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Antonia Pagkali,1 Anastasios Makris,1 Kalliopi Brofidi,2 Aris P Agouridis,3,4 Theodosios D Filippatos2 1School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 2Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece; 3School of Medicine, European University Cyprus, Nicosia, Cyprus; 4Department of Internal Medicine, German Oncology Center, Limassol, CyprusCorrespondence: Theodosios D Filippatos, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece, Tel + (30)2810392960, Fax + (30)2810392359, Email filtheo@uoc.grAbstract: Non-Alcoholic Fatty Pancreas disease (NAFPD), characterized by fat accumulation in pancreatic tissue, is an emerging clinical entity. However, the clinical associations, the underlying molecular drivers, and the pathophysiological mechanisms of NAFPD have not yet been characterized in detail. The NAFPD spectrum not only includes infiltration and accumulation of fat within and between pancreatic cells but also involves several inflammatory processes, dysregulation of physiological metabolic pathways, and hormonal defects. A deeper understanding of the underlying molecular mechanisms is key to correlate NAFPD with clinical entities including non-alcoholic fatty liver disease, metabolic syndrome, diabetes mellitus, atherosclerosis, as well as pancreatic cancer and pancreatitis. The aim of this review is to examine the pathophysiological mechanisms of NAFPD and to assess the possible causative/predictive risk factors of NAFPD-related clinical syndromes.Keywords: non-alcoholic fatty pancreas disease, NAFPD, steatotic pancreatic disease, metabolic dysfunction-associated steatotic pancreatic disease, MASPD

Ioanna Papakitsou,1 George Vougiouklakis,1 Moses S Elisaf,2 Theodosios D Filippatos1 1Department of Internal Medicine, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion, Crete, Greece; 2Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, GreeceCorrespondence: Theodosios D FilippatosDepartment of Internal Medicine, School of Medicine, University of Crete, University Hospital of Heraklion, Voutes, Crete, Heraklion, Crete 71500, GreeceTel +30 281 340 2817Email filtheo@uoc.grAbstract: Dapagliflozin belongs in the family of sodium-glucose cotransporter 2 (SGLT2) inhibitors and acts by reducing glucose reabsorption in the proximal tubule. The aim of this review is to present the differential pharmacology and clinical utility of dapagliflozin. Dapagliflozin is orally administered, has a long half-life of 12.9 hours and (similar to empagliflozin) is a much weaker SGLT1 inhibitor compared with canagliflozin. Dapagliflozin significantly decreases glycated hemoglobin and fasting glucose levels in patients with type 2 diabetes mellitus (T2DM). The drug improves body weight, blood pressure, uric acid, triglycerides and high-density lipoprotein cholesterol. In the DECLARE-TIMI 58 trial, a large trial of 17,160 T2DM patients with established cardiovascular disease (CVD) or without established CVD but with multiple risk factors, dapagliflozin compared with placebo resulted in a significantly lower rate of the composite outcome of CVD death or hospitalization for heart failure (HHF); this effect was mainly due to a lower rate of HHF in the dapagliflozin group (HR: 0.73; 95%CI: 0.61–0.88), whereas no difference was observed in the rate of CVD death (HR: 0.98; 95%CI: 0.82–1.17). Moreover, dapagliflozin was noninferior to placebo with respect to major adverse CVD events. Dapagliflozin exerts beneficial effects on albuminuria. Additionally, in the DECLARE-TIMI 58 trial it significantly reduced the composite renal endpoint (40% decrease in glomerular filtration rate, end stage renal disease, or renal death) in both patients with established CVD and patients with multiple risk factors (overall HR: 0.53; 95%CI: 0.43–0.66). However dapagliflozin, like the other SGLT2 inhibitors, is associated with an increased risk of genital and urinary tract infections (usually mild mycotic infections) and acute kidney injury in cases of reduced extracellular volume. Dapagliflozin is a useful antidiabetic treatment which also exerts beneficial effects in the management of heart failure and diabetic kidney disease.Keywords: dapagliflozin, sodium-glucose cotransporter 2, cardiovascular disease, diabetes, kidney, adverse effects

Theodosios D Filippatos, Andromachi Makri, Moses S Elisaf, George Liamis Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece Abstract: Decreased serum sodium concentration is a rather frequent electrolyte disorder in the elderly population because of the presence of factors contributing to increased antidiuretic hormone, the frequent prescription of drugs associated with hyponatremia and also because of other mechanisms such as the “tea and toast” syndrome. The aim of this review is to present certain challenges in the evaluation and treatment of hyponatremia in the elderly population and provide practical solutions. Hyponatremia in elderly subjects is mainly caused by drugs (more frequently thiazides and antidepressants), the syndrome of inappropriate antidiuretic hormone secretion (SIAD) or endocrinopathies; however, hyponatremia is multifactorial in a significant proportion of patients. Special attention is needed in the elderly population to exclude endocrinopathies as a cause of hyponatremia before establishing the diagnosis of SIAD, which then requires a stepped diagnostic approach to reveal its underlying cause. The treatment of hyponatremia depends on the type of hyponatremia. Special attention is also needed to correct serum sodium levels at the appropriate rate, especially in chronic hyponatremia, in order to avoid the osmotic demyelination syndrome. In conclusion, both the evaluation and the treatment of hyponatremia pose many challenges in the elderly population. Keywords: sodium, prognosis, hypopituitarism, elderly, pituitary

Orlistat, an anti-obesity drug, is a potent and specific inhibitor of intestinal lipases. In light of the recent US FDA approval of the over-the-counter sale of orlistat (60 mg three times daily), clinicians need to be aware that its use may be associated with less well known, but sometimes clinically relevant, adverse effects. More specifically, the use of orlistat has been associated with several mild-to-moderate gastrointestinal adverse effects, such as oily stools, diarrhoea, abdominal pain and faecal spotting. A few cases of serious hepatic adverse effects (cholelithiasis, cholostatic hepatitis and subacute liver failure) have been reported. However, the effects of orlistat on non-alcoholic fatty liver disease are beneficial. Orlistat-induced weight loss seems to have beneficial effects on blood pressure. No effect has been observed on calcium, phosphorus, magnesium, iron, copper or zinc balance or on bone biomarkers. Interestingly, the use of orlistat has been associated with rare cases of acute kidney injury, possibly due to the increased fat malabsorption resulting from the inhibition of pancreatic and gastric lipase by orlistat, leading to the formation of soaps with calcium and resulting in increased free oxalate absorption and enteric hyperoxaluria. Orlistat has a beneficial effect on carbohydrate metabolism. No significant effect on cancer risk has been reported with orlistat.Orlistat interferes with the absorption of many drugs (such as warfarin, amiodarone, ciclosporin and thyroxine as well as fat-soluble vitamins), affecting their bioavailability and effectiveness. This review considers orlistat-related adverse effects and drug interactions. The clinical relevance and pathogenesis of these effects is also discussed. [ABSTRACT FROM AUTHOR]

The rising prevalence of obesity-related illnesses, such as metabolic steatotic liver disease (MASLD), represents a significant global public health concern. This disease affects approximately 30 % of the adult population and is the result of metabolic abnormalities rather than alcohol consumption. Additionally, MASLD is associated with an increased risk of cardiovascular disease (CVD), chronic liver disease, and a variety of cancers, particularly gastrointestinal cancers. Clonal hematopoiesis (CH) is a biological state characterized by the expansion of a population of blood cells derived from a single mutated hematopoietic stem cell. The presence of CH in the absence of a diagnosed blood disorder or cytopenia is known as clonal hematopoiesis of indeterminate potential (CHIP), which itself increases the risk of hematological malignancies and CVD. Steatotic liver disease may also complicate the clinical course of cancer patients receiving antineoplastic agents, a condition referred to as chemotherapy induced steatohepatitis (CASH). This review will present an outline of the various aspects of MASLD, including complications. Furthermore, it will summarize the existing knowledge on the emerging association between CHIP and MASLD and present the available data on patient cases with concurrent MASLD and hematological neoplasms. Finally, it will provide a brief overview of the chemotherapeutic drugs associated with CASH, the underlying pathophysiologic mechanisms and their clinical implications., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Lipoprotein(a) [Lp(a)] is a strong, genetically determined, pathogenetic factor of atherosclerotic cardiovascular disease (ASCVD). The aim of this post-hoc analysis was to compare the effect of hypolipidemic treatment on Lp(a) levels of patients with mixed hyperlipidemia., Material and Methods: We previously randomized patients with mixed hyperlipidemia (low-density lipoprotein [LDL-C] > 160 mg/dl and triglycerides > 200 mg/dl) to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or omega-3 fatty acids 2 g/day (RΩ group, n = 30). In the present post-hoc analysis, we included only the patients whose Lp(a) levels were assessed (16, 16 and 15 in the R, RF and RΩ groups, respectively). Lipid profile and Lp(a) were measured at baseline and after 3 months of treatment., Results: Significant reductions in total cholesterol, LDL-C, non-high-density lipoprotein-cholesterol (non-HDL-C) and triglyceride levels were observed in all groups. A significant increase in Lp(a) levels was noted in the R ( p = 0.017) and RF ( p = 0.029) groups, while no significant difference was seen in the RΩ group ( p = NS). Regarding Lp(a) elevations, no differences were found between groups. In the R group, a strong negative correlation between the changes in Lp(a) and LDL-C ( r = -0.500, p = 0.049) was observed, while a significant negative correlation between the changes in Lp(a) and triglycerides ( r = -0.531, p = 0.034) was noted in the RF group., Conclusions: Rosuvastatin and/or fenofibrate treatment increases Lp(a) levels in patients with mixed hyperlipidemia. Novel therapies should target Lp(a) level reduction to decrease the residual ASCVD risk in patients with mixed hyperlipidemia., Competing Interests: Theodosios D. Filippatos reports participation in advisory board for Lilly and lecture honoraria from Boehringer Ingelheim, Mylan, Astra Zeneca, Lilly, Recordati, Bausch Health, Servier, Viatris, Omega-Pharma and Innovis. Michael Kostapanos receives consultancy fees by GlaxoSmithKline (GSK) and Amarin Pharmaceuticals. He is also a Clinical Research Physician Director (as complementary worker by secondment) in the GSK Clinical Unit Cambridge. The remaining authors have no conflicts of interest to declare., (Copyright: © 2024 Termedia & Banach.)

Introduction: High-flow nasal oxygen (HFNO) and prone positioning may improve outcomes of coronavirus disease 2019 (COVID-19) patients treated in the intensive care unit (ICU). The aim of this study was to describe outcomes following the timely application of HFNO and prone positioning in COVID-19 patients treated in a ward setting., Methods: The study included 89 prospectively recruited subjects at the COVID-19 ward unit of the University Hospital of Heraklion, Greece, between March and December 2020., Results: Seventy-four (83%) of the 89 subjects in the study had severe COVID-19. Of those, 33 (45%) required HFNO treatment and prone positioning and 15 (45%) were transferred to the ICU, with 4 of them being intubated. Severe COVID-19 and HFNO needs were associated with an increased pneumonia severity index (PSI) score on admission and a worse PaO 2 /FiO 2 ratio. In multivariate analysis, PSI was the only independent predictor of subsequent HFNO needs (OR=1.022). Overall intubation and mortality rates were 5.6% and 3.4%, respectively., Conclusion: This study shows that for patients with severe COVID-19 hospitalized in medical wards, standard COVID-19 treatment, along with the timely utilization of HFNO and prone positioning, resulted in excellent outcomes with fewer ICU admission rates.

Background and Aims: To systematically investigate all relevant evidence on the association between high-density lipoprotein cholesterol (HDL-C) and multiple myeloma (MM)., Methods: We searched PubMed and Cochrane library databases (up to 20 September 2022) for studies with evidence on HDL-C in patients with MM. A qualitative synthesis of published prospective and retrospective studies for the role of HDL-C and other lipid profile parameters in MM was performed. Additionally, a meta-analysis on HDL-C mean differences (MD) between MM cases and controls was performed., Results: Fourteen studies (3 prospective, 11 retrospective) including 895 MM patients were eligible for this systematic review. Ten studies compared HDL-C levels in MM patients with healthy controls. In these 10 studies (n = 17,213), pooled analyses showed that MM patients had significantly lower HDL-C levels compared to healthy controls (MD: -13.07 mg/dl, 95% CI: -17.83, -8.32, p < 0.00001). Regarding secondary endpoints, total cholesterol (TC) (MD: -22.19 mg/dl, 95% CI: -39.08, -5.30) and apolipoprotein A-I (apoA-I) (-40.20 mg/dl, 95% CI: -55.00, -25.39) demonstrated significant decreases, while differences in low-density lipoprotein cholesterol (LDL-C) (MD: -11.33 mg/dl, 95% CI: -36.95, 14.30) and triglycerides (MD: 9.93 mg/dl, 95% CI: -3.40, 23.26) were not shown to be significant., Conclusions: HDL-C, as well as TC and apoA-I, levels are significantly decreased in MM. Hence, lipid profile parameters should be taken into account when assessing such patients., 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., (© 2023 The Authors.)

Background and Aims: Lipoprotein(a) [Lp(a)] and interleuking-6 (IL-6), an inflammation biomarker, have been established as distinct targets of the residual atherosclerotic cardiovascular disease (ASCVD) risk. We aimed to investigate the association between them, and the potential clinical implications in ASCVD prevention., Methods: A literature search was conducted in PubMed until December 31st, 2022, using relevant keywords., Results: Elevated lipoprotein(a) [Lp(a)] levels constitute the most common inherited lipid disorder associated with ASCVD. Although Lp(a) levels are mostly determined genetically by the LPA gene locus, they may be altered by acute conditions of stress and chronic inflammatory diseases. Considering its resemblance with low-density lipoproteins, Lp(a) is involved in atherosclerosis, but it also exerts oxidative, thrombotic, antifibrinolytic and inflammatory properties. The cardiovascular efficacy of therapies lowering Lp(a) by >90% is currently investigated. On the other hand, interleukin (IL)-1b/IL-6 pathway also plays a pivotal role in atherosclerosis and residual ASCVD risk. IL-6 receptor inhibitors [IL-6(R)i] lower Lp(a) by 16-41%, whereas ongoing trials are investigating their potential anti-atherosclerotic effect. The Lp(a)-lowering effect of IL-6(R)i might be attributed to the inhibition of the IL-6 response elements in the promoter region of the LPA gene., Conclusions: Although the effect of IL-6(R)i on Lp(a) levels is inferior to that of available Lp(a)-lowering therapies, the dual effect of the former on both inflammation and apolipoprotein (a) synthesis may prove of equal or even greater significance when it comes ASCVD outcomes. More trials are required to establish IL-6(R)i in ASCVD prevention and elucidate their interplay with Lp(a) as well as its clinical significance., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fotios Barkas has received honoraria from Amgen, Novartis, Novo Nordisc and Viatris.Petros P Sfikakis has received consultant fees from Actelion, Pfizer, Genesis, MSD, UCB, Boehringer Ingelheim, Enorasis, Farmaserv-Lilly, Gilead, Abbvie, and Novartis. He has received grants and research support from Abbvie, Roche, Pfizer, Faran, Amgen, Jannsen, Boehringer Ingelheim, and Gilead.Evangelos Liberopoulos reports personal fees and non-financial support from Amgen, personal fees from Servier, personal fees from Boehringer-Ingelheim, personal fees and non-financial support from AstraZeneca, personal fees from MSD, personal fees from Lilly, personal fees and non-financial support from Bayer, personal fees from Novartis, personal fees from Chiesi, outside the submitted work.Theodosios D. Filippatos reports participation in advisory board for Lilly and lecture honoraria from Boehringer Ingelheim, Mylan, Astra Zeneca, Lilly, Recordati, Bausch Health, Servier, Viatris, Omega-Pharma and Innovis.Kausik K. Ray has received honoraria for consulting, lectures from Kowa, Amgen, Regeneron Pharmaceuticals, Sanofi, Daiichi Sankyo, Pfizer, Viatris, AstraZeneca, Eli Lilly, Esperion, New Amsterdam Pharma, Novartis, Silence Therapeutics, Bayer, Boehringer Ingelheim, Novo Nordisk, SCRIBE, CRISPR, Cargene, Vaxxinity, Abbott, Resverlogix. In addition, he has received research grant support to his institution from Sanofi, Daiichi Sankyo, Amgen, Pfizer and MSD and support from the NIHR Imperial Biomedical Research Centre.Anastasios Makris and Aris P. Agouridis have no conflict of interest to declare., (© 2023 The Authors.)

Background: Glucagon-like peptide 1 (GLP-1) analogs regulate body weight and liver steatosis. Different body adipose tissue (AT) depots exhibit biological variability. Accordingly, GLP-1 analog effects on AT distribution are unclear., Objectives: To investigate GLP1-analog effects on adiposity distribution., Search Methods: PubMed, Cochrane, and Scopus databases were screened for eligible randomized human trials. Pre-defined endpoints included visceral AT (VAT), subcutaneous AT (SAT), total AT (TAT), epicardial AT (EAT), liver AT (LAT), and waist-to-hip ratio (W:H). Search was conducted until May 17, 2022., Data Collection and Analysis: Data extraction and bias assessment were performed by two independent investigators. Treatment effects were estimated using random effects models. Analyses were performed on Review Manager v5.3., Main Results: Out of the 367 screened studies, 45 were included in the systematic review and 35 were used in the meta-analysis. GLP-1 analogs reduced VAT, SAT, TAT, LAT, and EAT, with non-significant effects on W:H. Overall bias risk was low., Conclusions: GLP-1 analog treatment reduces TAT, affecting most studied AT depots, including the pathogenic VAT, EAT, and LAT. GLP-1 analogs may have significant roles in combating metabolic, obesity-associated diseases via reductions of key AT depot volumes., (© 2023 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Patients receiving treatment with B-cell-depleting monoclonal antibodies, such as anti-CD20 monoclonal antibodies, such as rituximab and obinutuzumab, either for hematological disease or another diagnosis, such as a rheumatological disease, are at an increased risk for medical complications and mortality from COVID-19. Since inconsistencies persist regarding the use of convalescent plasma (CP), especially in the vulnerable patient population that has received previous treatment with B-cell-depleting monoclonal antibodies, further studies should be performed in thisdirection. The aim of the present study was to describe the characteristics of patients with previous use of B-cell-depleting monoclonal antibodies and describe the potential beneficial effects of CP use in terms of mortality, ICU admission and disease relapse. In this retrospective cohort study, 39 patients with previous use of B-cell-depleting monoclonal antibodies hospitalized in the COVID-19 department of a tertiary hospital in Greece were recorded and evaluated. The mean age was 66.3 years and 51.3% were male. Regarding treatment for COVID-19, remdesivir was used in 89.7%, corticosteroids in 94.9% and CP in 53.8%. In-hospital mortality was 15.4%. Patients who died were more likely to need ICU admission and also had a trend towards a longer hospital stay, even though the last did not reach statistical significance. Patients treated with CP had a lower re-admission rate for COVID-19 after discharge. Further studies should be performed to identify the role of CP in patients with treatment with B-cell-depleting monoclonal antibodies suffering from COVID-19.

We evaluated the quality of evidence from phase III/IV clinical trials of drugs against obesity using the principles of Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. Our systematic review evaluates the quality of clinical evidence from existing clinical trials and not the pharmacological efficacy of anti-obesity therapies. A literature search using select keywords in separate was performed in PubMed and ClinicalTrials.gov databases for phase III/IV clinical trials during the last ten years. Our findings indicate that the quality of existing clinical evidence from anti-obesity trials generally ranges from low to moderate. Most trials suffered from publication bias. Less frequently, trials suffered from the risk of bias mainly due to lack of blindness in the treatment. Our work indicates that additional higher-quality clinical trials are needed to gain more confidence in the estimate of the effect of currently used anti-obesity medicines, to allow more informed clinical decisions, thus reducing the risk of implementing potentially ineffective or even harmful therapeutic strategies.

Older individuals have an increased risk for severe coronavirus disease 2019 (COVID-19) and a higher risk for complications and death. The aim of this study was to investigate the clinical characteristics of older patients admitted with COVID-19 and describe their outcomes. This was a retrospective cohort study of patients older than 65 years admitted to the COVID-19 Department of the University Hospital of Heraklion. Data recorded and evaluated included age, gender, Infectious Diseases Society of America (IDSA) severity score, Charlson comorbidity index (CCI), high-flow nasal oxygen (HFNO) use, admission to the Intensive Care Unit (ICU), laboratory exams, treatment administered, and outcome. In total, 224 patients were evaluated in the present study. The median age was 75 years and 105 (46.9%) were female. In 50 patients (22.7%), HFNO was used and 23 (10.3%) were admitted to the ICU. Mortality was 13.4% (30 patients). Patients that died had higher age, were more likely to be male, had an IDSA severity score of 3, had prior HFNO use, had been admitted to the ICU, and were also more likely to have a higher white blood cell (WBC) count, CRP, ferritin, procalcitonin, d-dimers, and troponin. A multivariate logistic regression analysis identified age and the need for HFNO use to be independently positively associated with mortality. To conclude, COVID-19 carries significant mortality in hospitalized older patients, which increases with age, while the need for HFNO also increased the likelihood of worse outcomes. Clinicians caring for patients with COVID-19 should bear in mind these two factors. Future studies could elaborate on the effect of new variants on the dynamics of mortality in older patients.

Fat accumulation in the pancreas associated with obesity and the metabolic syndrome (MetS) has been defined as "non-alcoholic fatty pancreas disease" (NAFPD). The aim of this review is to describe the association of NAFPD with obesity, MetS, type 2 diabetes mellitus (T2DM) and atherosclerosis and also increase awareness regarding NAFPD. Various methods are used for the detection and quantification of pancreatic fat accumulation that may play a significant role in the differences that have been observed in the prevalence of NAFPD. Endoscopic ultrasound provides detailed images of the pancreas and its use is expected to increase in the future. Obesity and MetS have been recognized as NAFPD risk factors. NAFPD is strongly associated with non-alcoholic fatty liver disease (NAFLD) and it seems that the presence of both may be related with aggravation of NAFLD. A role of NAFPD in the development of "prediabetes" and T2DM has also been suggested by most human studies. Accumulation of fat in pancreatic tissue possibly initiates a vicious cycle of beta-cell deterioration and further pancreatic fat accumulation. Additionally, some evidence indicates a correlation between NAFPD and atherosclerotic markers (e.g., carotid intima-media thickness). Weight loss and bariatric surgery decreases pancreatic triglyceride content but pharmacologic treatments for NAFPD have not been evaluated in specifically designed studies. Hence, NAFPD is a marker of local fat accumulation possibly associated with beta-cell function impairment, carbohydrate metabolism disorders and atherosclerosis., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Hyponatremia is the most common electrolyte disorder, commonly affecting older hospitalized individuals; however, the literature is not clear regarding its effect on mortality. The aim of this 2-year observational prospective cohort study was to evaluate the mortality and re-admission rates, the clinical and laboratory characteristics and the causes of hyponatremia in patients older than 65 years admitted with a corrected serum sodium of 130 mEq/L or less in an internal medicine ward of a tertiary Greek university hospital. During the observation period, 138 patients (mean age 80.5 years, 36.2% male) fulfilled the inclusion criteria and were prospectively followed for 1 year after admission. Symptoms of hyponatremia were present in 59.4% of patients. Hypovolemia was the main sole cause of hyponatremia, but in about one third of patients, hyponatremia was multifactorial. Only a low proportion of patients (12.3%) fulfilled the criteria of the syndrome of inappropriate antidiuresis (SIAD) at admission according to the current guidelines. The re-admission rates at 3- and 12-months following discharge was 34.2% and 51.8%, respectively. Mortality during hospitalization was 17.4% and was higher compared to non-hyponatremic admitted older patients, while the total mortality at 1 year after admission was 28.3%, indicating that hyponatremia at admission is a marker of significant mortality during and after hospitalization in elderly patients.

Purpose of Review: Despite significant progress in plasma lipid lowering strategies, recent clinical trials highlight the existence of residual cardiovascular risk. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (Apo C-III) have been identified as novel lipid-lowering targets., Recent Findings: Apo C-III and ANGPTL3 have emerged as novel regulators of triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C) levels. ANGPTL3 is an inhibitor of lipoprotein lipase (LPL), reducing lipolysis of Apo B-containing lipoproteins. Loss-of-function ANGPLT3 mutations are associated with reduced plasma cholesterol and TG, while novel ANGPLT3 inhibition strategies, including monoclonal antibodies (evinacumab), ANGPLT3 antisense oligonucleotides (IONIS-ANGPTL3-L Rx ), and small interfering RNA (siRNA) silencing techniques (ARO-ANG3), result in increased lipolysis and significant reductions of LDL-C and TG levels in phase I and II clinical trials. Similarly, Apo C-III inhibits LPL while promoting the hepatic secretion of TG-rich lipoproteins and preventing their clearance. Loss-of-function APOC3 mutations have been associated with reduced TG levels. Targeting of Apo C-III with volanesorsen, an APOC3 siRNA, results in significant reduction in plasma TG levels but possibly also increased risk for thrombocytopenia, as recently demonstrated in phase I, II, and III clinical trials. ARO-APOC3 is a novel siRNA-based agent targeting Apo C-III which is currently under investigation with regard to its lipid-lowering efficiency. ANGPTL3 and Apo C-III targeting agents have demonstrated striking lipid-lowering effects in recent clinical trials; however, more thorough safety and efficacy data are required. Here, we evaluate the role of ANGPLT3 and Apo C-III in lipid metabolism, present the latest clinical advances targeting those molecules, and outline the remaining scientific challenges on residual lipid-associated cardiovascular risk.

Competing Interests: TDF reports lecture honoraria from Boehringer Ingelheim, Mylan, Astra Zeneca, Lilly, Recordati, Bausch Health, Servier, and Innovis. The other authors state there is no conflict of interest.

Low-density lipoprotein cholesterol targets may not be achieved by statin monotherapy, especially in high-risk patients. Furthermore, in some patient subgroups, atherogenic dyslipidemia is observed. As a result, a combination of a statin with other hypolipidemic drugs may have additional benefits, especially in the form of a single tablet. The aim of this review is to present the novel fixed-dose drug combinations for the management of hyperlipidemia. Statins, ezetimibe, and fibrates have established their efficacy and safety in the treatment of hypercholesterolemia and hypertriglyceridemia. Clinical trials have shown that these hypolipidemic drug classes can be safely combined in order to augment the lipid-lowering efficacy. Furthermore, novel hypolipidemic drugs such as bembedoic acid and berberine have shown some promising initial results. The combination of different hypolipidemic regimens in a fixed-dose formulation can enhance the adherence to hypolipidemic treatment leading to improved outcomes. Moreover, complementary mechanisms of action of the combined hypolipidemic drugs may also provide additional benefits such as improvement in carbohydrate metabolism. As a result, fixed-dose combinations of hypolipidemic agents may provide an attractive option for the effective and safe management of hypercholesterolemia.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. Two trials have shown significant reductions of cardiovascular (CV) events with empagliflozin and canagliflozin, which could not be attributed solely to their antidiabetic effects. The aim of the review is the critical presentation of suggested mechanisms/hypotheses for the SGLT2 inhibitors' cardioprotection. The search of the literature revealed many possible cardioprotective mechanisms, because SGLT2 inhibitors (i) increase natriuresis and act as diuretics with unique properties leading to a reduction in preload and myocardial stretch (the diuretic hypothesis); (ii) decrease blood pressure and afterload (the blood pressure lowering hypothesis), (iii) favor the production of ketones, which can act as a 'superfuel' in the cardiac and renal tissue (the 'thrifty substrate' hypothesis), (iv) improve many metabolic variables (the metabolic effects hypothesis), (v) exert many anti-inflammatory effects (the anti-inflammatory effects hypothesis), (vi) can act through the angiotensin II type II receptors in the context of simultaneous renin-angiotensin-aldosterone-system (RAAS) blockade leading to vasodilation and positive inotropic effects (the RAAS hypothesis), (vii) directly decrease the activity of the upregulated in heart failure Na + -H + exchanger in myocardial cells leading to restoration of mitochondrial calcium handling in cardiomyocytes (the sodium hypothesis). Additionally, some SGLT2 inhibitors exhibit also SGLT1 inhibitory action possibly resulting in an attenuation of oxidative stress in ischemic myocardium (the SGLT1 inhibition hypothesis). Thus, many mechanisms have been suggested (and possibly act cumulatively) for the cardioprotective effects of SGLT2 inhibitors.

Over the last 3 decades, hypolipidaemic treatment has significantly reduced both Cardiovascular (CV) risk and events, with statins being the cornerstone of this achievement. Nevertheless, residual CV risk and unmet goals in hypolipidaemic treatment make novel options necessary. Recently marketed monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown the way towards innovation, while other ways of PCSK9 inhibition like small interfering RNA (Inclisiran) are already being tested. Other effective and well tolerated drugs affect known paths of lipid synthesis and metabolism, such as bempedoic acid blocking acetyl-coenzyme A synthesis at a different level than statins, pemafibrate selectively acting on peroxisome proliferator-activated receptor (PPAR)- alpha receptors and oligonucleotides against apolipoprotein (a). Additionally, other novel hypolipidaemic drugs are in early phase clinical trials, such as the inhibitors of apolipoprotein C-III, which is located on triglyceride (TG)-rich lipoproteins, or the inhibitors of angiopoietin-like 3 (ANGPTL3), which plays a key role in lipid metabolism, aiming to beneficial effects on TG levels and glucose metabolism. Among others, gene therapy substituting the loss of essential enzymes is already used for Lipoprotein Lipase (LPL) deficiency in autosomal chylomicronaemia and is expected to eliminate the lack of Low- Density Lipoprotein (LDL) receptors in patients with homozygous familial hypercholesterolaemia. Experimental data of High-Density Lipoprotein (HDL) mimetics infusion therapy have shown a beneficial effect on atherosclerotic plaques. Thus, many novel hypolipidaemic drugs targeting different aspects of lipid metabolism are being investigated, although they need to be assessed in large trials to prove their CV benefit and safety., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Numerous clinical trials have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors exert a favorable effect on the indices of renal function (albuminuria, glomerular filtration rate decline over time) and the incidence of hard renal endpoints such as renal death or time to initiation of renal replacement therapy., Materials and Methods: In this review, we describe in detail the evidence regarding the nephroprotective mechanisms of SGLT2 inhibitors and describe the risk factors that may predispose to the development of acute kidney injury in patients receiving these drugs., Results: Although the impact of these drugs on renal hemodynamics seems to represent the most important renoprotective mechanism of action, many other effects of these compounds, including beneficial effects on metabolism and blood pressure, have been proposed to contribute to the observed clinical benefit., Conclusions: SGLT2 inhibitors clearly act beneficially in terms of kidney function with many proposed mechanisms., (Copyright © 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: Current data suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may affect many metabolic pathways beyond lowering LDL cholesterol. The aim of the present manuscript is to present these so-called pleiotropic effects of PCSK9 inhibitors., Recent Findings: PCSK9 may affect the activity of other receptors beyond LDL receptors (LDLR), such as cluster of differentiation 36 (CD36), very-low-density-lipoprotein (VLDL) receptors, apolipoprotein (Apo) E receptors, LDLR-related protein 1 (LRP-1) and ATP-Binding Cassette Transporter (ABCA1). Thus, a role of PCSK9 in the development of atherosclerosis, in vascular wall inflammation and in platelet function has been suggested. Additionally, PCSK9 inhibitors may affect lipid variables beyond LDL cholesterol, carbohydrate variables, as well as they may affect brain and kidney function. Additionally, a controversial role of PCSK9 in sepsis, hepatitis C infection and Alzheimer's disease has been suggested., Summary: These possible pleiotropic effects of PCSK9 inhibitors need further research, as they may affect cardiovascular risk and provide further insights in the development of atherosclerosis and other diseases such as Alzheimer's disease or chronic viral infection and sepsis.

: Obesity predisposes for atrial fibrillation, heart failure, sudden cardiac death, renal disease and ischemic stroke, which are the main causes of cardiovascular hospitalization and mortality. As obesity and the cardiovascular effects on the vessels and the heart start early in life, even from childhood, it is important for health policies to prevent obesity very early before the disease manifestation emerge. Key roles in the prevention are strategies to increase physical exercise, reduce body weight and to prevent or treat hypertension, lipids disorders and diabetes earlier and efficiently to prevent cardiovascular complications.

: Obesity is a key factor for cardiovascular diseases and complications. Obesity is associated with hypertension, dyslipidemia and type II diabetes, which are the major predictors of cardiovascular disease in the future. It predisposes for atrial fibrillation, heart failure, sudden cardiac death, renal disease and ischemic stroke that are the main causes of cardiovascular hospitalization and mortality. As obesity and the cardiovascular effects on the vessels and the heart start early in life, even from childhood, it is important for health policies to prevent obesity very early before the disease manifestation emerge. Key roles in the prevention are strategies to increase physical exercise, reduce body weight and to prevent or treat hypertension, lipids disorders and diabetes earlier and efficiently to prevent cardiovascular complications.Epidemiology and mechanisms of obesity-induced hypertension, diabetes and dyslipidemia will be reviewed and the role of lifestyle modification and treatment strategies in obesity will be updated and analyzed. The best treatment options for people with obesity, hypertension, diabetes and dyslipidemia will discussed.

Clinical trials and meta-analyses have shown that statins can dose dependently increase the incidence of new-onset diabetes mellitus (DM) especially in patients with underlying abnormalities of carbohydrate homeostasis. Mendelian randomization studies support these findings since genetic variants in the gene encoding the target of statins, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, are associated with increased incidence of new-onset DM, suggesting that the so-called diabetogenic effect of statins is an "on-target effect" possibly related to their main mechanism of action, that is the increased low-density lipoprotein (LDL) receptor expression. Additionally, Mendelian randomization studies have shown that genetic variants as proxies of other drugs that increase LDL receptor expression (ezetimibe and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) also increase the risk of new-onset DM. This concept is supported by the fact of decreased DM prevalence in patients with familial hypercholesterolemia who have decreased LDL receptor expression. In contrast, hypolipidemic drugs, such as the cholesteryl ester transfer protein inhibitors, that decrease LDL cholesterol without directly interfering with the LDL receptor expression do not seem to detrimentally affect carbohydrate homeostasis. However, the clinical trials of ezetimibe and PCSK9 inhibitors have not shown an increased DM risk, possibly suggesting that other potential non-well-defined "off-target effects" of hypolipidemic drugs may affect carbohydrate homeostasis. Thus, the long-term effect of hypolipidemic drugs on DM risk depends not only on their final mechanism of hypolipidemic action but also on other "on-target" and "off-target" effects of these drugs.

Aims: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that affect serum electrolytes levels. The aim of this review is the detailed presentation of the associated mechanisms of the SGLT2 inhibitors-induced electrolyte abnormalities., Materials and Methods: Eligible trials and relevant articles published in PubMed (last search in July 2017) are included in the review., Results: SGLT2 inhibitors induce small increases in serum concentrations of magnesium, potassium and phosphate. The small increase in serum phosphate concentration may result in reduced bone density and increased risk of bone fractures, mainly seen with canagliflozin, but recent meta-analyses did not show increased risk of bone fractures with SGLT2 inhibitors., Conclusion: The increases in serum electrolytes levels may play a role in the cardiovascular protection that has been recently reported with empagliflozin and canagliflozin., (Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk factor, but other lipid variables such as triglycerides (TRGs), high-density lipoprotein cholesterol (HDL-C) and lipoprotein a [Lp(a)] also affect cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors significantly lower LDL-C concentration but also modestly improve the concentrations of TRGs and HDL-C and more robustly decrease Lp(a) levels. The review presents the associated mechanisms of the beneficial effects of PCSK9 inhibitors on the other than LDL-C lipid variables, including the effects on lipid/apolipoprotein secretion and clearance and the heteroexchange between lipoproteins, as well as the possible effects on other variables involved in lipid metabolism such as sortilin. Proprotein convertase subtilisin/kexin type 9 inhibitors improve the overall lipid profile, and these beneficial effects may play a role in the reduction of cardiovascular risk.

Sodium-glucose linked transporter type 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with positive cardiovascular and kidney effects. The aim of this review is to present the safety issues associated with SGLT2 inhibitors. Urogenital infections are the most frequently encountered adverse events, although tend to be mild to moderate and are easily manageable with standard treatment. Although no increased acute kidney injury risk was evident in the major trials, the mechanism of action of these drugs requires caution when they are administered in patients with extracellular volume depletion or with drugs affecting renal hemodynamics. Canagliflozin raised the risk of amputations and the rate of fractures in the CANVAS trial, although more data are necessary before drawing definite conclusions. The risk of euglycemic diabetic ketoacidosis seems to be minimal when the drugs are prescribed properly. Regarding other adverse events, SGLT2 inhibitors do not increase the risk of hypoglycemia even when co-administered with insulin, but a decrease in the dose of sulphonylureas may be needed. The available data do not point to a causative role of SGLT2 inhibitors on malignancy risk, however, these drugs should be used with caution in patients with known hematuria or history of bladder cancer. SGLT2 inhibitors seem to be safe and effective in the treatment of diabetes but more studies are required to assess their long-term safety.

Introduction: Type 2 diabetes mellitus has become a growing epidemic and therefore efficient treatment strategies that target its management are needed. The treatment of diabetic patients often requires the combination of antidiabetic drug classes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) block glucose reabsorption in the proximal renal tubules. Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glucose metabolism by blocking the enzyme that degrades incretins leading to increased insulin secretion. Areas covered: The aim of the review is to present the available data on pharmacokinetic properties/pharmacodynamics, metabolic and cardiovascular effects of empagliflozin plus linagliptin combination. Expert opinion: Both empagliflozin and linagliptin have established safety and efficacy in the treatment of diabetes. Available data demonstrate the absence of pharmacological interactions when the two drugs are given together. The complementary mechanisms of action would be expected to provide additive benefits on carbohydrate metabolism variables, but the results from clinical trials have shown that the empagliflozin/linagliptin combination provides only mild improvements of glycated hemoglobin compared with either monotherapy. However, the single-tablet formulation of empagliflozin/linagliptin is expected to provide better compliance and thus improved glycaemic control coupled with a favourable safety profile. Thus, the fixed-dose combination of empagliflozin/linagliptin has the capacity to both effectively and safely manage diabetic patients.

Gitelman syndrome is the most common inherited tubular disease resulting from mutations of the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter in the early distal convoluted tubules. The review presents the underlying pathophysiologic mechanisms of acid-base and electrolyte abnormalities observed in patients with Gitelman syndrome. The syndrome is usually characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria. Additionally, increased chloride excretion and renin/aldosterone levels, hypophosphatemia (occasionally), hyponatremia (rarely) and glucose intolerance/insulin resistance have been reported. The knowledge of the pathophysiologic mechanisms is useful for the treatment of patients with Gitelman syndrome as well as for the understanding of other tubular diseases.

The direct oral anticoagulant rivaroxaban is useful in various indications that include venous deep vein thrombosis prophylaxis/treatment after knee/hip replacement surgery and prevention of stroke in patients with non-valvular atrial fibrillation. Its mechanism of action has been mostly associated with hemorrhage-related adverse effects; thus a number of non-hemorrhage-related adverse effects of the drug have received less attention or go unrecognized. These adverse effects mainly include liver injury, hypersensitivity reactions, leukocytoclastic vasculitis and hair loss. Clinicians should be aware of these rare adverse reactions and advise their patients to contact them as soon as they observe any unexpected clinical response.

Aims: Body fat accumulation is implicated in the development of cardiovascular disease (CVD). Our objective was to explore potential associations between anthropometric indices and the 10-year CVD incidence in Greek adults without previous CVD., Methods: During 2001-2, we enrolled 3042 adults without CVD from the general population of Attica, Greece. In 2011-2, the 10-year study follow-up was performed, recording the CVD incidence in 1958 participants with baseline body mass index (BMI) ≥18.5kg/m 2 ., Results: The study 10-year CVD incidence was 15.8%, exhibiting a gradual increase according to the baseline body mass index (BMI) category. Baseline BMI ≥30kg/m 2 was related with significantly higher 10-year CVD risk compared to BMI <25kg/m 2 , even after adjustment for age and other known CVD risk factors. Baseline BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio and waist-to-hip-to-height ratio were independently associated with the 10-year CVD risk in multi-adjusted models. Gender-specific analyses showed that these associations were more evident in men compared to women, with baseline BMI exhibiting an independent association with the 10-year CVD incidence in men., Conclusions: Our results indicate that even simple anthropometric indices exhibit independent associations with CVD risk in a representative sample of the Greek general population without previous CVD., (Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with low-density lipoprotein (LDL) catabolism, but its serum concentration is not uniformly associated with cardiovascular disease in clinical studies. Obesity is linked with increased cardiovascular risk, but the effect of increased body weight and short-term weight loss on serum PCSK9 levels is not well studied., Material and Methods: The aim of this prospective pilot study was to assess differences in serum PCSK9 levels (determined with a quantitative sandwich enzyme immunoassay) between otherwise healthy drug-naïve obese subjects and healthy individuals with normal body weight. Additionally, PCSK9 levels were determined at baseline and after a 3-month weight-loss program with a low-fat diet in a randomly assigned subgroup of the obese subjects ( n = 15)., Results: Obese subjects ( n = 35) were older (age: 43 ±11 years) and had significantly higher body mass index, total cholesterol, triglycerides, LDL cholesterol (LDL-C), apolipoprotein B and homeostasis model assessment of insulin resistance (HOMA) index levels, as well as significantly lower high-density lipoprotein cholesterol (HDL-C) concentration, compared with normal-weight subjects ( n = 20, age: 35 ±6 years). Serum PCSK9 levels were significantly higher in obese subjects compared with normal-weight individuals, even after adjustment for age, LDL-C, triglycerides, HDL-C, apolipoprotein A1, apolipoprotein B, apolipoprotein E, glucose, insulin and HOMA index levels ( p = 0.018). Obese subjects experienced significant weight loss (from 109 ±22 to 104 ±23 kg, p < 0.01), but serum PCSK9 levels did not significantly change after the 3-month weight-loss program., Conclusions: Serum PCSK9 levels are higher in obese subjects than in normal-weight individuals. Short-term weight loss with a low-fat diet does not significantly affect PCSK9 levels.

Cholesteryl ester transfer protein (CETP) inhibitors significantly increase serum high-density lipoprotein cholesterol (HDL) cholesterol levels and decrease low-density lipoprotein cholesterol (LDL) cholesterol concentration. However, three drugs of this class failed to show a decrease of cardiovascular events in high-risk patients. A new CETP inhibitor, anacetrapib, substantially increases HDL cholesterol and apolipoprotein (Apo) AI levels with a profound increase of large HDL2 particles, but also pre-β HDL particles, decreases LDL cholesterol levels mainly due to increased catabolism of LDL particles through LDL receptors, decreases lipoprotein a (Lp(a)) levels owing to a decreased Apo (a) production and, finally, decreases modestly triglyceride (TRG) levels due to increased lipolysis and increased receptor-mediated catabolism of TRG-rich particles. Interestingly, anacetrapib may be associated with a beneficial effect on carbohydrate homeostasis. Furthermore, the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial showed that anacetrapib administration on top of statin treatment significantly reduces cardiovascular events in patients with atherosclerotic vascular disease without any significant increase of adverse events despite its long half-life. Thus, anacetrapib could be useful for the effective management of dyslipidemias in high-risk patients that do not attain their LDL cholesterol target or are statin intolerable, while its role in patients with increased Lp(a) levels remains to be established., Competing Interests: This review was conducted independently; no funding was received for writing this manuscript or for covering the costs to publish in open access. M.E. reports personal fees from Astra-Zeneca, grants and personal fees from Merck Sharp & Dohme, personal fees from Pfizer, Abbott, Sanofi-Aventis, Boehringer Ingelheim, Eli-Lilly and GlaxoSmithKline. A.K. and T.F. have given talks and attended conferences sponsored by various pharmaceutical companies, including Bristol-Myers Squibb, Pfizer, Lilly, Abbott, Amgen, AstraZeneca, Novartis, Vianex, Teva and Merck Sharp & Dohme.