The effect of rosuvastatin alone or in combination with fenofibrate or omega-3 fatty acids on lipoprotein(a) levels in patients with mixed hyperlipidemia.

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.

Pathophysiological Mechanisms and Clinical Associations of Non-Alcoholic Fatty Pancreas Disease.

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.

High-density lipoprotein cholesterol and multiple myeloma: A systematic review and meta-analysis.

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.

High-Flow Nasal Oxygen for Severe COVID-19 Pneumonia in Greek Patients: A Prospective Observational Study.

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 PaO2/FiO2 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.

Lipoprotein(a), Interleukin-6 inhibitors, and atherosclerotic cardiovascular disease: Is there an association?

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.

GLP-1 analogs and regional adiposity: A systematic review and meta-analysis.

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.

Convalescent Plasma Treatment of Patients Previously Treated with B-Cell-Depleting Monoclonal Antibodies Suffering COVID-19 Is Associated with Reduced Re-Admission Rates.

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.

Medicines for Obesity: Appraisal of Clinical Studies with Grading of Recommendations, Assessment, Development, and Evaluation Tool.

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.

Hydropneumothorax as a complication of necrotizing pneumonia.

Introduction: Hydropneumothorax with a bronchopleural fistula is an infrequent but severe complication of necrotizing pneumonia associated with high morbidity and mortality. Few cases in the adult population have been reported. Case report: This is a case of a 76-year-old male patient who developed pneumonia caused by Pseudomonas aeruginosa and Klebsiella pneumoniae complicated by hydropneumothorax. He was managed conservatively with chest tube placement but denied surgical management and eventually died despite initial improvement. Conclusions: Early recognition and appropriate management of pneumonia complications, such as hydropneumothorax, including thoracic surgeon interventions, are crucial as this complication can be fatal. Factors like the patient's overall status, preferences, and comorbidities may have a crucial effect on clinical decisions and outcomes.

COVID-19 in Older Individuals Requiring Hospitalization.

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.

Increased Mortality in Elderly Patients Admitted with Hyponatremia: A Prospective Cohort Study.

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.

ANGPTL3 and Apolipoprotein C-III as Novel Lipid-Lowering Targets.

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-LRx), 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.

Differential pharmacology and clinical utility of dapagliflozin in type 2 diabetes.

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.

Emerging Fixed-Dose Combination Treatments for Hyperlipidemia.

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.

SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses.

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.

Novel Hypolipidaemic Drugs: Mechanisms of Action and Main Metabolic Effects.

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.