggest the preferential use of SGLT2is in those with evidence of heart failure and impaired kidney function, while both SGLT2i and GLP1-RAs with proven effect could be use in those with prevalent atherosclerotic cardiovascular disease. This review discusses all these elements of differentiation along with others that in the future may help establishing the best cardiorenal benefit for individuals with T2DM., Competing Interests: Declaration of Competing Interest SDP has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis Pharmaceuticals Co. and Merck Sharpe & Dohme; and is a consultant for or has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Merck Sharp & Dohme, Novartis Pharmaceuticals Co., Novo Nordisk, Sanofi and Takeda. AD, RM, CB and GD have no competing interests to declare., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Context: In subjects with normal glucose tolerance (NGT) 1-hour postload plasma glucose (1-h oral glucose tolerance test [OGTT]) of >155 mg/dL predicts type 2 diabetes (T2DM) and is associated with subclinical atherosclerosis., Objective: The purpose of this study was to evaluate β-cell function, insulin resistance, and cardiovascular risk profile in subjects with NGT with a 1-h OGTT glucose of >155 mg/dL., Patients and Methods: The GENFIEV (Genetics, PHYsiopathology, and Evolution of Type 2 diabetes) study is a multicenter study recruiting individuals at high risk of T2DM. A total of 926 subjects underwent a 75-g OGTT for assessment of plasma glucose and C-peptide for mathematical modeling of β-cell function (derivative and proportional control). Fasting insulin, lipid profile, and clinical parameters were determined as well., Results: A 1-hour OGTT glucose of >155 mg/dL was found in 39% of subjects with NGT, 76% with impaired fasting glucose (IFG), 90% with impaired glucose tolerance (IGT), and 99% and 98% with IFG + IGT or newly diagnosed T2DM, respectively. Among subjects with NGT (n = 474), those with 1-hour OGTT glucose of >155 mg/dL were more insulin-resistant and had worse β-cell function than those with 1-hour OGTT glucose of ≤155 mg/dL. Moreover, glycosylated hemoglobin, blood pressure, low-density lipoprotein cholesterol, and triglycerides were higher in subjects with NGT with 1-hour OGTT glucose of >155 mg/dL, whereas high-density lipoprotein cholesterol was lower compared with that in subjects with NGT with 1-hour OGTT glucose of ≤155 mg/dL. Compared with subjects with IGT, those with NGT with 1-hour OGTT glucose of >155 mg/dL had comparable cardiovascular risk profile and insulin resistance but slightly better β-cell function., Conclusions: Among subjects with NGT, those with 1-hour OGTT glucose of >155 mg/dL showed lower insulin sensitivity, impaired β-cell function, and worse cardiovascular risk profile and therefore are at greater risk of developing T2DM and cardiovascular disease.

Coronary artery disease and type 2 diabetes are chronic diseases of substantial and growing prevalence. Although diabetes is a strong independent risk factor for cardiovascular events, this risk is not confined to glucose levels above the diagnostic threshold for diabetes. Rather, there is now a growing consensus that nondiabetic hyperglycemia measured by fasting glucose, postload glucose or glycated hemoglobin is a progressive, continuous risk factor for cardiovascular outcomes. Whether dysglycemia is a marker for a more complex metabolic condition or may directly contribute to excess cardiovascular risk is still a matter of debate. While strategies designed to normalize glucose levels in people with type 2 diabetes remain inconclusive, diabetes prevention trials suggest that along with reduction of the rate of conversion toward diabetes, a significant improvement in cardiovascular risk factors occurs. Moreover, a number of ongoing studies may provide answers to this question. Recognition that nondiabetic hyperglycemia is associated with an increased cardiovascular risk may suggest new ways for preventing cardiovascular disease.

Cardiovascular disease accounts for a great majority of deaths in patients with type 2 diabetes. According to the World Health Organization, the prevalence of cardiovascular disease in diabetic patients ranges from 26 to 36%. Fatality rate after myocardial infarction is greater in diabetic patients, and overall prognosis after coronary heart disease is worse. Based on these observations, it has been proposed that diabetes should be considered as a coronary heart disease risk equivalent. If that is the case, prevention of diabetes and early intervention should be pursued. This view is supported by the notion that cardiovascular risk is already increased in people with impaired glucose tolerance. Moreover, higher-than-optimum blood glucose is a major cause of cardiovascular mortality in most world regions of the world. Whether dysglycemia is a marker for a more complex metabolic condition or may directly contribute to excess cardiovascular risk is still a matter of debate. However, experimental work has shown how increased glucose level can trigger multiple mechanisms of susceptibility to atherosclerosis, and diabetes prevention trials have indicated that along with reduction of the rate of conversion toward diabetes, significant improvement in cardiovascular risk factors occurs. Moreover, in the STOP-NIDDM trial, targeting postprandial glucose was associated with reduction in new cases of hypertension, myocardial infarction, and any cardiovascular events. In conclusion, dysglycemia should be included in the list of established cardiovascular risk factors and early treatment introduced in the attempt to improve cardiovascular morbidity and mortality.

The current board of the interassociative Italian association of medical diabetologists (AMD)/Italian society of diabetology (SID) Diabetes and Pregnancy Italian Study Group commented about two recent papers published in the New England Journal of Medicine that investigated the screening and diagnostic methods for gestational diabetes mellitus (GDM). It is well recognized that effective screening and accurate, early diagnosis of GDM contributes to better management of these women in order to reduce adverse maternal and fetal/neonatal outcomes. However, there is worldwide controversy concerning which screening (selective or universal; one step or two steps) and which diagnostic criteria (glucose thresholds) are appropriate. The main findings of these papers are discussed along with their implications for the management of pregnant women. [ABSTRACT FROM AUTHOR]

The article examines results of the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial on early insulin therapy for patients with type 2 diabetes. The ORIGIN trial aims to determine whether insulin replacement therapy in early stage of the disease can reduce cardiovascular (CV) outcomes more than standard treatment. The authors suggest that the ORIGIN trial shows that insulin treatment is not associated with increased CV or neoplasm event rate.

OBJECTIVE-To ascertain to which extent the use of HbA1c and oral glucose tolerance test (OGTT) for diagnosis of glucose tolerance could identify individuals with different pathogenetic mechanisms and cardiovascular risk profile. RESEARCH DESIGN AND METHOD-A total of 844 subjects (44%men; age 49.5±11 years; BMI 29±5 kg/m2) participated in this study. Parameters of β-cell function were derived from deconvolution of the plasma C-peptide concentration after a 75-g OGTT and insulin sensitivity assessed by homeostasismodel assessment of insulin resistance (IR). Cardiovascular risk profile was based on determination of plasma lipids and measurements of body weight, waist circumference, and blood pressure. Glucose regulation categories by OGTT and HbA1c were compared with respect to insulin action, insulin secretion, and cardiovascular risk profile. RESULT-OGTT results showed 42% of the subjects had prediabetes and 15% had type 2 diabetes mellitus (T2DM), whereas the corresponding figures based on HbA1c were 38 and 11%, with a respective concordance rate of 54 and 44%. Subjects meeting both diagnostic criteria for prediabetes presented greater IR and impairment of insulin secretion and had aworse cardiovascular risk profile than those with normal glucose tolerance at both diagnostic methods. In a logistic regression analyses adjusted for age, sex, and BMI, prediabetic subjects, and even more T2DM subjects by OGTT, had greater chance to have IR and impaired insulin secretion. CONCLUSION-HbA1c identifies a smaller proportion of prediabetic individuals and even a smaller proportion of T2DM individuals than OGTT, with no difference in IR, insulin secretion, and cardiovascular risk profile. Subjects fulfilling both diagnostic methods for prediabetes or T2DM are characterized by a worse metabolic profile. [ABSTRACT FROM AUTHOR]

Summary: Background and aim: To evaluate the prevalence of the metabolic syndrome as defined by NCEP ATP III criteria in an Italian cohort of adult subjects. Methods and results: A total of 2100 subjects aged 19 years or more, were randomly selected from the general population of the Lucca area. Metabolic syndrome was defined by the clustering of three or more of the following abnormalities: waist circumference greater than 102 cm in men and 88 cm in women; serum triglycerides level of at least 150 mg/dl (1.69 mmol/l); high-density lipoprotein cholesterol less than 40 mg/dl (1.04 mmol/l) in men and 50 mg/dl (1.29 mmol/l) in women; blood pressure greater than 130/85 mmHg; or serum glucose greater than 110 mg/dl (6.1 mmol/l). The prevalence of the metabolic syndrome was 18% in women and 15% in men. The prevalence increased from 3% among subjects aged 20–29 years to 25% in subjects aged 70 years or older. Application of this estimated prevalence data to the Italian adult population suggests that 3.6 million women and 3 million men may have the metabolic syndrome. Conclusions: The prevalence of metabolic syndrome in a cohort likely representative of the Italian adult population is high. The recognition of the syndrome may represent an important challenge for physicians and healthcare and requires immediate strategies aimed to reduce level of individual metabolic traits. [Copyright &y& Elsevier]