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Atherosclerotic cardiovascular disease (ASCVD) remains the main cause of death worldwide, and thus its prevention, early diagnosis and treatment is of paramount importance. Dyslipidemia represents a major ASCVD risk factor that should be adequately managed at different clinical settings. 2023 guidelines of the Hellenic Atherosclerosis Society focus on the assessment of ASCVD risk, laboratory evaluation of dyslipidemias, new and emerging lipid-lowering drugs, as well as diagnosis and treatment of lipid disorders in women, the elderly and in patients with familial hypercholesterolemia, acute coronary syndromes, heart failure, stroke, chronic kidney disease, diabetes, autoimmune diseases, and non-alcoholic fatty liver disease. Statin intolerance is also discussed.

Background & Aims: The effect of lipid-lowering treatment (LLT) on metabolic dysfunction associated steatotic liver disease (MASLD) is unclear. This is relevant for patients with familial hypercholesterolemia (FH) who are on lifelong LLT. We aimed to evaluate the effect of LLT on MASLD indices in this population., Methods: Patients with at least possible diagnosis of FH were included into the Hellenic FH Registry (HELLAS-FH) registry. We analyzed the effect of statin monotherapy, statin/ezetimibe and statin/ezetimibe/proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i) on MASLD indices, i.e., original triglyceride-glucose index (TyGO) and triglyceride-glucose index (TyG). We compared changes of TyG and TyGO before any treatment and after at least one year of stable LLT., Results: We included 1289 patients: n = 569 in the statin monotherapy group (mean age = 51 ± 15 years, 52.7 % males), n = 629 in the statin/ezetimibe group (52 ± 14 years, 51.8 %), and n = 91 in the statin/ezetimibe/PCSK9i group (54 ± 13 years, 58.2 %). Compared with baseline, TyGO and TyG decreased significantly following statin monotherapy (8.61 vs 8.49 and 4.65 vs 4.59, respectively, both p < 0.01), statin/ezetimibe (8.59 vs 8.41 and 4.64 vs 4.55, respectively, both p < 0.01) and statin/ezetimibe/PCSK9i (8.79 vs 8.55 and 4.74 vs 4.62, respectively, both p < 0.01). There was no difference regarding the change of TyGO and TyG between groups after adjusting for baseline levels. A greater percentage of patients in the statin/ezetimibe and statin/ezetimibe/PCSK9i groups exhibited TyGO-defined MASLD resolution compared with statin monotherapy (p < 0.05). After adjustment for possible confounders, LLT was significantly associated with MASLD resolution., Conclusions: MASLD indices were significantly improved in all LLT groups in FH patients. Statin/ezetimibe and statin/ezetimibe/PCSK9i were associated with greater TyGO-defined MASLD resolution compared with statin monotherapy., Competing Interests: Conflict of interest CB, CVR, GL, AG, GS, PA, VK, GA, EP, CV, ID, FG, KAP, AA, VK, CK, DA, CA has nothing to declare. IS has given talks, received honoraria, and participated in clinical trials sponsored by MSD, AMGEN, SANOFI. LR has received research grants and honoraria from Amgen, Sanofi-Aventis, Viatris, Novartis, Vianex and Servier. GK has given talks, attended conferences and participated in trials sponsored by Amgen, Angelini, MSD, Lilly, Vianex and Sanofi and has also accepted travel support to conferences from Amgen, Sanofi and MSD. KT has participated in educational, research and advisory activities sponsored by AMGEN, ANGELINI, ASTRA-ZENECA, BAYER, BOEHRINGER-INGELHEIM, ELPEN, LILLY, MSD, MYLAN, NOVO NORDISK, SANOFI and VIANEX. ES has participated in educational and advisory activities sponsored by AstraZeneca, Medtronic, MSD, Sanofi and Servier. VK has given talks and attended conferences sponsored by AstraZeneca, MSD, Sanofi-Aventis, and Vianex. MD has participated in educational, research and advisory activities sponsored by Menarini, Elpen, AstraZeneca, MSD, Bayer, Sanofi, Novartis, and Servier. KS has received honoraria from Amgen. VL has given lectures, attended conferences and participated in trials sponsored by Novo Nordisk, Sanofi-Aventis, Novartis, AstraZeneca, Boehringer-Ingelheim, MSD, GSK, Vianex, Elli Lilly, ELPEN, Mylan and Aegereon. AB has received honoraria from Vianex, Amarin and Sanofi. EL has participated in educational, research and advisory activities sponsored by AstraZeneca, MSD, Lilly, Bayer, Amgen, Sanofi, Boehringer-Ingelheim, Novartis, Novo Nordisk, Valeant and Servier. EZ has received honoraria for lectures from Amgen. Sanofi, MSD, and Astra Zeneca. HM participated in educational, research and consulting activities supported by healthcare companies, including Amgen, AstraZeneca, Boehringer Ingelheim, Elpen, Novartis, Sanofi, Vianex, Ultragenyx, Winmedica. EL has participated in educational, research and advisory activities sponsored by AstraZeneca, MSD, Lilly, Bayer, Amgen, Sanofi, Boehringer-Ingelheim, Novartis, Novo Nordisk, Valeant and Servier. CSM reports grants through his institution from Merck, Massachusetts Life Sciences Center, and Boehringer Ingelheim, has been a shareholder of and has received grants through his institution and personal consulting fees from Coherus Inc. and AltrixBio; he reports personal consulting fees and support with research reagents from Ansh Inc., collaborative research support from LabCorp Inc., reports personal consulting fees from Genfit, Lumos, Amgen, Corcept, Aligos, Intercept, 89 Bio, Madrigal, and Regeneron, reports travel support and fees from TMIOA, Elsevier, and the Cardio Metabolic Health Conference. None is related to the work presented herein. ENL has participated in educational, research and advisory activities sponsored by AstraZeneca, MSD, Lilly, Bayer, Amgen, Sanofi, Boehringer Ingelheim, Novartis, Novo Nordisk, Valeant and Servier., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on nonpharmacological, behavioral, and lifestyle modifications that target its underlying cause-energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

Background: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD., Methods: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed., Results: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders., Conclusion: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Familial hypercholesterolemia (FH) and obesity are well-established risk factors of atherosclerotic cardiovascular disease (ASCVD). Despite high prevalence, their joint association with ASCVD remains largely unknown., Objective: To investigate the association of obesity with prevalent ASCVD in individuals with heterozygous FH (HeFH) enrolled in the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH)., Methods: FH diagnosis was based on Dutch Lipid Clinic Network (DLCN) criteria. Adults with at least possible FH diagnosis (DLCN score ≥3) and available body mass index (BMI) values were included. Homozygous FH individuals were excluded., Results: 1655 HeFH adults (mean age 51.0 ± 14.4 years, 48.6% female) were included; 378 (22.8%) and 430 (26.0%) were diagnosed with probable and definite FH, respectively. Furthermore, 371 participants (22.4%) had obesity and 761 (46.0%) were overweight. Prevalence of ASCVD risk factors increased progressively with BMI. Prevalence of coronary artery disease (CAD) was 23.4% (3.2% for stroke and 2.7% for peripheral artery disease [PAD]), and increased progressively across BMI groups. After adjusting for traditional ASCVD risk factors and lipid-lowering medication, individuals with obesity had higher odds of established CAD (OR: 1.54, 95% CI: 1.04-2.27, p = 0.036) as well as premature CAD (OR: 1.74, 95% CI: 1.17-2.60, p = 0.009) compared with those with normal BMI. No association was found with stroke or PAD., Conclusions: Over half of adults with HeFH have overweight or obesity. Obesity was independently associated with increased prevalence of CAD in this population., (Copyright © 2024. Published by Elsevier Inc.)

Aims: Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals., Methods: Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD., Results: Adult patients ( n  = 2156, mean age 50 ± 15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets., Conclusion: The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD) remains the main cause of death worldwide, and thus its prevention, early diagnosis and treatment is of paramount importance. Dyslipidemia represents a major ASCVD risk factor that should be adequately managed at different clinical settings. 2023 guidelines of the Hellenic Atherosclerosis Society focus on the assessment of ASCVD risk, laboratory evaluation of dyslipidemias, new and emerging lipid-lowering drugs, as well as diagnosis and treatment of lipid disorders in women, the elderly and in patients with familial hypercholesterolemia, acute coronary syndromes, heart failure, stroke, chronic kidney disease, diabetes, autoimmune diseases, and non-alcoholic fatty liver disease. Statin intolerance is also discussed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V.)

Background: Familial hypercholesterolemia (FH) carries a high risk of atherosclerotic cardiovascular disease (ASCVD). As the population ages, the age-related influence on clinical characteristics and outcomes becomes increasingly pertinent. This cross-sectional analysis from the HELLAS-FH registry aims to explore potential differences in clinical characteristics, treatment, ASCVD, and goal achievement between those younger and older than 65 years with FH., Results: A total of 2273 adults with heterozygous FH (51.4% males) were studied. Elderly FH patients ( n = 349) had a higher prevalence of ASCVD risk factors, such as hypertension (52.1% vs. 20.9%, p < 0.05) and type 2 diabetes (16.9% vs. 6.0%, p < 0.05), compared to younger patients ( n = 1924). They also had a higher prevalence of established ASCVD (38.4% vs. 23.1%, p < 0.001), particularly CAD (33.0% vs. 20.2%, p < 0.001), even after adjusting for major ASCVD risk factors. Elderly patients were more frequently and intensively receiving lipid-lowering treatment than younger ones. Although post-treatment LDL-C levels were lower in elderly than younger patients (125 vs. 146 mg/dL, p < 0.05), both groups had similar attainment of the LDL-C target (3.7% vs. 3.0%)., Conclusions: Elderly FH patients have a higher prevalence of ASCVD, particularly CAD. Despite more aggressive treatment, the achievement of LDL-C targets remains very poor. These results emphasize the importance of early FH diagnosis and treatment in reducing ASCVD.

A steady rise in cardiovascular morbidity and mortality has been observed in young adults within the last decades. This trend corresponds to an increasing prevalence of traditional cardiovascular risk factors such as obesity and diabetes mellitus type 2 among young adults living in developed countries. Moreover, age-specific risk factors, such as substance abuse, contraceptive medication, and pregnancy-related diseases also correlate with an increased incidence of cardiovascular diseases. In this review, we discuss the available data for young adults on the epidemiology and the rationale for the causality of traditional and newly emerging risk factors of atherosclerotic cardiovascular diseases. We focus on gender-related differences in the exposure to these risk factors, investigate the recent data regarding screening and risk stratification in the young adult population, and describe the current state of the art on lifestyle and therapeutic intervention strategies in the primary prevention setting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AG received grants and personal fees from Amgen, Sanofi, Mylan Viatris, MSD, Akcea Therapeutics, Amryt and Ultragenyx. GS received grants from Numares, Sanofi, Bayer, and Eli Lilly, and personal fees from Sanofi, Daiichi-Sankyo, Bayer, and Amgen. AL received grants from Amgen and personal fees from AstraZeneka., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Obesity, which has currently reached pandemic dimensions, is usually accompanied by diabetes mellitus type 2 (T2DM). These two conditions share common pathophysiological mechanisms. Adipose tissue secretes cytokines which are involved in inflammation and various endocrine functions. As for T2DM, it is characterized also by inflammation, mitochondrial dysfunction, and hyperinsulinemia. These conditions occur also in other diseases related to obesity and T2DM, like cardiovascular disease (CVD) and nonalcoholic fatty liver disease (NAFLD). Thus, management of obesity-related complications with lifestyle modification, anti-obesity drugs, and bariatric surgery, all contribute to improvement in any of these conditions. This review provides an overview of the literature addressing the association between obesity and T2DM, briefly discussing the pathophysiological mechanisms linking these conditions and outlining the management approach at the overlap of obesity and T2DM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Resistant hypertension (RH) is defined as the failure to achieve blood pressure control despite using triple combination therapy with a renin-angiotensin system inhibitor (RAS-i), a calcium antagonist, and a diuretic. The endothelin (ET) system is implicated in the regulation of vascular tone, primarily through vasoconstriction, intervenes in cardiac contractility with inotropic effects, and contributes to water and sodium renal reabsorption. ET inhibitors, currently approved for the treatment of pulmonary hypertension, seem to be also useful for essential hypertension and RH as well. Studies into the development of new dual ET inhibitors, which inhibit both type A and B ET (ET A and ET B ) receptors, present initial results of managing RH. Aprocitentan (ACT-132577) is a novel, orally active and well tolerated dual ET receptor antagonist, which has been examined in several experimental studies and clinical trials with promising results for RH control. The recent publication of the large PRECISION study in The Lancet journal provides further reassurance regarding the efficacy and safety of aprocitentan for RH, with the aim of overcoming unmet needs in the management of this difficult group of patients.

Familial hypercholesterolemia (FH) and type 2 diabetes mellitus (T2DM) are both associated with a high risk of atherosclerotic cardiovascular disease (ASCVD). Little is known about the prevalence of T2DM and its association with ASCVD risk in FH patients. This was a cross-sectional analysis from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH) including adults with FH (n = 1719, mean age 51.3 ± 14.6 years). Of FH patients, 7.2% had a diagnosis of T2DM. The prevalence of ASCVD, coronary artery disease (CAD), and stroke was higher among subjects with T2DM compared with those without (55.3% vs. 23.3%, 48.8% vs. 20.7%, 8.3% vs. 2.7%, respectively, p < 0.001). When adjusted for age, systolic blood pressure, smoking, body mass index, hypertension, waist circumference, triglyceride levels, high-density lipoprotein cholesterol levels, and gender, T2DM was significantly associated with prevalent ASCVD [OR 2.0 (95% CI 1.2−3.3), p = 0.004]. FH patients with T2DM were more likely to have undergone coronary revascularization than those without (14.2% vs. 4.5% for coronary artery bypass graft, and 23.9% vs. 11.5% for percutaneous coronary intervention, p < 0.001). T2DM is associated with an increased risk for prevalent ASCVD in subjects with FH. This may have implications for risk stratification and treatment intensity in these patients.

Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D., Competing Interests: Declaration of competing interest NK has given talks, attended conferences and participated in trials sponsored by Amgen, Astra Zeneca, Boehringer Ingelheim, Elpen, Menarini, Novartis, Novo Nordisk, Sanofi, Servier, Vianex and Viatris. None is related to the work presented herein. CSM reports (for last year) grants through his institution from Merck, has been a shareholder of and has received grants through his Institution and personal consulting fees from Coherus Inc. and AltrixBio, reports personal consulting fees and support with research reagents from Ansh Inc., collaborative research support from LabCorp Inc., reports personal consulting fees from Amgen, Corcept, Regeneron, Madrigal, 89Bio, reports travel support and fees from TMIOA, Elsevier, College Internationale Researche Servier and the Cardio Metabolic Health Conference. None is related to the work presented herein. AD, NR, CB, AF and ES have nothing to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is closely related with the metabolic syndrome and cardiovascular disease. Currently there is no approved medication for NAFLD. Although it has been suggested that statins can be safely used by patients with elevated liver enzymes, their effect on NAFLD has not been clearly defined. The aim of this study is to evaluate the effectiveness of statins on biochemical and histological parameters in patients with NAFLD., Methods: We searched PubMed, Web of Science, and SCOPUS for clinical trials and observational studies concerning the effects of statins on the development and treatment of NAFLD, regardless of the type or dosage of statin, the duration of treatment or the methods used for the diagnosis of NAFLD (biopsy or imaging technique) up to November 2021., Results: We identified 13 studies. Liver function tests and lipid profile were significantly improved. There was a significant decrease in steatosis grade (standardized mean difference, SMD -1.73, 95% CI -2.11 to -1.35; p < 0.00001; I 2  = 98%) and in NAFLD activity score (NAS) (SMD -1.09 (95% CI -1.39 to -0.79; p < 0.00001; I 2  = 93%))., Conclusions: Statins effectively decrease liver enzymes and beneficially affect liver histology in NAFLD patients., Competing Interests: Conflicts of interest Over the past 3 years, CSM has been a shareholder of and reports grants through his Institution and personal consulting fees from Coherus Inc and AltrixBio, he reports grants through his institution from Merck, he reports grants through his institution and personal consulting fees from Novo Nordisk, reports personal consulting fees and support with research reagents from Ansh Inc, reports personal consulting fees from Genfit, Lumos, Amgen, Corcept, Intercept, Astra Zeneca and Regeneron, reports support (educational activity meals at and through his institution) from Amarin, Novo Nordisk and travel support and fees from TMIOA, Elsevier, College Internationale Researche Servier and the Cardio Metabolic Health Conference. None is related to the work presented herein. C.S.M. also reports that he was member of the California Walnut Commission Scientific Advisory Board and has received travel and grant support by the California Walnut Commission, outside the submitted work. The remaining authors declare no conflicts of interest. The remaining authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Adhering to specific dietary patterns might hold promise as a lifestyle modification treatment of non-alcoholic fatty liver disease (NAFLD). The aim of this systematic review was to examine the effect of dietary patterns on changes in hepatic fat content, liver enzymes and metabolic syndrome components. We searched Pubmed, Embase, CINAHL and Web of Science for randomised controlled trials published in English until April 2020, comparing a specific dietary pattern with no treatment, usual care, or a different diet in adults with NAFLD. Studies were included if NAFLD had been diagnosed using biopsy, magnetic resonance imaging, or proton magnetic resonance spectroscopy. Data from three trials in adults with NAFLD but without diabetes (n = 128; mean age 49.9 ± 5.0 years, range 42-55 years) were included in the qualitative synthesis; across them, risk of bias was considered low, unclear and high for 33%, 38% and 29% of domains, respectively. There was moderate evidence that a low-carbohydrate, compared to a low-calorie diet (-27%, P = 0.008, one study, n = 18) and the Mediterranean, compared to a low-fat, high-carbohydrate diet (-4.4%, P = 0.030, one study, n = 12) result in greater reductions in hepatic fat content, but no such evidence was found for the Fatty Liver in Obesity dietary pattern (based on the principles of the Mediterranean diet), compared to the American Heart Association diet (-0.6%, P = 0.706, one study, n = 98). No between-group differences were reported for other outcomes across studies. A post hoc analysis, including two eligible studies assessing the effect of the Mediterranean, compared to a low-fat diet, irrespective of baseline presence of diabetes, showed strong evidence that the Mediterranean diet reduces hepatic fat content (-4.1%, 95% CI = -5.8 to -2.3, P < 0.001; I 2  = 0%) and triglyceride concentrations (-16.9 mg/dL, 95% CI = -26.3 to -7.7, P < 0.001; I 2  = 0%). Well-designed, adequately powered and rigorous randomised controlled trials are needed to provide robust evidence on the effect of these dietary patterns, but also other whole dietary approaches, on NAFLD progression., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Humanin (HN) is a 24-amino acid mitochondrial-derived polypeptide with cyto-protective and anti-apoptotic effects that regulates the mitochondrial functions under stress conditions. Accumulating evidence suggests the role of HN against age-related diseases, such as Alzheimer's disease. The decline in insulin action is a metabolic feature of aging and thus, type 2 diabetes mellitus is considered an age-related disease, as well. It has been suggested that HN increases insulin sensitivity, improves the survival of pancreatic beta cells, and delays the onset of diabetes, actions that could be deployed in the treatment of diabetes. The aim of this review is to present the in vitro and in vivo studies that examined the role of HN in insulin resistance and diabetes and to discuss its newly emerging role as a therapeutic option against those conditions., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to declare., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction : Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce blood glucose and glycosylated hemoglobin (HbA1c), the risk of hospitalization for heart failure (HF) and the incidence of serious adverse kidney function events (chronic kidney disease, CKD) in patients with type 2 diabetes mellitus (T2DM). Ertugliflozin is the last SGLT2i approved by Food and Drug Administration (FDA) in the USA and European Medical Agency (EMA) in Europe for the treatment of T2DM alone or in combination with other drugs. Areas covered : The authors critically discuss in this drug evaluation the safety and efficacy of the ertugliflozin + metformin combination in patients with T2DM without complications, those with CKD, or those with heart failure (HF). Furthermore, the authors discuss the results of the VERTIS CV trial ( MK-8835-004) , the trials NCT01986881 and NCT01986855 and other smaller studies. Expert opinion : The ertugliflozin + metformin combination is safe and effective in patients with T2DM with renal impairment, HF of any kind, or those without diabetic complications. These have practical implications that will help diabetologists, cardiologists, internists, nephrologists and general practitioners in selecting the proper combination of SGLT2i on top of metformin, if needed.

This document presents the consensus recommendations of the Hellenic Stroke Organization and the Hellenic Atherosclerosis Society for lipid modification in patients with ischemic stroke or transient ischemic attack. This clinical guide summarizes the current literature on lipid management and can be of assistance to the physicians treating stroke patients in clinical practice.

Introduction : Statins are powerful lipid-lowering agents which reduce cardiovascular (CV)-related morbidity and mortality. However, a large proportion of patients cannot attain the target low-density lipoprotein cholesterol (LDL-C) levels, despite receiving maximally tolerated doses of high-intensity statins. Also, adherence to treatment may be reduced due to statin-induced myopathy or other side effects. For these reasons, guidelines recommend adding the cholesterol absorption inhibitor ezetimibe. Areas covered : Authors discuss the main pharmacological characteristics of rosuvastatin and ezetimibe, their lipid-lowering and pleiotropic effects, as well as the clinical effects of the fixed dose combination of these drugs when used to treat dyslipidemia. Expert opinion : The rosuvastatin/ezetimibe combination is safe and effective in patients with hypercholesterolemia or dyslipidemia with or without diabetes and with or without cardiovascular disease. This drug combination enabled higher proportions of patients to achieve recommended LDL-C goals than rosuvastatin monotherapy or the simvastatin/ezetimibe combination, without additional adverse events. Despite the lack of additional CV outcomes data and comparisons with atorvastatin/ezetimibe, rosuvastatin/ezetimibe appears as a potent and generally well-tolerated drug combination eligible for the management of hypercholesterolemia and dyslipidemia in adults. Recently, the 40 mg rosuvastatin/10 mg ezetimibe fixed combination was approved and is also evaluated.

Background and Aims: We assessed the association of Mediterranean diet with NAFLD and their interaction in predicting ten-year diabetes onset and first fatal/non-fatal cardiovascular disease (CVD) incidence., Methods: The ATTICA prospective observational study in Athens, Greece included 1,514 men and 1,528 women (>18 years old) free-of-CVD at baseline. Liver steatosis and fibrosis indices were calculated. Mediterranean diet adherence was assessed through MedDietScore. At the ten-year follow-up visit, CVD evaluation was performed in an a priori specified subgroup of n = 2,020 participants and diabetes onset in n = 1,485 free-of-diabetes participants., Results: MedDietScore was inversely associated with steatosis and fibrosis; e.g. in the case of the TyG index the Odds Ratio (OR) of the 3rd vs. 1st MedDietScore tertile was = 0·53, [95% Confidence Interval (95% CI) (0·29, 0·95)] and the associations persisted in multi-adjusted models. NAFLD predicted incident diabetes prospectively over a ten year period [HR = 1·87, 95% CI (0·75, 4·61)] and the association remained significant only in subjects with low MedDietScore (below median) whereas diabetes onset among subjects with higher MedDietScore was not influenced by NAFLD. Similarly, NAFLD predicted CVD [Hazard Ratio (HR) = 3·01, 95%CI(2·28, 3·95)]; the effect remained significant only in subjects with MedDietScore below median [HR = 1·38, 95% CI (1·00, 1·93)] whereas it was essentially null [HR = 1·00,95% CI (0·38, 2·63)] among subjects with higher score. Mediation analysis revealed that adiponectin and adiponectin-to-leptin ratio were the strongest mediators., Conclusions: We report an inverse association between Mediterranean diet and NAFLD. Mediterranean diet protected against diabetes and CVD prospectively among subjects with NAFLD., Competing Interests: Conflict of interest See funding below. The rest of the authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Aims: Despite the established link between familial hypercholesterolemia (FH) and increased risk of coronary heart disease (CHD), its association with other common atherosclerotic and metabolic diseases has not been extensively studied. The aim of this study was to report the prevalence of peripheral arterial disease (PAD) [i.e., common carotid artery disease (CCAD) and lower extremity arterial disease (LEAD)], aortic valve stenosis, chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) in patients with FH., Materials & Methods: This was a cross-sectional study retrieving data from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH)., Results: A total of 1,633 adult patients (850 males) with heterozygous FH (HeFH) were included (mean age 51.3±14.6 years at registration and 44.3±15.9 years at diagnosis). Any common carotid artery stenosis (CCAS) was diagnosed in 124 out of 569 patients with available related data (21.8%), while the prevalence of CCAD (defined as a CCAS ≥50%) was 4.2%. The median (interquartile range - IQR) CCAS was 30% (20-40), whereas the median (IQR) carotid intima-media thickness (CIMT) was 0.7 (0.1-1.4) mm. LEAD was reported in 44 patients (prevalence 2.7%). The prevalence of aortic valve stenosis and CKD was 2.0% and 6.4%, respectively. NAFLD was present in 24% of study participants., Conclusion: HeFH is associated with a relatively high prevalence of any CCAS and CCAD. The prevalence of LEAD, CKD and aortic valve stenosis was relatively low, whereas the prevalence of NAFLD was similar to that of the general population., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease and important unmet medical need. Current guidelines recommend, under specific restrictions, pioglitazone or vitamin E in patients with NASH and significant fibrosis, but the use of both remains off-label. We summarize evidence on medications for the treatment of nonalcoholic steatohepatitis (NASH), since NASH has been mainly associated with higher morbidity and mortality. Some of these medications are currently in phase 3 clinical trials, including obeticholic acid (a farnesoid X receptor agonist), elafibranor (a peroxisome proliferator activated receptor [PPAR]-α/δ dual agonist), cenicriviroc (a CC chemokine receptor antagonist), MSDC-0602 K (a PPAR sparing modulator), selonsertib (an apoptosis signal-regulating kinase-1 inhibitor) and resmetirom (a thyroid hormone receptor agonist). A significant research effort is also targeting PPARs and selective PPAR modulators, including INT131 and pemafibrate, with the expectation that novel drugs may have beneficial effects similar to those of pioglitazone, but without the associated adverse effects. Whether these and other medications could offer tangible therapeutic benefits, alone or in combination, apparently on a background of lifestyle modification, i.e. exercise and a healthy dietary pattern (e.g. Mediterranean diet) remain to be proven. In conclusion, major advances are expected for the treatment of NASH., Competing Interests: Declaration of competing interest SAP: No conflict of interest. ESK: No conflict of interest. CB: No conflict of interest. EJR: No conflict of interest. CSM: served as a consultant for Aegerion, Regeneron, Coherus, Genfit and NovoNordisk, has received grants through his Institution by Coherus, Novo Nordisk and Esai and is shareholder of Coherus, Pangea Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chronic energy deficiency can impair the hypothalamic-pituitary-gonadal (HPG) axis and lead to hypothalamic anovulation in underweight women. This review presents the syndromes related to underweight status that are associated with infertility, summarizes the underlying mechanisms, and reviews the available treatment options. Eating disorders, such as anorexia nervosa (AN), constitute the most common cause of infertility in underweight women, who, in addition, experience miscarriages, and sexual dysfunction. The relative energy deficiency in sports (RED-S; former terminology: athlete's triad) involves menstrual dysfunction due to low energy availability, which results in anovulation. Moreover, lipodystrophies, malnutrition, starvation, systematic illnesses (malignancies, endocrinopathies, infectious diseases, advanced chronic diseases, neurologic illnesses), and the utilization of drugs can cause excessive weight loss. They may result in fertility problems due to the loss of adipose tissue and the subsequent hormonal disturbances. Each of these conditions requires multidisciplinary management. Nutritional counseling should target the restoration of energy balance by increasing intake and reducing output. Medical treatment, recommended only for patients who did not respond to standard treatment, may include antipsychotics, antidepressants, or leptin administration. Finally, psychiatric treatment is considered an integral part of the standard treatment., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: To investigate circulating levels and liver gene expression of 3 hormonal pathways associated with obesity, insulin resistance, and inflammation to identify leads towards potential diagnostic markers and therapeutic targets in patients with nonalcoholic fatty liver disease (NAFLD)., Methods: We compared circulating levels of (1) proglucagon-derived hormones (glucagon-like peptide [GLP]-1, GLP-2, glicentin, oxyntomodulin, glucagon, major proglucagon fragment [MPGF]), (2) follistatins-activins (follistatin-like [FSTL]3, activin B), (3) IGF axis (insulin-like growth factor [IGF]-1, total and intact IGF binding protein [IGFBP]-3 and IGFBP-4, and pregnancy-associated plasma protein [PAPP]-A) in 2 studies: (1) 18 individuals with early stage NAFLD versus 14 controls (study 1; early NAFLD study) and in (2) 31 individuals with biopsy proven NAFLD (15 with simple steatosis [SS] and 16 with nonalcoholic steatohepatitis [NASH]), vs 50 controls (24 lean and 26 obese) (study 2). Liver gene expression was assessed in 22 subjects (12 controls, 5 NASH, 5 NASH-related cirrhosis)., Results: Patients in early stages of NAFLD demonstrate higher fasting MPGF and lower incremental increase of glicentin during oral glucose tolerance test than controls. In more advanced stages, FSTL3 levels are higher in NASH than simple steatosis and, within NAFLD patients, in those with more severe lobular and portal inflammation. The IGF-1/intact IGFBP-3 ratio is lower in patients with liver fibrosis. Genes encoding follistatin, activin A, activin B, and the IGF-1 receptor are higher in NASH., Conclusion: MPGF and glicentin may be involved in early stages of NAFLD, whereas FSTL3 and IGF-1/intact IGFBP3 in the progression to NASH and liver fibrosis respectively, suggesting potential as diagnostic markers or therapeutic targets., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Renovascular hypertension (RVH) remains among the most prevalent and important, but also potentially reversible, causes of secondary hypertension. The predominant causes of renal artery stenosis (RAS) are atherosclerotic renovascular arterial stenosis (ARAS) and renal fibromuscular dysplasia. This condition can lead to progressive renal injury, cardiovascular complications and 'flash pulmonary edema'. Duplex Doppler ultrasonography, computed tomographic angiography and magnetic resonance angiography are the most commonly used diagnostic methods. There are three therapeutic options available: medical therapy including renin-angiotensin-aldosterone system antagonists, lipid-lowering agents, and antiplatelet therapy, percutaneous angioplasty with or without stent placement and surgical revascularization. Three large trials failed to demonstrate the superiority of renal artery revascularization over pharmaceutical therapy in controlling blood pressure and preserving renal function. For this reason, today revascularization is only recommended for patients with progressive worsening of renal function, recurrent 'flash pulmonary edema' and rapid increase in antihypertensive requirement in patients with previously well-controlled hypertension. However, more properly designed trials are needed in order to identify which patient populations would probably benefit from renal revascularization., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: To describe novel methods regarding innovation for pharmacists and student pharmacists to leverage local and national events, such as hackathons and innovation labs, that provide guidance and resources for developing novel products and solutions in health care., Data Sources: Not applicable., Summary: The profession of pharmacy exists in a diverse and complex system where collaboration is essential for innovation and can leverage existing resources to accelerate this. Hackathons occur over one or more days and offer a venue and resources to support innovation as interprofessional teams develop and pitch new product ideas for potential investment. Innovation labs serve as more permanent locations that offer resources and expertise to help realize ideas and guide development into potentially viable solutions and products for health care., Conclusion: Although currently hosted hackathons and design spaces may prove to be beneficial to pharmacists looking to innovate, they are frequently located in urban areas or large academic institutions that are not readily accessible to the larger pharmacy community. Fostering opportunities, whether as local hackathons or innovation labs, can potentially help to accelerate the innovation cycle for the pharmacy profession. These resources can be developed in local communities or through national pharmacy societies and organizations to increase access., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting 30% of the general population and 40% to 70% of obese individuals. Adipose tissue plays a crucial role in its pathogenesis, as it produces and secretes pro- and anti-inflammatory cytokines called adipokines. Adiponectin and leptin have well-determined actions in terms of NAFLD pathophysiology. Adiponectin deficiency is associated with a pro-inflammatory condition, as it is observed in obesity and other metabolic disorders. On the other hand, increased leptin levels, above the normal levels, act as a pro-inflammatory stimulus. Regarding other adipokines (resistin, visfatin, chemerin, retinol-binding protein 4, irisin), data about their contribution to NAFLD pathogenesis and progression are inconclusive. In addition, pharmacological agents like thiazolidinediones (pioglitazone and rosiglitazone), that are used in the management of NAFLD exert favourable effects on adipokine levels, which in turn may contribute to the improvement of liver function. This review summarizes the current knowledge and developments in the association between adipokines and NAFLD and discusses possible therapeutic implications targeting the modulation of adipokine levels as a potential tool for the treatment of NAFLD., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2018 Korean Endocrine Society.)

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease (30% of the general population) and up to 40% of cases advance to the more severe form of the disease: nonalcoholic steatohepatitis (NASH), which is causally related to cirrhosis and cardiovascular disease (CVD). There is no generally accepted effective treatment for NAFLD/NASH. The joint guidelines of the European Association for the Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD) and the European Association for the Study of Obesity (EASO) suggest the "off label" use of pioglitazone in patients without type 2 diabetes mellitus (T2DM) and pioglitazone in subjects with T2DM or vitamin E or their combination for the treatment of NASH; however pioglitazone has considerable limitations: weight gain, bone fractures in women, and heart failure. The aim of this narrative review is to assess the existing evidence supporting statin use for the treatment of NASH and the reduction of the high CVD risk of these patients. Animal data suggest that there is some benefit from statin use in liver histology in models of NASH. In humans, 3 post hoc analyses of randomised controlled trials (n=1,600, n=1,123, n=8,864) suggest that the use of atorvastatin (even in 80 mg/day) has a beneficial effect on NAFLD/NASH, in terms of liver enzyme reduction and ultrasonographic amelioration. Moreover, and most importantly, statin treatment halved CVD morbidity and mortality in statin-treated NAFLD/NASH patients compared with statin-treated participants with normal liver structure and function and reduced by 2/3rds CVD events in comparison with NAFLD/NASH patients that were not on a statin (90% of this population is not on statins because of the unjustified fear for liver damage). Three biopsy studies (n=20, n=107 and n=356) showed that statin treatment had a protective effect on steatosis, steatohepatitis and fibrosis. Data suggest that statin treatment in humans substantially improve or cure NAFLD/NASH, but above all substantially reduce CVD morbidity and mortality. Administration of potent statins appears safe and effective in saving lives in NAFLD/NASH patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: Arterial Stiffness (AS) and Non-Alcoholic Fatty Liver Diseases (NAFLD) are 2 related, prevalent, risk predictors of Cardiovascular Disease (CVD). We assessed the effect of low dose (5 mg/day) vs. high dose (20-40 mg/day) rosuvastatin on aortic elasticity and central haemodynamics as well as on NAFLD in patients with Arterial Hypertension (AH)., Methods: Forty patients with optimally controlled AH were randomised to 2 rosuvastatin doses and followed for 6 months. 24h AS was assessed by Mobil-O-Graph, which calculates (adjusted for age and gender) Pulse Wave Velocity (PWV), adjusted for Heart Rate (HR) augmentation index (AIx75%) and central haemodynamics. The diagnosis of NAFLD was based on >5% liver steatosis on ultrasound and moderately elevated serum levels of liver enzymes., Results: Both doses of rosuvastatin reduced Central Pulse Pressure (cPP), PWV and AIx75% (adjusted for HR) to normal values (p = NS adjusted for age, gender and HR). Liver enzymes were reduced in those with NAFLD to normal, but steatosis was reduced more by the 20-40 mg/day rosuvastatin dose (p=0.01) compared with the 5 mg/day dose., Conclusion: Both doses of rosuvastatin had a beneficial effect on AS; the high dose was more efficient in reducing PWVs and central haemodynamics, and also the high dose was more effective in ameliorating NAFLD. Given that AH control was optimal and lipid values attained targets, 4 other CVD predictors were also addressed. Larger and longer term studies are needed to demonstrate the clinical benefit of such treatment preference., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Statin treatment exhibits a beneficial effect on non-alcoholic fatty liver disease (NAFLD) and on cardiovascular disease (CVD) in patients with NAFLD., Objective: The aim of this review is to summarize the role of proprotein convertase subtilisin kexin type- 9(PCSK9) in the pathogenesis of NAFLD and discuss the effects of the new hypolipidaemic drugs PCSK9 inhibitors on NAFLD., Results: Data indicates that high intrahepatic or circulating PCSK9 levels increase muscle and liver lipid storage, adipose energy storage and hepatic fatty acids, as well as triglycerides storage and secretion, thus contributing to the pathogenesis of NAFLD. The findings of animal and human studies, aiming to reduce PCSK9 with inhibitors (human IGG antibodies, antisense particles against PCSK9 mRNA, and small anti PCSK9 antibodies) point towards liver protection from NAFLD through inhibition of PCSK9 expression in the induction of degradation of hepatic HNF1a protein, insulin resistance (IR), and other mechanisms., Conclusions: The use of PCSK9 inhibitors ameliorates NAFLD, aside from beneficial effects on CVD and independently of low density lipoprotein cholesterol level reduction., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The implications and prognosis of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) are substantially different. The aim of the present review is to describe and compare the pathological and clinical implications of these two conditions. Patients with NASH have a higher risk of progressing to cirrhosis than patients with NAFL but without steatohepatitis, who tend to have a non-progressive disease and only a minority progresses to NASH. Patients with NASH also are at greater risk to develop hepatocellular cancer (HCC) and NASH is the third commonest cause of HCC. In contrast, only few cases of HCC have been reported in patients with isolated NAFL. Given that nonalcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, it is also strongly related to cardiovascular disease (CVD). Again, it appears that patients with NASH have higher cardiovascular risk than patients with NAFL. Finally, all-cause mortality is also higher in patients with NASH than in patients with NAFL; mortality rates in the latter patients do not differ from the general population. In conclusion, NAFL and NASH have different prognosis and therefore it is imperative to develop accurate, noninvasive methods that will identify the presence of steatohepatitis in this population., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Competing Interests: Conflict of Interest: The authors report no specific funding in relation to this research and there is no conflict of interest to disclose.