The Effect of Semaglutide on Mortality and COVID-19-Related Deaths: An Analysis From the SELECT Trial.

BACKGROUND: Patients with overweight and obesity are at increased risk of death from multiple causes, including cardiovascular (CV) death, with few therapies proven to reduce the risk. OBJECTIVES: This study sought to assess the effect of semaglutide 2.4 mg on all-cause death, CV death, and non-CV death, including subcategories of death and death from coronavirus disease-2019 (COVID-19). METHODS: The SELECT (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity) trial randomized 17,604 participants ≥45 years of age with a body mass index ≥27 kg/m2 with established CV disease but without diabetes to once-weekly subcutaneous semaglutide 2.4 mg or placebo; the mean trial duration was 3.3 years. Adjudicated causes of all deaths, COVID-19 cases, and associated deaths were captured prospectively. RESULTS: Of 833 deaths, 485 (58%) were CV deaths, and 348 (42%) were non-CV deaths. Participants assigned to semaglutide vs placebo had lower rates of all-cause death (HR: 0.81; 95% CI: 0.71-0.93), CV death (HR: 0.85; 95% CI: 0.71-1.01), and non-CV death (HR: 0.77; 95% CI: 0.62-0.95). The most common causes of CV death with semaglutide vs placebo were sudden cardiac death (98 vs 109; HR: 0.89; 95% CI: 0.68-1.17) and undetermined death (77 vs 90; HR: 0.85; 95% CI: 0.63-1.15). Infection was the most common cause of non-CV death and occurred at a lower rate in the semaglutide vs the placebo group (62 vs 87; HR: 0.71; 95% CI: 0.51-0.98). Semaglutide did not reduce incident COVID-19; however, among participants who developed COVID-19, fewer participants treated with semaglutide had COVID-19-related serious adverse events (232 vs 277; P = 0.04) or died of COVID-19 (43 vs 65; HR: 0.66; 95% CI: 0.44-0.96). High rates of infectious deaths occurred during the COVID-19 pandemic, with less infectious death in the semaglutide arm, and resulted in fewer participants in the placebo group being at risk for CV death. CONCLUSIONS: Compared to placebo, patients treated with semaglutide 2.4 mg had lower rates of all-cause death, driven similarly by CV and non-CV death. The lower rate of non-CV death with semaglutide was predominantly because of fewer infectious deaths. These findings highlight the effect of semaglutide on mortality across a broad population of patients with CV disease and obesity. (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity [SELECT]; NCT03574597).

Blood pressure measurement and assessment of arterial structure and function: an expert group position paper.

Measuring blood pressure (BP) and investigating arterial hemodynamics are essential in understanding cardiovascular disease and assessing cardiovascular risk. Several methods are used to measure BP in the doctor's office, at home, or over 24 h under ambulatory conditions. Similarly, several noninvasive methods have been introduced for assessing arterial structure and function; these methods differ for the large arteries, the small ones, and the capillaries. Consequently, when studying arterial hemodynamics, the clinician is faced with a multitude of assessment methods whose technical details, advantages, and limitations are sometimes unclear. Moreover, the conditions and procedures for their optimal implementation, and/or the reference normality values for the parameters they yield are not always taken into sufficient consideration. Therefore, a practice guideline summarizing the main methods and their use in clinical practice is needed. This expert group position paper was developed by an international group of scientists after a two-day meeting during which each of the most used methods and techniques for blood pressure measurement and arterial function and structure evaluation were presented and discussed, focusing on their advantages, limitations, indications, normal values, and their pragmatic clinical application.

iPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial Hypercholesterolemia.

Defects in the low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. LDLR deficiency in hepatocytes leads to elevated blood cholesterol levels, which damage vascular cells, especially endothelial cells, through oxidative stress and inflammation. However, the distinctions between endothelial cells from individuals with normal and defective LDLR are not yet fully understood. In this study, we obtained and examined endothelial derivatives of induced pluripotent stem cells (iPSCs) generated previously from conditionally healthy donors and compound heterozygous FH patients carrying pathogenic LDLR alleles. In normal iPSC-derived endothelial cells (iPSC-ECs), we detected the LDLR protein predominantly in its mature form, whereas iPSC-ECs from FH patients have reduced levels of mature LDLR and show abolished low-density lipoprotein uptake. RNA-seq of mutant LDLR iPSC-ECs revealed a unique transcriptome profile with downregulated genes related to monocarboxylic acid transport, exocytosis, and cell adhesion, whereas upregulated signaling pathways were involved in cell secretion and leukocyte activation. Overall, these findings suggest that LDLR defects increase the susceptibility of endothelial cells to inflammation and oxidative stress. In combination with elevated extrinsic cholesterol levels, this may result in accelerated endothelial dysfunction, contributing to early progression of atherosclerosis and other cardiovascular pathologies associated with FH.

Comparative Efficacy and Safety of Statin Monotherapy and Statin plus Ezetimibe Combination in a Real-World Setting.

BACKGROUND: The objective of this study was to conduct a comparative evaluation of the effectiveness of ezetimibe in combination with statins or statin monotherapy in patients with hypercholesterolemia in a real-world setting. METHODS: It was a retrospective multicenter observational study conducted in Russia. We included patients who received statins or a combination of statins with ezetimibe for ≥3 months. The primary endpoint of this study was the frequency of achieving low-density lipoprotein cholesterol (LDL-C) goal levels at the time of enrollment in the study (%). RESULTS: The full analysis set consisted of 1000 patients: 250 subjects in the statin monotherapy group and 750 subjects in the combination group. The groups did not differ in clinical, demographic, or laboratory variables, except for a higher prevalence of hypertension and higher baseline lipid values in the statin monotherapy group. During treatment, the LDL-C concentration decreased by 1.10 ± 1.04 mmol/L (change of -27.5 ± 28.5% from baseline) in the statin monotherapy group and by 1.55 ± 1.17 mmol/L (change of -38.2 ± 25.6% from baseline) in the combination therapy group, p < 0.001. The target LDL-C level was achieved in 22.4% of the patients in the monotherapy group compared with 28.8% of the patients in the combination therapy group, p = 0.049. CONCLUSIONS: In real-world clinical practice, statin/ezetimibe combination therapy demonstrated a more frequent achievement of target LDL-C levels compared with statin monotherapy. The addition of ezetimibe to statin therapy increased the probability of achieving LDL-C level goals by 29%.

Effectiveness and Safety of Fenofibrate in Routine Treatment of Patients with Hypertriglyceridemia and Metabolic Syndrome.

Background: Multiple trials have demonstrated the efficacy of fenofibrate for the management of dyslipidemia. Real-world evidence may provide important insights into the effectiveness and safety of fenofibrate in patients with metabolic syndrome and elevated triglyceride (TG) levels, but such evidence is currently scarce. MATERIALS AND METHODS: A non-interventional study was conducted among routine healthcare providers. Patients with TG levels of >2.3 mmol/L on stable statin therapy starting fenofibrate treatment were enrolled. Data on medical history, fenofibrate treatment, change in lipid levels, and C-reactive protein (CRP) were collected from medical records every 3 months for 6 to 7 months of observation. RESULTS: Overall, 988 patients receiving fenofibrate were enrolled (median age [95% CI] 60 [26.0-86.0] years), and 46.4% of the participants were females. Most patients had concomitant cardiovascular disease. A baseline TG level of 3.6 ± 1.5 mmol/L was reduced by 50.1% to 1.7 ± 0.58 mmol/L at 6 months of treatment (p < 0.001). Baseline non-high-density lipoprotein cholesterol (non-HDL-C) levels decreased by 33.7% at 6 months. Total cholesterol and low-density lipoprotein levels by the end of follow-up were reduced by 24.7 and 25.5% (p < 0.001 for both). C-reactive protein level decreased more than 39% from baseline. CONCLUSIONS: Fenofibrate in a real-world setting significantly reduced TG, LDL-C, and non-HDL-C levels. In addition, a C-reactive protein level reduction of 39% was achieved.

Lipoprotein(a) and Low-Molecular-Weight Apo(a) Phenotype as Determinants of New Cardiovascular Events in Patients with Premature Coronary Heart Disease.

BACKGROUND: Lipoprotein(a) (Lp(a)) is a genetic risk factor of atherosclerotic cardiovascular diseases (ASCVDs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is related to vascular inflammation and detected in atherosclerotic plaques. A temporary increase in the circulating concentration of PCSK9 and Lp(a) was shown in patients with myocardial infarction (MI). The aim of this study was to evaluate the role of the apo(a) phenotype and the Lp(a) concentration as well as its complex with PCSK9 in the development of cardiac events and MI in patients with a premature manifestation of coronary heart disease (CHD). METHODS: In a prospective study with retrospective data collection, we included 116 patients with premature CHD who were followed for a median of 14 years. The medical history and information on cardiovascular events after an initial exam as well as data on the levels of lipids, Lp(a), PCSK9, PCSK9-Lp(a) complex, and apo(a) phenotype were obtained. RESULTS: The patients were divided into two groups depending on the presence of a low- (LMW, n = 52) or high-molecular weight (HMW, n = 64) apo(a) phenotype. LMW apo(a) phenotype (odds ratio 2.3 (1.1 to 4.8), p = 0.03), but not elevated Lp(a) (1.9 (0.8-4.6), p = 0.13), was an independent predictor for the development of MI after adjustment for sex, age of CHD debut, initial lipids levels, and lipid-lowering treatment. The apo(a) phenotype also determined the relationship between Lp(a) and PCSK9 concentrations. The level of the PCSK9-Lp(a) complex was higher in LMW apo(a) patients. CONCLUSION: The LMW apo(a) phenotype is a risk factor for non-fatal MI in a long-term prospective follow-up of patients with premature CHD, and this link could be mediated via PCSK9.

Non-HDL-cholesterol in dyslipidemia: Review of the state-of-the-art literature and outlook.

Dyslipidemia refers to unhealthy changes in blood lipid composition and is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Usually, low-density lipoprotein-cholesterol (LDL-C) is the primary goal for dyslipidemia management. However, non-high-density lipoprotein cholesterol (non-HDL-C) has gained attention as an alternative, reliable goal. It encompasses all plasma lipoproteins like LDL, triglyceride-rich lipoproteins (TRL), TRL-remnants, and lipoprotein a [Lp(a)] except high-density lipoproteins (HDL). In addition to LDL-C, several other constituents of non-HDL-C have been reported to be atherogenic, aiding the pathophysiology of atherosclerosis. They are acknowledged as contributors to residual ASCVD risk that exists in patients on statin therapy with controlled LDL-C levels. Therefore, non-HDL-C is now considered an independent risk factor or predictor for CVD. The popularity of non-HDL-C is attributed to its ease of estimation and non-dependency on fasting status. It is also better at predicting ASCVD risk in patients on statin therapy, and/or in those with obesity, diabetes, and metabolic disorders. In addition, large follow-up studies have reported that individuals with higher baseline non-HDL-C at a younger age (<45 years) were more prone to adverse CVD events at an older age, suggesting a predictive ability of non-HDL-C over the long term. Consequently, non-HDL-C is recommended as a secondary goal for dyslipidemia management by most international guidelines. Intriguingly, geographical patterns in recent epidemiological studies showed remarkably high non-HDL-C attributable mortality in high-risk countries. This review highlights the independent role of non-HDL-C in ASCVD pathogenesis and prognosis. In addition, the need for a country-specific approach to dyslipidemia management at the community/population level is discussed. Overall, non-HDL-C can become a co-primary or primary goal in dyslipidemia management.

Lipoprotein(a) in an adult sample from the Russian population: distribution and association with atherosclerotic cardiovascular diseases.

Introduction: Lipoprotein(a) (Lp(a)) is recognized as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). The aim of this study was to estimate the distribution of Lp(a) levels in working age adults from the Russian population and to assess its association with ischemic heart disease (IHD), myocardial infarction (MI), stroke, diabetes mellitus (DM), and arterial hypertension (AH). Material and methods: This substudy of the population-based study "Epidemiology of Cardiovascular Diseases and their Risk Factors in Some Regions of the Russian Federation" (ESSE-RF) included 8461 subjects aged 25-64 years (63.7% women) without lipid-lowering drugs. Atherosclerotic cardiovascular disease was self-reported. Lp(a), apolipoproteins AI and B, and lipid and glucose levels in blood serum were determined. Results: The prevalence of Lp(a) ≥ 30 mg/dl was 20.5% and 23.0%, and prevalence of Lp(a) ≥ 50 mg/dl was 13.3% and 15.2%, in men and women, respectively. An association of Lp(a) with IHD, MI, and AH, but not with stroke and DM, was shown. A cut-off level of Lp(a) of 9 mg/dl was determined, above which there was increased frequency of MI (by 59.2%, p = 0.02), IHD (by 33.4%, p < 0.001), and AH (by 11.6%, p < 0.001). In the multivariate analysis only the association of Lp(a) with IHD (1.19 (1.01-1.41), p = 0.038) and MI (1.57 (1.06-2.38), p = 0.028) remained significant. Conclusions: Lipoprotein(a) level ≥ 30 mg/dl was detected in every fifth adult aged 25-64 years. Increased risk of MI and IHD starts at an Lp(a) serum level above 9 mg/dl.

The Concentration of PCSK9-Lp(a) Complexes and the Level of Blood Monocytes in Males with Coronary Atherosclerosis.

In this study we analyzed the concentration of lipoprotein(a) (Lp(a)), PCSK9-Lp(a) complexes and the circulating monocyte subsets in coronary atherosclerosis. For this study, 257 patients with coronary atherosclerosis and 68 patients without stenotic atherosclerosis in the coronary, carotid and lower extremity arteries (control group) were enrolled. The monocyte subpopulations (classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16++) were analyzed by direct immunofluorescence and flow cytometry. The Lp(a) and PCSK9-Lp(a) complexes in the serum were detected by ELISA. The concentration of Lp(a) was higher in the coronary atherosclerosis group compared with the controls (23.0 (9.1; 73.3) mg/dL versus 10.7 (4.7; 25.0) mg/dL, p < 0.05). No correlations between the level of Lp(a) and the concentration of the PCSK9-Lp(a) complexes, nor between the level of Lp(a) or PCSK9 and the total number of monocytes, were observed in either group. A slight positive correlation between the concentration of PCSK9-Lp(a) complexes and the absolute level of monocytes was obtained (r = 0.20, p = 0.002) in the patients with atherosclerosis due to the intermediate monocyte subsets (r = 0.33, p = 0.04). According to regression analysis, both the PCSK9-Lp(a) complexes concentration and BMI were related to the absolute number of blood monocytes in patients with atherosclerosis. Further studies are required to determine the pathogenetic contribution of PCSK9-Lp(a) complexes to the development of atherosclerosis.

Clearance and Utilization of Dicarbonyl-Modified LDL in Monkeys and Humans.

The kinetics of elimination of various dicarbonyl-modified low-density lipoproteins from the bloodstream of Macaca mulatta monkeys were investigated. The low-density lipoproteins (LDL) in the monkey blood plasma were isolated by density gradient ultracentrifugation and labeled in vitro with the fluorescent dye FITC; thereupon, they were modified with different natural low molecular-weight dicarbonyls: malondialdehyde (MDA), glyoxal, or methylglyoxal. The control native FITC-labeled LDL and dicarbonyl-modified FITC-labeled LDL were injected into the monkey's ulnar vein; thereafter, blood samples were taken at fixed time intervals during 24 h. The plasma level of FITC-labeled LDL was determined with spectrofluorimetry. The study established that glyoxal- and monkeysglyoxal-labeled LDL circulated in monkey virtually at the same time as native (non-modified) LDL. In contrast, MDA-modified LDL disappeared from the blood extremely rapidly. Administration of the PCSK9 inhibitor involocumab (which increases LDL utilization) to patients with coronary heart disease (CHD) was found to significantly reduce levels of MDA-modified LDL.