107 research outputs found
Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus
Statin therapy modestly increases new-onset diabetes risk. The effect of proprotein convertase subtilisin/kexin type 9 inhibition on new-onset diabetes, glycemia, and weight remains unclear. We studied the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on fasting plasma glucose, glycated hemoglobin, weight, and new-onset diabetes mellitus. We pooled 1-year (48-week) data for participants who had completed an evolocumab parent study before entering an open-label extension (OLE) trial. Data were available for 4,802 participants (1,602 on standard of care [SOC]; 3,200 on evolocumab plus SOC) in 2 OLE trials. Evolocumab lowered low-density lipoprotein cholesterol by approximately 60% compared with SOC alone. Over the first year of the OLE trials, there was no difference in median (Q1, Q3) change in glycated hemoglobin (0.1% [-0.1, 0.2] for both SOC and evolocumab plus SOC) and fasting plasma glucose (0.06 mmol/L [-0.28, 0.38 mmol/L] for SOC and 0.06 mmol/L [-0.28, 0.44 mmol/L] for evolocumab plus SOC). Mean weight change (standard error) at 1 year was -0.1 kg (0.2) on SOC compared with 0.3 kg (0.1) on evolocumab plus SOC. The exposure-adjusted incidence rate (95% confidence intervals) for new-onset diabetes per 100 patient years was 3.7 (2.9 to 4.7) on control/SOC alone and 3.9 (3.2 to 4.6) on evolocumab/evolocumab plus SOC treatment. Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment
Phospholipase D-derived phosphatidic acid is involved in the activation of the CD11b/CD18 integrin in human eosinophils
On Perception and Consciousness in HPPD:A Systematic Review
Hallucinogen-persisting perception disorder (HPPD) features as a diagnostic category in the DSM-5, ICD-11, and other major classifications, but our knowledge of the phenomenology of the perceptual symptoms involved and the changes in consciousness during the characteristic “flashbacks” is limited. We systematically evaluated original case reports and case series on HPPD to define its phenomenology, associated (psycho)pathology, and course. Our search of PubMed and Embase yielded 66 relevant publications that described 97 people who, together, experienced 64 unique symptoms of HPPD. Of these, 76% concerned symptoms characteristic of Alice in Wonderland syndrome, over 50% non-visual symptoms, and 38% perceptual symptoms not clearly linked to prior intoxication states. This is in contrast with the DSM-5 diagnostic criteria for HPPD. Even though less than half of the patients showed a protracted disease course of over a year, a third achieved remission. However, in patients with co-occurring depression (with or without anxiety) HPPD symptoms persisted longer and treatment outcomes were more often negative. Thus, unlike the acute stages of psychedelic drug intoxication, which may be accompanied by altered states of consciousness, HPPD is rather characterized by changes in the content of consciousness and an attentional shift from exogenous to endogenous phenomena. Since HPPD is a more encompassing nosological entity than suggested in the DSM-5, we recommend expanding its diagnostic criteria. In addition, we make recommendations for clinical practice and future research
Musical hallucinations, secondary delusions, and lack of insight: results from a cohort study
IntroductionAlthough musical hallucinations do not tend to be accompanied by delusions, occasionally patients persistently accuse others of being responsible for causing the music they perceive, sometimes with severe social consequences such as frequently calling the police or moving house. In this study we seek to broaden our understanding of this rare type of musical hallucination that comes with secondary delusions and lack of insight, and to explore associations, underlying mechanisms, and treatment possibilities.MethodsThe present study is part of a cohort study on musical hallucinations carried out in the Netherlands from 2010 through 2023. Participants underwent testing with the aid of the MuHa Questionnaire, Launay-Slade Hallucinations Scale (LSHS), Schizotypal Personality Questionnaire (SPQ), Hamilton Depression Rating Scale (HDRS), and Mini Mental State Examination (MMSE). Additionally, they underwent a brain MRI, electroencephalogram, and audiological testing.ResultsFive patients out of a group of N = 81 (6%) lacked insight and presented with secondary delusions regarding the perceived music. They were all female, of advanced age, and hearing-impaired, and were diagnosed with cognitive impairment. In three patients (60%), risperidone was started. This had a positive effect on the hallucinations and secondary delusions.ConclusionThe pathophysiological process underlying musical hallucinations is multifactorial in nature. We consider cognitive impairment the most likely contributing factor of the secondary delusions and lack of insight encountered in our patients, and antipsychotics the most beneficial treatment. On the basis of these small numbers, no definite conclusions can be drawn, so further research is needed to elucidate the underlying mechanisms and to develop evidence-based treatment methods for people experiencing this rare and debilitating combination of symptoms. Since the black box warning of risperidone cautions against the use of this drug in elderly persons with dementia, a proper comparison with the efficacy and safety of other antipsychotics for this group is paramount
Target achievement and cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia
Background
Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown.
Methods
We used data collected in the first 26Â weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306).
Results
Twenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) – equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively.
Conclusions
Approximately three quarters and half of patients who took lomitapide for at least 2Â years reached LDL-C goals of 100Â mg/dL and 70Â mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further.
Trial registration
NCT00730236
(registered 8 Aug 2008) and
NCT00943306
(registered 22 July 2009)
RNA-based therapy in the management of lipid disorders: a review
This review focuses on antisense oligonucleotides and small interfering ribonucleic acid therapies approved or under development for the management of lipid disorders. Recent advances in RNA-based therapeutics allow tissue-specific targeting improving safety. Multiple potential target proteins have been identified and RNA-based therapeutics have the potential to significantly improve outcomes for patients with or at risk for atherosclerotic cardiovascular disease. The advantages of RNA-based lipid modifying therapies include the ability to reduce the concentration of almost any target protein highly selectively, allowing for more precise control of metabolic pathways than can often be achieved with small molecule-based drugs. RNA-based lipid modifying therapies also make it possible to reduce the expression of target proteins for which there are no small molecule inhibitors. RNA-based therapies can also reduce pill burden as their administration schedule typically varies from weekly to twice yearly injections. The safety profile of most current RNA-based lipid therapies is acceptable but adverse events associated with various therapies targeting lipid pathways have included injection site reactions, inflammatory reactions, hepatic steatosis and thrombocytopenia. While the body of evidence for these therapies is expanding, clinical experience with these therapies is currently limited in duration and the results of long-term studies are eagerly awaited
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data. METHODS: In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ("parent trials") of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined. RESULTS: As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003). CONCLUSIONS: During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918.)
A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia
BACKGROUND Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/ kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. METHODS We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. RESULTS Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. CONCLUSIONS At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks
Long-term safety and efficacy of alirocumab in South African patients with heterozygous familial hypercholesterolaemia : the ODYSSEY open-label extension study
BACKGROUND : Alirocumab reduces low-density lipoprotein
cholesterol (LDL-C) levels by up to 61%. The ODYSSEY
Open-Label Extension study investigated the effect of
alirocumab in patients with heterozygous familial hypercholesterolaemia
(HeFH) over 144 weeks.
METHODS : Eligible patients with HeFH had completed an
earlier double-blind, randomised, placebo-controlled parent
study. Patients were initiated on 75 mg alirocumab Q2W
subcutaneous (SC) unless baseline LDL-C was > 8.9 mmol/l,
in which case they received 150 mg alirocumab Q2W. Dose
titration to 150 mg Q2W was at the investigator’s discretion.
RESULTS : The study enrolled 167 patients and the parent study
mean (± SD) baseline LDL-C level was 3.65 ± 1.9 mmol/l.
Mean LDL-C level was reduced by 48.7% at week 144; mean
on-treatment LDL-C was 2.30 ± 1.24 mmol/l. Eight patients
reported injection-site reactions, with one treatment discontinuation.
Treatment emergent anti-drug antibodies were
identified in five patients but these did not affect the efficacy.
CONCLUSION : Alirocumab effectively and safely reduced LDL-C
in these patients.http://www.cvja.co.zahj2020Physiolog
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