Cardiovascular Events In High-risk Patients Research Articles

Long-term lipoprotein apheresis reduces cardiovascular events in high-risk patients with isolated lipoprotein(a) elevation

Long-term lipoprotein apheresis reduces cardiovascular events in high-risk patients with isolated lipoprotein(a) elevation

GLP-1 in patients with myocardial infarction complicated by cardiogenic shock-an IABP-SHOCK II-substudy.

Glucagon-like peptide-1 (GLP-1) is a gut-derived peptide secreted in response to nutritional and inflammatory stimuli. Elevated GLP-1 levels predict adverse outcome in patients with acute myocardial infarction or sepsis. GLP-1 holds cardioprotective effects and GLP-1 receptor agonists reduce cardiovascular events in high-risk patients with diabetes. In this study, we aimed to investigate the capacity of GLP-1 to predict outcome in patients with cardiogenic shock (CS) complicating myocardial infarction. Circulating GLP-1 levels were serially assessed in 172 individuals during index PCI and day 2 in a prospectively planned biomarker substudy of the IABP-SHOCK II trial. All-cause mortality at short- (30days), intermediate- (1year), and long-term (6years) follow-up was used for outcome assessment. Patients with fatal short-term outcome (n = 70) exhibited higher GLP-1 levels [86 (interquartile range 45-130) pM] at ICU admission in comparison to patients with 30-day survival [48 (interquartile range 33-78) pM; p < 0.001] (n = 102). Repeated measures ANOVA revealed a significant interaction of GLP-1 dynamics from baseline to day 2 between survivors and non-survivors (p = 0.04). GLP-1 levels above vs. below the median proved to be predictive for short- [hazard ratio (HR) 2.43; 95% confidence interval (CI) 1.50-3.94; p < 0.001], intermediate- [HR 2.46; 95% CI 1.62-3.76; p < 0.001] and long-term [HR 2.12; 95% CI 1.44-3.11; p < 0.001] outcome by multivariate Cox-regression analysis. Elevated plasma levels of GLP-1 are an independent predictor for impaired prognosis in patients with myocardial infarction complicated by CS. The functional relevance of GLP-1 in this context is currently unknown and needs further investigations. www. gov Identifier: NCT00491036.

Cardiologists' knowledge and perceptions of the seasonal influenza immunisation

BackgroundSeasonal influenza immunisation reduces cardiovascular events in high-risk patients, but 50% do not receive routine immunisation. The perceptions and current role of cardiologists in recommending and prescribing influenza immunisation has not been well described. MethodsWe used an exploratory sequential mixed methods design. Semi-structured interviews of 10 cardiologists were performed to identify themes for quantitative evaluation. 63 cardiologists undertook quantitative evaluation in an online survey. The interviews and surveys addressed (a) attitudes and behaviours regarding influenza immunisation and (b) preventative care in cardiology. ResultsOne quarter (25.4%, n = 16) of cardiologists recommended influenza immunisation to all patients. Less than half (49.2%, n = 31) recommended influenza immunisation to secondary prevention patients. Almost 1/3 of respondents (31.7%, n = 20) were uncertain or unaware of the guidelines regarding influenza immunisation and patients with cardiac disease. Most cardiologists believed that general practitioners were responsible for ensuring patients received influenza immunisation (76.2%, n = 48). ConclusionsDespite reducing cardiovascular events in high-risk patients, influenza immunisation is not widely recommended by cardiologists. Further clinician education is needed to address the knowledge gaps which prevent recommendation and uptake of this guideline directed treatment.

Abstract 16909: Eicosapentaenoic Acid and Docosahexaenoic Acid Have Competing Effects on Membrane Lipid Dynamics Due to Differences in Structure

Background: Omega-3 fatty acids (n3-FAs) incorporate into vascular cell membranes where they modulate protein function and signal transduction. The n3-FA eicosapentaenoic acid (EPA) delivered in ethyl ester form (icosapent ethyl) reduced a broad range of cardiovascular events in high-risk patients (REDUCE-IT). This was not observed with mixed n3-FA formulations containing docosahexaenoic acid (DHA) in STRENGTH and other trials. These discordant outcomes indicate DHA may counter certain EPA effects due to its additional carbons and double bond. We compared these n3-FA effects on membrane lipid dynamics and width, key determinants of protein function. Methods: Membrane lipid fluidity was measured by fluorescence anisotropy approaches in large unilamellar vesicles (LUVs) of 100 nm diameter containing 1-palmitoyl-2-oleoyl-3-sn-phosphatidylcholine (POPC) and 50 mol% cholesterol with EPA and/or DHA (0-10 mol%). LUVs were treated with the fluorescent probe, 1,6-diphenyl-1,3,5-hexatriene (DPH), at 1 mol% and evaluated using a spectrofluorometer with a polarization accessory. Membrane width ( i.e ., unit cell periodicity) of the samples was determined by small angle x-ray scattering (SAXS). Results: DHA alone increased bulk lipid fluidity as indicated by a dose-dependent reduction in apparent rotational correlation time (ARCT); at 10 mol%, there was a ~20% (p&lt;0.05) reduction from ~19 to ~16 nsec compared to control (untreated membranes). By contrast, EPA had no significant disordering effect except when combined at equimolar levels; the EPA/DHA combination showed a reduction in ARCT to ~18 nsec at 10 mol% that was different from EPA alone (p&lt;0.05). Consistent with these findings, SAXS analysis showed DHA containing membranes had a reduced width compared to EPA by 5% or 3 Å (p&lt;0.05) due to increased trans-gauche isomerizations in the phospholipid acyl chains. Conclusion: EPA maintained membrane fluidity while DHA increased fluidity and thereby reduced membrane width due to its additional carbons and double bond. The EPA/DHA combination increased membrane fluidity compared to control and EPA alone. The disordering effects of DHA may counter EPA stabilizing effects and explain discordant clinical outcomes with different n3-FA formulations.

Bridging the gap in cardiovascular care in diabetic patients: are cardioprotective antihyperglycemic agents underutilized?

ABSTRACT Introduction Atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) are two major complications of type 2 diabetes (T2DM). Cardiovascular protection is a key objective, yet not fully reached in clinical practice. Areas covered Both glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM and SGLT2is in reducing hospitalization for HF in placebo-controlled randomized trials. However, real-life studies worldwide revealed that only a minority of patients with T2DM receive either a GLP-1RA or an SGLT2i and surprisingly even less patients with established ASCVD or HF are treated with these cardioprotective antihyperglycemic agents. Expert opinion Bridging the gap between evidence-based cardiovascular protection with GLP-1RAs and SGLT2is and their underuse in daily clinical practice in patients with T2DM at high risk is crucial from a public health viewpoint. However, the task appears hazardous and the goal not attained considering the current failure. Education of specialists/primary care physicians and patients is critical. Multifaceted and coordinated interventions involving all actors (physicians, patients and broadly health-care system) must be implemented to stimulate the adoption of these cardioprotective antihyperglycemic medications as part of routine cardiovascular care among patients with T2DM.

Postoperative stellate ganglion block to reduce myocardial injury after laparoscopic radical resection for colorectal cancer: protocol for a randomised trial

IntroductionStellate ganglion block (SGB) is usually used in the department of algiatry. But preoperative SGB may reduce adverse cardiovascular events in high-risk patients, although evidence remains sparse. Therefore, we aim...

Long-term lipid apheresis reduces cardiovascular events in high-risk patients with isolated lipoprotein(A) elevation

Long-term lipid apheresis reduces cardiovascular events in high-risk patients with isolated lipoprotein(A) elevation

Relationship between Serum Proprotein Convertase Subtilisin/Kexin Type 9 Concentration and Prevalence of Coronary Artery Calcium in a Community-Based Sample of Japanese Men.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular events in high-risk patients. However, the influence of circulating PCSK9 concentration on atherosclerotic plaque formation in the general population remains unknown. We assessed the relationship between serum PCSK9 concentration and coronary artery calcium (CAC) prevalence in the general population. Community-dwelling Japanese men (n=622) aged 46-82 years without a history of cardiovascular disease and lipid-lowering medications were included. Serum PCSK9 concentration and CAC score were measured using the Agatston method, and the multivariable analysis was used to assess their association. CAC was defined as an Agatston score of ＞10. We conducted further analysis stratified by age (＜60, 60-69, and ≥ 70 years). The average age, LDL-C, and median serum PCSK9 concentration were 68 years, 122 mg/dL, and 240 ng/mL, respectively. After multivariable adjustment for traditional cardiovascular risk factors, no significant association was observed between serum PCSK9 concentration and CAC prevalence (adjusted relative risk [aRR] 1.05, 95% confidence interval [CI] 0.97-1.13). With age stratification, serum PCSK9 concentration was significantly associated with CAC prevalence in men aged ＜60 years (aRR 1.38, 95% CI 1.01-1.88) but not in men aged 60-69 years (aRR 0.96, 95% CI 0.85-1.10) or ≥ 70 years (aRR 1.08, 95% CI 0.99-1.19). A higher serum PCSK9 concentration was associated with a higher CAC prevalence in men aged ＜60 years, which was independent of traditional cardiovascular risk factors.

Eicosapentaenoic acid (EPA) treatment increased the ratio to arachidonic (EPA/AA) and reduced adhesion molecule expression in vascular endothelium during inflammation

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Amarin Pharmaceutical, Inc. Elucida Research LLC. Background Omega-3 fatty acid (n3-FA) treatment reduces cardiovascular (CV) risk in relation to circulating EPA/AA ratios. Treatment with icosapent ethyl (IPE), a highly purified EPA formulation, increased the EPA/AA ratio in treated patients (MARINE, ANCHOR). Unlike mixed n3-FA formulations, IPE reduced a composite of CV events in high-risk patients (REDUCE-IT) in relation to on-treatment EPA levels. These benefits of EPA may result in part from effects on vascular endothelial function and fatty acid content during inflammation. Purpose We measured the effect of EPA on human endothelial cells (HUVECs) during inflammatory activation, monitoring the release of soluble intercellular adhesion molecule-1 (sICAM-1) and changes in fatty acid content. Methods HUVECs were challenged with IL-6 (12 ng/mL) for 2 hours and then treated with EPA (40 µM) or vehicle for 24 hours. Total protein content was measured in cell lysates. Total fatty acids were extracted and derivatized using methanol containing 14% boron trifluoride to form fatty acid methyl esters (FAME). Gas chromatography measured total fatty acid content from C14-C24 and normalized to total protein. Levels of sICAM-1 were measured in cell supernatant using immunochemistry. Results EPA treatment increased the EPA/AA ratio by &amp;gt;20-fold compared to IL-6 treatment alone (1.55 ± 0.11 vs. 0.07 ± 0.003, p&amp;lt;0.001). The increased EPA/AA ratio correlated with EPA and docosapentaenoic acid (DPA) levels in lysates, which increased by 19-fold (26.71 ± 1.28 vs. 1.28 ± 0.05 mg/g protein, p&amp;lt;0.001) and 4-fold (29.42 ± 1.91 vs. 6.17 ± 0.36 mg/g protein, p&amp;lt;0.001), respectively, compared to IL-6. While IL-6 treatment increased sICAM-1 release (83%, p&amp;lt;0.001), subsequent treatment with EPA reduced sICAM-1 release by 39% (p&amp;lt;0.001). Conclusion In human ECs, EPA increased the EPA/AA ratio along with other n3-FAs under conditions of inflammation. Changes in the EPA/AA ratio correlated with reductions in sICAM-1 release with IL-6 exposure. As on-treatment EPA levels predict reduced CV risk, these direct vascular benefits of EPA may contribute to reduced CV risk observed in outcome trials.

The Use of Artificial Intelligence in Predicting Cardiovascular Events in High-Risk Patients

The article aims to explore the potential of artificial intelligence in predicting cardiovascular events in high-risk patients, by reviewing studies recent studies and the discussion of the advantages and limitations of artificial intelligence techniques in this area. The systematic review included 12 studies that addressed the application of artificial intelligence algorithms to predict cardiovascular events in high-risk patients, such as those with a prior history of cardiovascular disease, hypertension, or diabetes. The studies used a variety of data sources, including medical imaging, clinical data, and genomic information. The results showed that artificial intelligence algorithms were significantly more accurate than traditional cardiovascular risk prediction models, especially in identifying patients at high risk of cardiovascular events. However, the studies also highlighted some limitations in the application of artificial intelligence, such as the need for large training datasets and the lack of transparency in the interpretation of results. The studies also evaluated the performance of different artificial intelligence algorithms, including artificial neural networks, decision trees and reinforcement learning algorithms. Although the results were variable, in general, neural network algorithms showed the best accuracy in predicting cardiovascular events. Patients' characteristics were also evaluated in the studies, and it was observed that clinical variables such as age, sex, blood pressure and cholesterol were the main predictors of cardiovascular events. The inclusion of genomic data also showed potential to improve prediction accuracy. Finally, the review discussed the advantages and limitations of artificial intelligence in predicting cardiovascular events in high-risk patients. Although artificial intelligence has significant potential to improve prediction accuracy, its implementation in clinical practice must take into account the limitations of algorithms and the need for transparency in the interpretation of results. In summary, the review highlights the potential of artificial intelligence in predicting cardiovascular events in high-risk patients, but also underscores the importance of a careful approach in its implementation in clinical practice.

PS-BPP01-4: THE RELATIONSHIP BETWEEN SERUM PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 CONCENTRATION AND THE PREVALENCE OF CORONARY ARTERY CALCIUM

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular events in high-risk patients. However, the influence of circulating PCSK9 concentration on atherosclerotic plaque formation in the younger, healthy population is not fully elucidated. We assessed the relationship between serum PCSK9 concentration and coronary artery calcium (CAC) prevalence in the general population with no history of cardiovascular disease in different age group. Methods: Community-dwelling Japanese men (n = 622) aged 46–82 years, without a history of cardiovascular disease or lipid-lowering medications, were included. Serum PCSK9 concentration and CAC score were measured using the Agatston method, and CAC was defined as an Agatston score of &gt; 10. Multivariable Poisson regression with robust error variance were used to estimate the relative risk (RR) and 95% confidence interval (CI) per 1 SD of the serum PCSK9 concentration for the presence of CAC. We conducted further analysis stratified by age (&lt; 60, 60–69, and 70 ≦ years). Results: The average age, LDL-C, and median serum PCSK9 concentration were 68 years, 122 mg/dL, and 240 ng/mL, respectively. After multivariable adjustment for traditional cardiovascular risk factors, no significant association was observed between serum PCSK9 concentration and CAC prevalence (adjusted relative risk [aRR] 1.05, 95% CI 0.97–1.13). With age stratification, serum PCSK9 concentration was significantly associated with CAC prevalence in men aged &lt; 60 years (aRR 1.38, 95% CI 1.01–1.88), but not in men aged 60–69 years (aRR 0.96, 95% CI 0.85–1.10) or ≧ 70 years (aRR 1.08, 95% CI 0.99–1.19). Conclusions: A higher serum PCSK9 concentration was associated with a higher CAC prevalence in men aged &lt; 60 years, which was independent of traditional cardiovascular risk factors. The results of our study suggest that serum PCSK9 concentration might be associated with earlier-stage atherosclerosis.

Increased serum IL-6 is predictive of long-term cardiovascular events in high-risk patients submitted to coronary angiography: an observational study

BackgroundInterleukin-6 (IL-6) is an inflammation-related cytokine associated with an elevated risk of cardiovascular events. In a previous study, we demonstrated that increased IL-6 was predictive of sub-clinical atherosclerotic coronary disease in intermediate-risk patients undergoing coronary angiography. In the present study, we investigated whether increased serum IL-6 is predictive of cardiovascular events in high-risk patients.MethodsIn this observational study, consecutive patients referred for elective coronary angiography due to stable chest pain/myocardial ischemia had IL-6 measured immediately before the procedure. Long-term follow-up was performed by phone call or e-mail, and their clinical registries were revised. The primary outcome was a composite of new myocardial infarction, new ischemic stroke, hospitalization due to heart failure, new coronary revascularization, cardiovascular death, and death due to all causes.ResultsFrom 141 patients submitted to coronary angiography and IL-6 analysis, 100 had complete follow-up data for a mean of 5.7 years. The median age was 61.1 years, 44% were men, and 61% had type-2 diabetes. The median overall time-to-event for the primary outcome was 297 weeks (95% confidence interval [CI] 266.95–327.16). A receiver operator characteristic curve defined the best cut-off value of baseline serum IL-6 (0.44 pg/mL) with sensitivity (84.37%) and specificity (38.24%) to define two groups. High (> 0.44 pg/mL) IL-6 levels were predictive of cardiovascular events. (p for interaction = 0.015) (hazard ratio = 2.81; 95% CI 1.38–5.72, p = 0.01). Subgroup analysis did not find interactions between patients with or without diabetes, obesity, or hypertension.ConclusionIn conclusion, an interleukin-6 level higher than 0.44 pg/mL, obtained just before elective coronary angiography, was associated with a poorer prognosis after a mean of 5,7-year. A pre-procedure IL-6 below 0.44 pg/mL, on the other hand, has a very good negative predictive value, suggesting a good prognosis, and may be useful to better indicate coronary angiography in high-risk patients..

Evolocumab on top of empagliflozin improves endothelial function of individuals with diabetes: randomized active-controlled trial

BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2i) improve endothelial dysfunction and reduce cardiovascular events in individuals with type 2 diabetes (T2D). Proprotein convertase subtilisin/kexin 9 (PCSK9i) inhibitors reduce cardiovascular events in high-risk patients. Whether the addition of PCSK9i to SGLT2i treatment adds benefits is not known.ObjectivesTo assess the PCSK9-i effect on the endothelial function of T2D individuals under treatment with SGLT2-i.MethodsIndividuals with T2D were randomized in a 1:1 ratio to a 16-week treatment with either empagliflozin (E) or empagliflozin plus evolocumab (EE). The primary endpoint was post-treatment change from baseline in flow-mediated dilation (FMD) at 1-min. Secondary outcomes included changes in plasma levels of nitric oxide metabolites and isoprostane.ResultsA total of 110 patients were enrolled, the mean age was 58 years, and 71% were men. The median post-treatment change in FMD at 1-min was 2.7% (interquartile range [IQR]: 0.9%) and 0.4% (IQR: 0.9%) in the EE and E groups, respectively (p < 0.001). There was a greater increase in plasma levels of nitrate [5.9 (16.5) vs. 2.6 (11.8); p = 0.001] and nitrite [0.14 (0.72) vs. 0.02 (0.74); p = 0.025] in the EE group than in the E group, respectively. Isoprostane reduction was more pronounced in the EE group when compared to the E group [−1.7 (5.9) vs. −1.1 (5.3); p < 0.001).ConclusionsIn individuals with T2D, the addition of evolocumab on top of empagliflozin improves endothelial function.

Eicosapentaenoic Acid (EPA) Modulates Expression of Inflammatory Proteins in Pulmonary Endothelial Cells following Exposure to Air Pollution Particles

Lead Author's Financial Disclosures Nothing to disclose. Study Funding Amarin Pharma Inc. and Elucida Research. Background/Synopsis Air pollution contributes to global mortality by causing systemic inflammation and endothelial dysfunction in vascular disease, including atherosclerosis. The omega-3 fatty acid eicosapentaenoic acid (EPA) reduced cardiovascular events in high-risk patients (REDUCE-IT). EPA and omega-3 fatty acids can improve cardiac function and lipid levels in subjects exposed to air pollution particulate matter (PM) but underlying the mechanism is not understood. Objective/Purpose To test the ability of EPA to modulate expression of inflammatory proteins and related pathways in pulmonary endothelial cells following exposure to air pollution PMs of different sizes. Methods Human pulmonary ECs (PECs) were pretreated with EPA (40 micromolar) for 2 h before addition of particulate matter (PMs) with two different diameter ranges for 8 h. The PMs had an average of 5.9 micrometers from collected urban air (urban PMs) and 2.8 micrometers (fine PMs). PMs were delivered to the cells at 50 microgram/mL. Cell extracts from each treatment group were analyzed with LC/MS-based proteomics to measure relative expression levels of proteins. Only significant (p<0.05) changes in expression between treatment groups >1- fold were analyzed using differential enrichment analysis of proteomics data (DEP) and included in gene set enrichment analysis (GSEA). Results EPA significantly modulated expression of 205 and 347 proteins relative to fine and urban PMs, respectively. Among pathways modulated by both PMs was neutrophil degranulation (Gene Ontology ID: 0043312), where fine and urban PMs modulated 36 and 13 proteins, respectively. Common to both PMs were eight proteins, including 1.5-fold and 1.3-fold increases in C-X-C motif chemokine 6 (CXCL6). EPA treatment modulated 22 and 35 proteins associated with neutrophil degranulation compared to fine and urban PMs, respectively. Relative to fine PMs, EPA increased expression of heat shock protein 90-β; and decreased expression of interleukin enhancer-binding factor 2 (ILF2). Compared to urban PMs, EPA decreased expression of CXCL6 and increased expression of glutathione S-transferase P. Conclusions EPA significantly modulated expression of various inflammatory proteins in pulmonary ECs during exposure to multiple air pollution PMs. These findings support a novel vascular benefit for EPA under inflammatory conditions caused by air pollution PMs. Nothing to disclose.

Effect of omega-3 fatty acids on cardiovascular events in high-risk patients with hypertriglyceridemia in Japan: a 3-year post-marketing surveillance study (OCEAN3 survey)

Background Studies on the efficacy of prescription omega-3 polyunsaturated fatty acids to reduce cardiovascular events have produced conflicting results. Research design and methods This 3-year prospective post-marketing surveillance study evaluated the effect of omega-3-acid ethyl esters (O3AEE; usual dosage 2 g/day) on cardiovascular events in high-risk statin-treated Japanese patients with hypertriglyceridemia. Statin-treated patients not receiving O3AEE were included as a reference cohort. The composite primary endpoint was cardiovascular death, myocardial infarction, stroke, angina requiring coronary revascularization, or peripheral arterial disease requiring surgery or peripheral arterial intervention. Results At 3 years, Kaplan–Meier estimated cumulative incidence of the primary endpoint was 2.5% (95% confidence interval, 2.1%–2.9%) in O3AEE-treated patients (N = 6,580) and 2.7% (2.4%–3.1%) in non-O3AEE-treated patients (N = 7,784; hazard ratio, 0.99; 95% confidence interval, 0.79–1.23). Incidence of heart failure requiring hospitalization was 0.4% with O3AEE versus 0.8% in non-O3AEE-treated patients (hazard ratio, 0.47; 95% confidence interval, 0.28–0.78; P<0.05). Conclusions Among patients receiving statins, cardiovascular event incidence did not differ significantly between O3AEE-treated patients and non-O3AEE-treated patients. Further studies are required before definitive conclusions can be drawn on the effect of O3AEE on cardiovascular event incidence in high-risk patients with hypertriglyceridemia. Trial registration ClinicalTrials.gov, NCT02285166.

Cardiovascular Safety and Benefits of Semaglutide in Patients With Type 2 Diabetes: Findings From SUSTAIN 6 and PIONEER 6

To exclude an excess risk of cardiovascular (CV) events, CV outcomes trials (CVOTs) have assessed the effects of new glucose-lowering therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), in patients with type 2 diabetes and established CV disease or CV risk factors. The CV safety of semaglutide vs. placebo, when added to standard care, was evaluated in the SUSTAIN 6 trial for the formulation administered once-weekly subcutaneously and in PIONEER 6 for the new once-daily oral formulation. In SUSTAIN 6 and PIONEER 6, both powered to demonstrate noninferiority (upper 95% confidence interval [CI] of the hazard ratio [HR] <1.8), there were fewer first major adverse CV events with semaglutide vs. placebo, with HRs of 0.74 (95% CI 0.58–0.95) and 0.79 (0.57–1.11), respectively. In SUSTAIN 6, the results were significant for noninferiority and superiority, although the latter was not prespecified. Surprisingly, CV and all-cause mortality were significantly reduced by oral semaglutide in PIONEER 6. The ongoing SOUL CVOT will further inform about CV outcomes with oral semaglutide vs. placebo (NCT03914326). Findings from SUSTAIN 6 and PIONEER 6 fall within the spectrum reported with other GLP-1RA CVOTs: noninferiority vs. placebo for major CV events was seen with lixisenatide and exenatide extended-release, while superiority was demonstrated with liraglutide, albiglutide, and dulaglutide. Beneficial outcomes have been recognized in international guidelines, which recommend subcutaneous liraglutide, semaglutide, and dulaglutide to reduce the risk of CV events in high-risk patients. Both indirect mechanisms via risk factor modification and direct effects via GLP-1 receptors in the CV system have been proposed to be responsible for CV event reductions. The exact mechanism(s) remains to be characterized, but appears to be mainly linked to anti-atherosclerotic effects. Further research is needed to elucidate the relevant mechanisms for CV benefits of GLP-1RAs.

Cardiovascular, Renal, and Metabolic Outcomes of Dapagliflozin Versus Placebo in a Primary Cardiovascular Prevention Cohort: Analyses From DECLARE-TIMI 58

International guidelines propose prescribing sodium-glucose cotransporter 2 (SGLT2) inhibitors to patients with type 2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT2 inhibitors in MRF patients. In DECLARE-TIMI 58, 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) were randomized to dapagliflozin versus placebo; patients were followed for a median of 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction. Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF) (hazard ratio [HR] 0.84, 95% CI 0.67-1.04) and the renal-specific outcome (HR 0.51, 95% CI 0.37-0.69) did not differ from that for patients with ASCVD (P interaction 0.99 and 0.72, respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95% CI 0.46-0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA1c, weight, systolic blood pressure, and urinary albumin-to-creatinine ratio were lower with dapagliflozin versus placebo and estimated glomerular filtration rate was higher (P < 0.001). In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin for important outcomes in a broad primary prevention population.

Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk

It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins. The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%). Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients. ClinicalTrials.gov Identifier: NCT02104817.

Prognostic irrelevance of plaque vulnerability following plaque sealing in high-risk patients with type 2 diabetes: an optical coherence tomography study

BackgroundType 2 diabetes mellitus (T2DM) is associated with an increased cardiovascular risk related at least in part to a more vulnerable plaque phenotype. However, patients with T2DM exhibit also an increased risk following percutaneous coronary intervention (PCI). It is unknown if plaque vulnerability of a treated lesion influences cardiovascular outcomes in patients with T2DM. In this study, we aimed to assess the association of plaque morphology as determined by optical coherence tomography (OCT) with cardiovascular outcome following PCI in high-risk patients with T2DM.Methods81 patients with T2DM and OCT-guided PCI were recruited. Pre-interventional OCT and systematic follow-up of median 66.0 (IQR = 8.0) months were performed.ResultsDuring follow-up, 24 patients (29.6%) died. The clinical parameters age (HR 1.16 per year, 95% CI 1.07–1.26, p < 0.001), diabetic polyneuropathy (HR 3.58, 95% CI 1.44–8.93, p = 0.006) and insulin therapy (HR 3.25, 95% CI 1.21–8.70, p = 0.019) predicted mortality in T2DM patients independently. Among OCT parameters only calcium-volume-index (HR 1.71 per 1000°*mm, 95% CI 1.21–2.41, p = 0.002) and lesion length (HR 1.93 per 10 mm, 95% CI 1.02–3.67, p = 0.044) as parameters describing atherosclerosis extent were significant independent predictors of mortality. However, classical features of plaque vulnerability, such as thickness of the fibrous cap, the extent of the necrotic lipid core and the presence of macrophages had no significant predictive value (all p = ns).ConclusionClinical parameters including those describing diabetes severity as well as OCT-parameters characterizing atherosclerotic extent but not classical features of plaque vulnerability predict mortality in T2DM patients following PCI. These data suggest that PCI may provide effective plaque sealing resulting in limited importance of local target lesion vulnerability for future cardiovascular events in high-risk patients with T2DM.

Baseline interleukin1beta expression in peripheral blood monocytes predicts the extent of weight loss and nonalcoholic fatty liver improvement in obese subjects with prediabetes or type 2 diabetes

Abstract Background Non-alcoholic fatty liver disease (NAFLD) represents a hallmark of metabolic syndrome. Interleukin-1β (IL-1β), a well-studied cytokine involved in obesity-related systemic inflammation as well as in the pathogenesis of type 2 diabetes (T2D), promotes hepatic steatosis by stimulating triglycerides and cholesterol accumulation in primary liver hepatocytes and lipid droplets formation. The most compelling evidence for a major role for IL-1β in metabolic imbalance and inflammation comes from the recent Canakinumab Anti-inflammatory Thrombosis Outcome (CANTOs)trial, where inhibition of IL-1β pathway was associated with a reduction of cardiovascular events in high-risk patients. Purpose The present study was designed to determine: i)whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on NAFLD extent and IL-1β expression in peripheral blood mononuclear cells from obese subjects with prediabetes or early T2D; ii)whether baseline IL-1β levels may predict the extent of weight loss and related metabolic changes. Methods Thirty-two metformin-treated obese subjects with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n=16)] or newly diagnosed T2D (n=16), were randomized to the glucagon-like peptide receptor agonist (GLP-RA) liraglutide (1.8 mg/d) or lifestyle counselling until achieving a modest and comparable weight loss (−7% of initial body weight). Visceral (VAT) and adipose tissue distribution were assessed by magnetic resonance. Gene expression of IL-1β in peripheral blood mononuclear cells was assessed by real time PCR. Results At baseline, IL-1β positively correlated to body mass index (BMI) (rho=0.421, p=0.016), fasting plasma glucose (rho=0.415, p=0.018), HbA1c (rho=0.349, p=0.050), VAT (rho=0.388, p=0.028), NAFLD (rho=0.454, p=0.009), platelet count (rho=0.510, p=0.003), chemerin (rho=0.455, p=0.009) and interleukin-1 receptor agonist (IL1-RA) (rho=0.519, p=0.002). After achievement of the weight loss target in the two groups, a comparable reduction of IL-1 β (p&amp;lt;0.001 lifestyle changes; p=0.029 liraglutide treatment) was observed in both arms, in parallel with a comparable improvement in glycaemic control, C-reactive protein (CRP),BMI and NAFLD. Furthermore, basal levels of IL-1β correlated directly with delta BMI (p=0.015) and delta NAFLD (p=0.002) (Figure 1). Conclusion In obese patients with initial impairment of glucose metabolism, IL-β-driven inflammation correlates with glycaemic control, adipose tissue distribution and platelet count. Successful weight loss, achieved with either lifestyle changes or an incretin-based therapy, is associated with a significant reduction of both IL-1β levels and NAFLD degree. Of interest, basal levels of IL-1β predicts the extent of weight loss and NAFLD improvement, regardless of the intervention. Our results may set the stage for ad-hoc studies investigating the usefulness of baseline IL-1β a levels as a drug-response biomarker. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This study was supported by a grant from the Italian Ministry of University and Research (PRIN no. 2010JS3PMZ to F.S.).