Effect of Evolocumab on Atherogenic Lipoproteins During the Peri- and Early Postinfarction Period: A Placebo-Controlled, Randomized Trial.
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SUBMITTER: Leucker TM
PROVIDER: S-EPMC8323059 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Statins lower low-density lipoprotein cholesterol (LDL-C) and improve clinical outcomes in patients with atherosclerotic cardiovascular disease (CVD). Patients with acute coronary syndromes (ACS) often do not achieve LDL-C targets despite potent statin treatment, and have a particularly high risk of early recurrent events. Evolocumab, a proprotein convertase subtilisin/kexin type (PCSK9)-inhibitor resulting in rapid, marked LDL-C reduction, has been studied in hypercholesterolemic subjects without CVD and stabilized patients with CVD; the feasibility, safety, and efficacy of this treatment initiated in the acute phase of ACS remain unknown. We report the design of evolocumab for early reduction of LDL-cholesterol levels in patients with ACS (EVOPACS), a phase-3, multicenter, randomized, double-blind, placebo-controlled trial to assess the feasibility, safety, and LDL-C-lowering efficacy of evolocumab on top of atorvastatin 40 mg in patients with ACS. The primary endpoint is percent change in LDL-C from baseline to 8 weeks. Secondary endpoints are adverse events and serious adverse events. Against a background of beneficial cardiovascular effects of statins beyond LDL-C lowering and in view of preclinical evidence of similar effects of PCSK9 inhibition, the study will also address a variety of exploratory endpoints including the change in C-reactive protein and other inflammatory biomarkers; platelet reactivity; and occurrence of contrast-induced acute kidney injury and myocardial injury in patients undergoing cardiac catheterization. An intracoronary imaging sub-study will investigate the change from baseline in the lipid core burden index in non-culprit lesions, as assessed by serial near-infrared spectroscopy. Recruitment began in January 2018 and enrollment of 308 patients is planned.
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Project description:Changes in gene expression were consistent with mechanism of action and show that clinical response to treatment with belimumab is associated with significant decrease in profibrotic genes and pathways. Additional study is needed to determine the role of belimumab in the treatment of dcSSc
2018-03-01 | GSE97248 | GEO
Project description:Introduction: Although prone to a higher degree of ischemia reperfusion injury (IRI), the use of extended criteria donor (ECD) organs has become reality in transplantation. We therefore postulated that peri-operative perfusion of renal transplants with anti-human T-lymphocyte globulin (ATLG) ameliorates IRI and results in improved graft function. Methods: We performed a randomized, single-blinded, placebo-controlled trial involving 50 kidneys (KTx). Prior to implantation organs were perfused and incubated with ATLG (AP) (n = 24 kidney). Control organs (CP) were perfused with saline only (n = 26 kidney). Primary endpoint was defined as graft function reflected by serum creatinine at day 7 post transplantation (post-tx). Results: AP-KTx recipients illustrated significantly better graft function at day 7 post-tx as reflected by lower creatinine levels, whereas no treatment effect was observed after 12 months surveillance. During the early hospitalization phase, 16 of the 26 CP-KTx patients required dialysis during the first 7 days post-tx, whereas only 10 of the 24 AP-KTx patients underwent dialysis. No treatment-specific differences were detected for various lymphocytes subsets in the peripheral blood of patients. Additionally, mRNA analysis of 0-h biopsies post incubation with ATLG revealed no changes of intragraft inflammatory expression patterns between AP and CP organs. Conclusion: We here present the first clinical study on peri-operative organ perfusion with ATLG illustrating improved graft function in the early period post kidney transplantation. Clinical Trial Registration: www.ClinicalTrials.gov, NCT03377283.
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Project description:Randomized controlled trials (RCTs) show that decreases in low-density lipoprotein cholesterol (LDL-C) by the use of statins cause a significant reduction in the development of cardiovascular disease (CVD). However, one of our previous studies showed that, among eight RCTs that investigated the effect of statins vs. a placebo on CVD development, 56-79% of patients had residual CVD risk after the trials. In three RCTs that investigated the effect of a high dose vs. a usual dose of statins on CVD development, 78-87% of patients in the high-dose statin arms still had residual CVD risk. The risk of CVD development remains even when statins are used to strongly reduce LDL-C, and this type of risk is now regarded as statin residual CVD risk. Our study shows that elevated triglyceride (TG) levels, reduced high-density lipoprotein cholesterol (HDL-C), and the existence of obesity/insulin resistance and diabetes may be important metabolic factors that determine statin residual CVD risk. Here, we discuss atherogenic lipoproteins that were not investigated in such RCTs, such as lipoprotein (a) (Lp(a)), remnant lipoproteins, malondialdehyde-modified LDL (MDA-LDL), and small-dense LDL (Sd-LDL). Lp(a) is under strong genetic control by apolipoprotein (a), which is an LPA gene locus. Variations in the LPA gene account for 91% of the variability in the plasma concentration of Lp(a). A meta-analysis showed that genetic variations at the LPA locus are associated with CVD events during statin therapy, independent of the extent of LDL lowering, providing support for exploring strategies targeting circulating concentrations of Lp(a) to reduce CVD events in patients receiving statins. Remnant lipoproteins and small-dense LDL are highly associated with high TG levels, low HDL-C, and obesity/insulin resistance. MDA-LDL is a representative form of oxidized LDL and plays important roles in the formation and development of the primary lesions of atherosclerosis. MDA-LDL levels were higher in CVD patients and diabetic patients than in the control subjects. Furthermore, we demonstrated the atherogenic properties of such lipoproteins and their association with CVD as well as therapeutic approaches.
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Project description:Background: Blocking the action of the pro-inflammatory cytokine interleukin-1 (IL-1) reduces beta-cell secretory dysfunction and apoptosis in vitro, diabetes incidence in animal models of Type 1 diabetes mellitus (T1D), and glycaemia via improved beta-cell function in patients with T2D. We hypothesised that canakinumab, a monoclonal antibody to IL-1B, improves beta-cell function in patients with new-onset T1D. Methods: In an individually randomised, two-group parallel trial involving 12 sites in US, 69 patients aged 6-45 with T1D, < 12 weeks of symptoms, and assigned by centralised computer-generated blocked randomisation with locked computer-file concealment to treatment with 2 mg/kg (maximum 300 mg) canakinumab (n=45) or placebo (n=22) monthly for 12 months as add-on to conventional therapy. Participants and care-givers, but not data monitoring unit, were masked to group assignment. The primary end-point was change in the two-hour area-under-the-curve C-peptide response to MMT 12 months.
2015-10-01 | GSE68049 | GEO
Project description:Diabetes and Arteriosclerosis progression are frequently observed in borderline Type 2 diabetes cases. Onset of complications (arteriosclerosis and renal damage) due to Type 2 diabetes is well documented; it is extremely important to prevent or delay their progression. Type 2 diabetes onset and progression has been controlled through dietary habits and exercise, although these remain insufficient. Chlorella ingestion improves blood glucose and cholesterol concentrations in mice and humans, although no reports have evaluated Chlorella effects in borderline diabetics. Therefore, we conducted a randomized, placebo-controlled trial for borderline diabetics using laboratory results and comprehensive gene analysis as outcomes. Chlorella ingestion suppressed resistin gene expression, suggesting that Chlorella may be useful for preventing diabetes onset and ameliorating arteriosclerosis. Subjects were randomly divided into two groups: Chlorella group (n = 28) ingesting Chlorella powder (8.0 g/day) and placebo group (n = 29) ingesting lactose formulation (8.0 g/day) for 12 weeks. Blood and urine were collected every 4 weeks for laboratory tests. Gene expression analysis used RNA extracted from peripheral blood samples before and after 12 weeks of Chlorella or lactose ingestion.
2015-10-17 | E-GEOD-41767 | biostudies-arrayexpress
Project description:BackgroundInteresterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism.ObjectivesTo test the impact of a commonly consumed IE compared with a non-IE equivalent fat on in vivo postprandial and in vitro lipid metabolism, compared with a reference oil [rapeseed oil (RO)].MethodsA double-blinded, 3-phase crossover, randomized controlled trial was performed in healthy adults (n = 20) aged 45-75 y. Postprandial plasma triacylglycerol and lipoprotein responses (including stable isotope tracing) to a test meal (50 g fat) were evaluated over 8 h. The test fats were IE 80:20 palm stearin/palm kernel fat, an identical non-IE fat, and RO (control). In vitro, mechanisms of digestion were explored using a dynamic gastric model (DGM).ResultsPlasma triacylglycerol 8-h incremental area under the curves were lower following non-IE compared with RO [-1.7 mmol/L⋅h (95% CI: -3.3, -0.0)], but there were no differences between IE and RO or IE and non-IE. LDL particles were smaller following IE and non-IE compared with RO (P = 0.005). Extra extra large, extra large, and large VLDL particle concentrations were higher following IE and non-IE compared with RO at 6-8 h (P < 0.05). No differences in the appearance of [13C]palmitic acid in plasma triacylglycerol were observed between IE and non-IE fats. DGM revealed differences in phase separation of the IE and non-IE meals and delayed release of SFAs compared with RO.ConclusionsInteresterification did not modify fat digestion, postprandial lipemia, or lipid metabolism measured by stable isotope and DGM analysis. Despite the lower lipemia following the SFA-rich fats, increased proatherogenic large triacylglycerol-rich lipoprotein remnant and small LDL particles following the SFA-rich fats relative to RO adds a new postprandial dimension to the mechanistic evidence linking SFAs to cardiovascular disease risk.
| S-EPMC8106759 | biostudies-literature
Project description:Diabetes and Arteriosclerosis progression are frequently observed in borderline Type 2 diabetes cases. Onset of complications (arteriosclerosis and renal damage) due to Type 2 diabetes is well documented; it is extremely important to prevent or delay their progression. Type 2 diabetes onset and progression has been controlled through dietary habits and exercise, although these remain insufficient. Chlorella ingestion improves blood glucose and cholesterol concentrations in mice and humans, although no reports have evaluated Chlorella effects in borderline diabetics. Therefore, we conducted a randomized, placebo-controlled trial for borderline diabetics using laboratory results and comprehensive gene analysis as outcomes. Chlorella ingestion suppressed resistin gene expression, suggesting that Chlorella may be useful for preventing diabetes onset and ameliorating arteriosclerosis.
2015-10-17 | GSE41767 | GEO
Project description:Abstract: BACKGROUND: Mechanistic studies suggest that proprotein convertase subtilisin/kexin type 9 monoclonal antibody inhibitors (PCSK9mAb) not only reduce low density lipoprotein cholesterol (LDL-C) but can also modulate inflammation. OBJECTIVES: This trial was designed to define the impact of evolocumab on circulating immune cell properties in high-risk ASCVD subjects. METHODS: Double-blind, placebo-controlled trial randomized 41 ASCVD subjects with type 2 diabetes with microalbuminuria and LDL-C level of >70 mg/dL on maximum tolerated statin therapy to receive either subcutaneous evolocumab 420 mg every 4 weeks or matching placebo. The primary outcomes were the change in lipoproteins, blood viscosity, and circulating immune cell transcriptional response at 2 weeks and 12 weeks with evolocumab compared with matching placebo. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population. RESULTS: All 41 randomized subjects completed the 2-week visit. Six subjects (4 evolocumab, 2 placebo) did not receive study medication consistently after the 2-week visit due to suspension of research activities during the COVID-19 pandemic. The groups were well-matched with respect to age, comorbidities, baseline LDL-C, white blood cell counts, and markers of systemic inflammation. Evolocumab reduced LDL-C by -68.8% (p<0.0001) and -52.8% (p<0.0001) at 2 and 12 weeks respectively. There were no differences in blood viscosity at baseline nor at 2 and 12 weeks. RNA-seq was performed on peripheral blood mononuclear cells (PBMC) with and without TLR4 stimulation (“Stress” transcriptomics). There were no group differences in transcriptional profiles in unstimulated PBMC; however, “stress” transcriptomics unmasked immune cell phenotypic differences between evolocumab and placebo groups at 2 and 12 weeks. CONCLUSIONS: This trial is the first to demonstrate that PCSK9 mAB with evolocumab can modulate circulating immune cell properties and highlights the importance of “stress” profiling of circulating immune cells that more clearly define immune contributions to ASCVD. (Funded by Amgen Inc.; ClinicalTrials.gov number, NCT03829046).
2025-01-11 | GSE254732 | GEO
Project description:Background: Blocking the action of the pro-inflammatory cytokine interleukin-1 (IL-1) reduces beta-cell secretory dysfunction and apoptosis in vitro, diabetes incidence in animal models of Type 1 diabetes mellitus (T1D), and glycaemia via improved beta-cell function in patients with T2D. We hypothesised that anakinra, a recombinant human IL-1 receptor antagonist, improves beta-cell function in patients with new-onset T1D. Methods: In an individually randomised, two-group parallel trial involving 14 European tertiary referral centers, 69 patients aged 18-35 with T1D, < 12 weeks of symptoms, and standard mixed meal test (MMT) stimulated C-peptide ≥ 200 pM were enrolled between January, 2009 and July, 2011 and assigned by centralised computer-generated blocked randomisation with locked computer-file concealment to treatment with 100 mg anakinra (n=35) subcutaneously once daily or placebo (n=34) for 9 months as add-on to conventional therapy. Participants and care-givers, but not data monitoring unit, were masked to group assignment. The primary end-point was change in the two-hour area-under-the-curve C-peptide response to MMT, and secondary end-points changes in insulin requirements, glycaemia, and inflammatory markers at one, three, six, and nine months. Findings: The study was prematurely terminated due to slow accrual and is closed to follow-up. No interim analysis was performed. Ten patients withdrew in the anakinra and eight in the placebo arm, leaving 25 and 26 patients to be analysed, respectively. There was no statistical difference in adverse event category reporting between arms. Interpretation: Anakinra-treatment in T1D was safe, but the trial failed to meet primary and secondary outcome measures.
2015-10-01 | GSE37025 | GEO