Changes In Triglyceride Levels Research Articles

Aspariginase-Triggered Hyperglycerimedia: An Analysis on Germline Regulatory Gene Variations in Adult Acute Lymphoblastic Leukemia Patients

Asparaginase (ASP) is considered as a backbone of successful treatment of acute lymphoblastic leukemia (ALL). Cell growth and division of malignant lymphoblasts are highly dependent on asparagine and glutamine. ASP depletes them from extracellular fluid which leads to apoptosis of lymphoblasts. Aside from the aimed antileukemic properties, asparaginase exposes patients to multiple adverse effects including severe hypertriglyceridemia which potentially hampers efficient leukemia therapy. Molecular background of ASP-induced hypertriglyceridemia and its regulators are not well known. We aimed to investigate constitutional genetic factors as biomarkers for hypertriglyceridemia following ASP therapy.We analyzed clinical and laboratory data recorded in The Finnish Hematology Registry (FHR) from 52 adult ALL patients treated at the Helsinki University Hospital, Department of Hematology in 2014-2016. Study subjects were selected for further analyses if germline whole exome sequencing (WES) had been performed, patients had received ASP and data on basic chemistry and lipids before and after ASP dosing were available. Sixteen patients fulfilled these criteria.The patients' germline DNA was extracted from a skin biopsy taken in conjunction with a bone marrow sampling. Roche MedExome kit was used to target the coding regions of the genome and sequencing was conducted using an Illumina HiSeq sequencer. The reads were processed and aligned to the GRCh37 human reference genome. SNVs and indels in the exome sequencing data were analyzed using an in-house developed analysis tool. Shared variants in patients with similar serum triglyceride level changes after ASP treatment were analyzed and variants in genes associated with lipid metabolism were selected as candidate target genes.Three patient groups were identified based on to the maximum triglyceride changes pre- and post ASP infusion (both clinical and exome data available, n=7, 5, and 4; respectively). Mean changes in the Groups 1-3 were 1.7, 8.4, and 72,7 mmol/L, respectively. Differences in patients' BMI or corticosteroids use did not explain the distribution. Hence, a germline determinant was hypothesized and a candidate gene analysis (xx known genes affecting lipid and ASP metabolisms) performed from patients' germline WES.Mean changes in the Groups 1-3 were 1.7, 8.4, and 72,7 mmol/L, respectively. Differences in patients' BMI or usage of corticosteroids did not explain the distribution. Hence, a germline determinant was hypothesized and candidate gene search performed on patients' germline WES.Four of the candidate variants in ATF5, NKX1-1, THEM4, and LPCAT2 were enriched in patients with ASP-induced hyperTG. None of the variants suggested here have been previously reported to be associated with ASP-induced hypertriglyceridemia, but another SNP in ATF5 has been linked to adverse outcome in ASP-treated patients. ATF5, a transcription factor, regulates asparagine synthetase biosynthesis and is also involved in the cell cycle and apoptosis regulation, in the cellular stress response and the ceramide pathway. NKX1-1 is a transcription factor and an essential regulator of organ development, and it is also probably associated with energy homeostasis. THEM4 is an acyl-CoA thioesterase and is probably involved in mitochondrial fatty acid metabolism as well as in AKT1 signaling and apoptosis. LPCAT2 is a member of the lysophospholipid acyltransferase family involved in the synthesis of phospholipids, but also in the biosynthesis of platelet-activating factor (PAF) in inflammatory conditions.Here, we present four candidate genes and variations in them possibly linking to ASP-induced hypertriglyceridemia in adult ALL patients. Prospective studies exploring the impact of these findings are called for.Figure 1. Patient groups (3) identified according to the maximum triglyceride changes pre (green dot) - and post (red dot) ASP infusion. [Display omitted] DisclosuresPorkka:Pfizer: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding.

Lipids and peripheral neuropathy.

Hyperlipidaemia is associated with the development of neuropathy. Indeed, a mechanistic link between altered lipid metabolism and peripheral nerve dysfunction has been demonstrated in a number of experimental and clinical studies. Furthermore, post hoc analyses of clinical trials of cholesterol and triglyceride-lowering pharmacotherapy have shown reduced rates of progression of diabetic neuropathy. Given, there are currently no FDA approved disease-modifying therapies for diabetic neuropathy, modulation of lipids may represent a key therapeutic target for the treatment of diabetic nerve damage. This review summarizes the current evidence base on the role of hyperlipidaemia and lipid lowering therapy on the development and progression of peripheral neuropathy. A body of literature supports a detrimental effect of dyslipidaemia on nerve fibres resulting in somatic and autonomic neuropathy. The case for an important modulating role of hypertriglyceridemia is stronger than for low-density lipoprotein cholesterol (LDL-C) in relation to peripheral neuropathy. This is reflected in the outcomes of clinical trials with the different therapeutic agents targeting hyperlipidaemia reporting beneficial or neutral effects with statins and fibrates. The potential concern with the association between proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy and cognitive decline raised the possibility that extreme LDL-C lowering may result in neurodegeneration. However, studies in murine models and data from small observational studies indicate an association between increased circulating PCSK9 levels and small nerve fibre damage with a protective effect of PCSK9i therapy against small fibre neuropathy. Additionally, weight loss with bariatric surgery leads to an improvement in peripheral neuropathy and regeneration of small nerve fibres measured with corneal confocal microscopy in people with obesity with or without type 2 diabetes. These improvements correlate inversely with changes in triglyceride levels. Hyperlipidaemia, particularly hypertriglyceridemia, is associated with the development and progression of neuropathy. Lipid modifying agents may represent a potential therapeutic option for peripheral neuropathy. Post hoc analyses indicate that lipid-lowering therapies may halt the progression of neuropathy or even lead to regeneration of nerve fibres. Well designed randomized controlled trials are needed to establish if intensive targeted lipid lowering therapy as a part of holistic metabolic control leads to nerve fibre regeneration and improvement in neuropathy symptoms.

297-OR: Triglyceride Reduction and Effect on Lipoprotein Metabolism in Patients with Type 2 Diabetes Mellitus Receiving Fixed-Dose Combination of Insulin Degludec and Liraglutide

Aim: To compare the effect of fixed-dose combination of Insulin Degludec and Liraglutide (IDegLira) on anthropometric, carbohydrate metabolism and lipid parameters, as well as on apoB-containing lipoprotein subclasses and HDL lipidome, in patients with type 2 diabetes (T2DM) regarding changes in triglyceride (TG) levels. Methods: Seventy-two uncontrolled patients with T2DM on oral antidiabetics were randomized to receive IDegLira or Insulin Degludec (IDeg) for a 12-week treatment. In the present study, 42 patients receiving IDegLira were included. Twenty-one presented a decrease, while the remaining an increase in TG levels. ApoB-containing lipoprotein subclasses levels were measured by LDL-Lipoprint method, whereas HDL lipidomic analysis via 1H-NMR spectroscopy. Results: In patients experiencing a decrease in TG levels after IDegLira administration, a significant decrease in body weight and BMI, by 4.4kg and 1.59kg/m2 respectively, was observed. Fasting glucose, HbA1c and HbA1c Glycation Index noted a decrease by 35 mg/dl, 1.4% and 1.1 respectively (p=0.018, p=0.004, p=0.004). IDegLira administration in this subgroup resulted in a significant reduction of total (TC) and LDL cholesterol (LDLC) by 22.5mg/dl and 13.2mg/dl, respectively. Small-dense LDLC (sdLDLC) levels significantly correlated with changes in TG levels (r=0.496, p=0.02). Furthermore, IDegLira administration resulted in significant enrichment of HDL particle core in esterified cholesterol, depletion of TG content and an atheroprotective shift in fatty acid pattern of HDLs. The aforementioned changes were significantly greater than those observed in patients receiving IDegLira and did not experience a TG reduction. Conclusions: TG reduction as a result of IDegLira administration is accompanied by greater changes in anthropometric and carbohydrate metabolism parameters, TC, LDLC, sdLDLC and HDL lipidome. Disclosure E. Pappa: None. C. Kostara: None. A. Dimou: None. E. T. Bairaktari: None. V. Tsimihodimos: None.

Associations between Hypertriglyceridemia and Circulating Neutrophil Subpopulation in Patients with Dyslipidemia.

Background There is strong evidence to suggest that the negative influence of triglyceride-rich lipoproteins (TRLs) on atherosclerosis development and progression is at least partially mediated by their proinflammatory effects. However, the effect of hypertriglyceridemia (HTG) on the subpopulation composition of circulating neutrophils has not been studied so far. The aim of this study was to examine correlations between the level of triglycerides (TGs) and the subpopulation composition of circulating neutrophils in middle-aged patients with dyslipidemia without established atherosclerotic cardiovascular diseases (ASCVDs). Methods Ninety-one patients with dyslipidemia, including 22 (24.2%) patients with HTG, were enrolled in the study. Phenotying of neutrophil subpopulations was performed through flow cytometry (Navios 6/2, Beckman Coulter, USA). For phenotyping of neutrophil subpopulations, conjugated monoclonal antibodies were used: CD16, PE-Cyanine7 (Invitrogen, USA); CD11b-FITC (Beckman Coulter, USA); CD62L-PE (Beckman Coulter, USA); and CD184 (CXCR4)-PE-CF594 (BD Biosciences, USA). Results Following the correlation analysis, the TG level directly correlated with the number of circulating leukocytes (r = 0.443; p < 0.0001) and neutrophils (r = 0.311; p=0.008). HTG patients displayed a significantly high number of circulating neutrophils with CD16hiCD11bhiCD62Lhi and CD16hiCD11bloCD62Lbr phenotypes. TG levels directly correlated with the number of circulating neutrophils having CD16hiCD11bhiCD62Lhi and CD16hiCD11bloCD62Lbr phenotypes. Following the linear regression analysis, statistically significant correlations between TG levels and neutrophil subpopulations having CD16hiCD11bloCD62Lbr and CD16hiCD11bbrCD62LloCXCR4hi phenotypes were established. Changes in TG levels could explain up to 19.1% of the variability in the number of studied neutrophil subpopulations. Conclusion Among middle-aged patients without established ASCVDs, patients with HTG demonstrated a significantly higher overall number of neutrophils and neutrophils having CD16hiCD11bhiCD62Lhi (mature neutrophils) and CD16hiCD11bloCD62Lbr (immunosuppressive neutrophils) than patients with normal TG levels. The TG level was associated with an increase in the number of CD16hiCD11bloCD62Lbr and CD16hiCD11bbrCD62LloCXCR4hi (ageing neutrophils) neutrophils, adjusted for the sex and age of the patients.

Omega-3 fatty acids reduce cardiometabolic risk in first-episode schizophrenia patients treated with antipsychotics: Findings from the OFFER randomized controlled study

Metabolic syndrome (MetS) increases the risk of premature mortality observed in schizophrenia (SCZ). N−3 polyunsaturated fatty acid (PUFA) deficiency has been reported in different stages of schizophrenia. N−3 PUFA supplementation was found to be beneficial in both chronic SCZ and MetS. No intervention studies based on n−3 PUFA as add-on therapy to antipsychotics have examined the changes in MetS risk in first-episode schizophrenia. AimThis randomized placebo-controlled trial assesses the effect of a 26-week intervention composed of either 2.2 g/day of n−3 PUFA or olive oil placebo on the frequency of MetS and the changes in its constituents as a secondary outcome measure. MethodsSeventy-one adult inpatients diagnosed with first-episode schizophrenia were randomly assigned to study groups. The active intervention used a 3:2 mixture of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Metabolic syndrome components were monitored throughout the study. ResultsA significant reduction in the frequency of MetS was observed in the EPA + DHA group (p = 0.0408); as well as some specific MetS components: e.g., a decrease in fasting blood glucose (p = 0.045). The beneficial effects of EPA + DHA were even more pronounced in patients treated mainly with olanzapine, e.g. significant reductions of total cholesterol (p = 0.037) and blood glucose levels (p = 0.034). Significant positive correlations were found between the general psychopathology subscale of PANSS (primary outcome) and triglyceride level changes. ConclusionN−3 PUFA supplementation in early SCZ may constitute a safe and affordable intervention that can reduce the risk of MetS and its lethal complications.

Вiковi та гендерні особливостi лiпiдного профiлю кровi хворих на гiпертонiю й iшемiчну хворобу серця

Cardiovascular disease (CVD) in the 21st century remains the leading cause of death worldwide. In Ukraine, during 2020, 365,515 ukrainians died from heart disease and da­mage of the circulatory system. It is known that hypertension (AH) is one of the most important risk factors for atherosclerosis, accelerates its development and complicates the course, and these two diseases often accompany each other. Especially common is a combination of coronary heart disease (CHD), its various forms (angina, myocardial infarction, arrhythmia) and hypertension. The aim of the study was to establish the age and sex characteristics of the lipid profile of the blood of patients with hypertension and coronary heart disease. Analyzed the statistical data of a survey of 775 people (of which 436 women and 339 men). The data on total cholesterol, triglycerides and high-density lipoprotein cholesterol content for patients with hypertension and coronary disease was analyzed in order to assess the blood lipid spectrum. Statistical analysis and data processing was performed using standard methods of variation Statistics in the Statistics 8.0 software. Changes in lipid metabolism in patients with ischemic heart disease and hypertension were studied. The performed analysis of age-related and gender-related dynamics of blood lipid spectrum parameters – total triglycerides, total cholesterol (CS), low- and high-density lipoprotein cholesterol (LDL cholesterol and HDL cholesterol), the prognostic coefficient of atherogenicity (CA). It was found that the level of total cholesterol in women in the age groups &lt;45 and 55–65 years old is higher than in similar groups in men. In age groups &gt; 65 years, gender difference in total cholesterol levels is not observed. In age group 45–55 years, there are gender-dependent differences in the value of the prognostic coefficient of atherogenicity. For women there were no age-related changes in triglyceride levels. For men there is a depen­dence of the triglyceride’s levels with the age of patients. There were no significant diffe­rences in the levels of low- and high-density lipoproteins depending on gender.

Decreased Triglyceride and Increased Serum Lipoprotein Lipase Levels Are Correlated to Increased High-Density Lipoprotein-Cholesterol Levels after Laparoscopic Sleeve Gastrectomy

Introduction: Laparoscopic sleeve gastrectomy (LSG) significantly increases high-density lipoprotein cholesterol (HDL-C) and lipoprotein lipase (LPL) in pre-heparin serum (pre-heparin LPL levels). LPL is a regulator of serum triglyceride (TG) and HDL-C production; this may be the mechanism for HDL-C increase after LSG. This study aimed to elucidate the mechanism of increase in HDL-C levels by examining the relationship between changes in serum HDL-C levels and LPL after LSG. Methods: We retrospectively reviewed 104 obese patients, who underwent LSG and were followed up for 12 months. We analyzed the relationship between changes in serum HDL-C levels and various clinical parameters after LSG. Results: A significant decrease was observed in the patients’ BMI and serum TG levels after LSG. Conversely, HDL-C levels and pre-heparin LPL levels were significantly increased after LSG. Simple linear regression showed that changes in HDL-C levels were significantly correlated with total weight loss percentage, change in TG levels, abdominal fat areas, and pre-heparin LPL levels. Additionally, the multiple regression model revealed that a decrease in TG levels and an increase in pre-heparin LPL levels were correlated with increased HDL-C levels after LSG. Discussion/Conclusion: These results show that a decrease in TG levels and an increase in LPL are mechanisms for increased HDL-C levels after LSG.

Post-load glucose subgroups and associated metabolic traits in individuals with type 2 diabetes: An IMI-DIRECT study.

AimSubclasses of different glycaemic disturbances could explain the variation in characteristics of individuals with type 2 diabetes (T2D). We aimed to examine the association between subgroups based on their glucose curves during a five-point mixed-meal tolerance test (MMT) and metabolic traits at baseline and glycaemic deterioration in individuals with T2D.MethodsThe study included 787 individuals with newly diagnosed T2D from the Diabetes Research on Patient Stratification (IMI-DIRECT) Study. Latent class trajectory analysis (LCTA) was used to identify distinct glucose curve subgroups during a five-point MMT. Using general linear models, these subgroups were associated with metabolic traits at baseline and after 18 months of follow up, adjusted for potential confounders.ResultsAt baseline, we identified three glucose curve subgroups, labelled in order of increasing glucose peak levels as subgroup 1–3. Individuals in subgroup 2 and 3 were more likely to have higher levels of HbA1c, triglycerides and BMI at baseline, compared to those in subgroup 1. At 18 months (n = 651), the beta coefficients (95% CI) for change in HbA1c (mmol/mol) increased across subgroups with 0.37 (-0.18–1.92) for subgroup 2 and 1.88 (-0.08–3.85) for subgroup 3, relative to subgroup 1. The same trend was observed for change in levels of triglycerides and fasting glucose.ConclusionsDifferent glycaemic profiles with different metabolic traits and different degrees of subsequent glycaemic deterioration can be identified using data from a frequently sampled mixed-meal tolerance test in individuals with T2D. Subgroups with the highest peaks had greater metabolic risk.

The triglyceride-lowering effects of PCSK9 inhibitor differ in patients with different baseline triglyceride levels

To investigate the triglyceride (TG)-lowering effects of PCSK9 inhibitor in patients with in different baseline triglyceride levels. Between February, 2019 and March, 2020, a total of 59 patients were treated with PCSK9 inhibitor (Evolocumab) in 5 hospitals, including Nanfang Hospital, Guangdong Provincial People's Hospital, First Affiliated Hospital of Sun Yat-sen University, Foshan Nanhai District People's Hospital and Yulin First People's Hospital. According to baseline triglyceride levels, the patients were divided into normal TG group (&lt; 1.70 mmol/L, n=24), mild hypertriglyceridemia group (1.70-2.29 mmol/L, n=11), moderate hypertriglyceridemia group (2.30-5.63 mmol/L, n=13), and severe hypertriglyceridemia group (≥5.64 mmol/L, n=11), and the changes in TG level after the treatment were compared among the 4 groups. In the groups with normal and mildly elevated baseline TG level, the patients did not show significant changes in TG levels after the treatment. In patients with moderately and severely elevated baseline TG levels, treatment with PCSK9 inhibitor significantly reduced their TG levels (P &lt; 0.005). PCSK9 inhibitor has a significant TG-lowering effect in patients with moderate to severe hypertriglyceridemia but not in patients with only mildly elevated baseline TG level.

Impact of Intravenous Omega-3-Enriched Lipid Emulsion on Liver Enzyme and Triglyceride Serum Levels of Children Undergoing Gastrointestinal Surgery.

PurposeTo investigate the impact of omega-3-enriched lipid emulsion (LE) on liver enzyme (aspartate transaminase [AST] and alanine aminotransferase [ALT]) and triglyceride (TG) levels of children undergoing gastrointestinal surgery.MethodsThis experimental randomized controlled group pretest-posttest design study included 14 children who underwent gastrointestinal surgery due to duodenal atresia, jejunal atresia, esophageal atresia, and need for parenteral nutrition for a minimum of 3 days at RSUD Dr. Soetomo Surabaya between August 2018 and January 2019. These children were divided into two groups, those who received standard intravenous LE (medium-chain triglyceride [MCT]/long-chain triglyceride [LCT]) and those who received intravenous omega-3-enriched LE. Differences in AST, ALT, and TG levels were measured before surgery and 3 days after the administration of parenteral nutrition.ResultsLiver enzyme and TG levels in each group did not differ significantly before versus 3 days after surgery. However, TG levels were significantly lower in the omega-3-enriched intravenous LE group (p=0.041) at 3 days after surgery, and statistically significant difference in changes in TG levels was noted at 3 days after surgery between MCT/LCT intravenous LE group and the omega-3-enriched intravenous LE group (p=0.008).ConclusionThe intravenous omega-3-enriched LE had a better TG-lowering effect than the MCT/LCT intravenous LE in children undergoing gastrointestinal surgery.

Low High-Density Lipoprotein Cholesterol to Monitor Long-Term Average Increased Triglycerides.

Increased triglyceride-rich remnants represent a causal risk factor for ischemic cardiovascular disease. We tested the hypothesis that low high-density lipoprotein (HDL) cholesterol can be used to monitor long-term high triglycerides/remnant cholesterol, just as high hemoglobin A1c (HbA1c) can be used to monitor long-term high glucose levels. We studied cross-sectionally 108 731 individuals, dynamically 1313 individuals with lipid measurement at 10 repeated visits, short-term 305 individuals during a fat load, and long-term 10 479 individuals with 2 lipid measurements 10 years apart. Levels of HDL cholesterol and triglycerides. Cross-sectionally, HDL cholesterol was inversely associated with triglycerides (R2 = 0.26) and remnant cholesterol (R2 = 0.26). Dynamically, major changes in triglyceride levels from measurement to measurement were mimicked by corresponding modest changes in HDL cholesterol. In the short-term after a fat load, median triglycerides increased 96% while HDL cholesterol decreased only 1%. Long-term, in individuals with measurements 10 years apart, those who initially had the highest triglycerides and corresponding lowest HDL cholesterol, still had highest triglycerides and lowest HDL cholesterol 10 years later. Prospectively, individuals with increased triglycerides/remnant cholesterol had increased risk of myocardial infarction; however, when the HDL cholesterol monitoring was removed, increased triglycerides/remnant cholesterol were largely no longer associated with increased risk of myocardial infarction. Low HDL cholesterol is a stable marker of average high triglycerides/remnant cholesterol. This suggests that low HDL cholesterol can be used to monitor long-term average high triglycerides and remnant cholesterol, analogous to high HbA1c as a long-term monitor of average high glucose levels.

2491. Virologic Response of Switching Tenofovir Disoproxil Fumarate (TDF)-Based Regimen to Abacavir (ABC)-Based Regimen vs. Lopinavir/Ritonavir(LPV/r) Plus Lamivudine(3TC) in HIV-Infected Patients with TDF-Induced Nephrotoxicity at 24 Weeks: A Prospective, Open-Label, Randomized, Controlled Trial

BackgroundTenofovir disoproxil fumarate (TDF)-induced nephrotoxicity is a well-recognized complication and one of the reasons for treatment switching in HIV-infected patients. Salvage regimens in renal impairment such as abacavir(ABC)-based regimen or two-drug regimens such as boosted protease inhibitor (PI) plus lamivudine (3TC) are the options for switching. However, ABC is contraindicated in patients with a high risk for cardiovascular disease. In resource-limited setting, only some PIs such as lopinavir and atazanavir are available options.MethodsWe conducted a prospective, open-label, randomized controlled trial in a tertiary center in Bangkok. We recruited HIV-infected adults who had viral suppression, with TDF-induced proximal tubulopathy and/or a significant decrease in estimated glomerular filtration rate(eGFR). The patients were randomized to receive ABC/3TC plus efavirenz (ABC-based regimen) or LPV/r+3TC. The primary outcome was the proportion of patients with viral suppression at 24 weeks. The secondary outcomes were the immunologic response, recovery of eGFR, proximal tubular function and change in lipid profile at 24 weeks.ResultsBetween August 2018 - February 2019, we screened 87 patients and enrolled 24 patients were randomly assigned to the ABC-based regimen and 23 patients to LPV/r+3TC regimen. In the intention-to-treat population, virologic response at 24 weeks was noted in 21 (87.5%) patients assigned to ABC-based regimen and 19 (82.6%) patients assigned to LPV/r+3TC regimen (P = 0.635). There were no differences in the improvement of the percentage change of eGFR, fractional excretion of phosphate, renal tubular reabsorption of phosphate (TmP/GFR), fractional excretion of uric and UPCI at 24 weeks. Triglyceride levels were significantly increased in LPV/r+3TC regimen compared with ABC-based regimen at 24 weeks (91.32% vs. 20.46%; P = 0.001).ConclusionOur study showed no difference in virologic suppression after switching to ABC-based regimen or LPV/r+3TC regimen in patients with TDF-induced nephrotoxicity. There was no difference in percentage change of eGFR, recovery of proximal tubular function in both arms after discontinuation of TDF. There was a significant change in triglyceride levels in LPV/r +3TC regimen.Disclosures All authors: No reported disclosures.

Influence Of Changes In Triglyceride Levels On Lipoprotein (A) Levels With Lipid Lowering Therapy

Background and Aims: Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular diseases. Although Lp(a) level is mainly determined by genetic variation, it was reported that triglyceride (TG) levels affect Lp(a) levels with clinical significance. This study investigated roles of changes in triglyceride levels on Lp(a) levels when drugs for hyperlipidemia were administered.

CAL02, a novel antitoxin liposomal agent, in severe pneumococcal pneumonia: a first-in-human, double-blind, placebo-controlled, randomised trial

Severe community-acquired pneumonia caused by Streptococcus pneumoniae is associated with high morbidity and mortality rates. CAL02, a novel antitoxin agent with an unprecedented mode of action, consists of liposomes that capture bacterial toxins known to dysregulate inflammation, cause organ damage, and impede immune defence. We aimed to assess the safety of CAL02 as an add-on therapy to antibiotics. This randomised, double-blind, multicentre, placebo-controlled trial was done in ten intensive care units (ICUs) in France and Belgium (but only six units enrolled patients), in patients with severe community-acquired pneumococcal pneumonia who required ICU admission and had been identified as being infected with S pneumoniae. We randomly assigned participants in two stages-the first stage randomly assigned six patients (1:1) to either low-dose CAL02 or placebo, and the second stage randomly assigned 18 patients (14:4) to either high-dose CAL02 or placebo, and stratified in four blocks (4:1, 4:1, 3:1, and 3:1), in addition to standard of care. Block randomisation was done with a computer-generated random number list. Participants, investigators, other site study personnel, the sponsor, and the sponsor's designees involved in study management and monitoring were masked to the randomisation list and treatment assignment. Patients were treated with low-dose (4 mg/kg) or high-dose (16 mg/kg) CAL02 or placebo (saline), in addition to standard antibiotic therapy. Two intravenous doses of study treatment were infused, with a 24 h interval, at a concentration of 10 mg/mL, stepwise, over a maximum of 2 h on days 1 and 2. The primary objective of the study was to assess the safety and tolerability of low-dose and high-dose CAL02 in patients with severe community-acquired pneumonia treated with standard antibiotic therapy, and the primary analysis was done on the safety population (all patients who received at least one dose of the study treatment). Efficacy was a secondary outcome. This trial is registered with ClinicalTrials.gov, number NCT02583373. Between March 21, 2016, and Jan 13, 2018, we screened 280 patients with community-acquired pneumonia. 19 patients were enrolled and randomly assigned, resulting in 13 patients in the CAL02 groups (three assigned to low-dose CAL02 and ten assigned to high-dose CAL02) and six in the placebo group. One patient randomly assigned to placebo was allocated to the wrong treatment group and received high-dose CAL02 instead of placebo. Thus, 14 patients received CAL02 (three received low-dose CAL02 and 11 received high-dose CAL02) and five patients received placebo, constituting the safety population. At baseline, the mean APACHE II score for the total study population was 21·5 (SD 4·9; 95% CI 19·3-23·7) and 11 (58%) of 19 patients had septic shock. Adverse events occurred in 12 (86%) of 14 patients in the CAL02 treatment groups combined and all five (100%) patients in the placebo group. Serious adverse events occurred in four (29%) of 14 patients in the CAL02 treatment groups combined and two (40%) of five patients in the placebo group. One non-serious adverse event (mild increase in triglycerides) in a patient in the high-dose CAL02 group was reported as related to study drug. However, analysis of the changes in triglyceride levels in the CAL02 groups compared with the placebo group revealed no correlation with administration of CAL02. No adverse events were linked to local tolerability events. All patients, apart from one who died in the low CAL02 group (death not related to the study drug) achieved clinical cure at the test of cure visit between days 15 and 22. The sequential organ failure assessment score decreased by mean 65·0% (95% CI 50·7-79·4) in the combined CAL02 groups compared with 29·2% (12·8-45·5) in the placebo group between baseline and day 8. The nature of adverse events was consistent with the profile of the study population and CAL02 showed a promising safety profile and tolerability. However, the difference between high-dose and low-dose CAL02 could not be assessed in this study. Efficacy was in line with the expected benefits of neutralising toxins. The results of this study support further clinical development of CAL02 and provide a solid basis for a larger clinical study. Combioxin.

Difference of changes in total and triglyseride cholesterol levels of insulin monotherapy use with combination insulin and metformin therapy in type II diabetes mellitus patients

Backround: Diabetes mellitus (DM) is a degenerative disease predicted by WHO to increase in Indonesia from 8.4 million in 2000 to around 21.3 million in 2030. Diabetes mellitus is closely related to dyslipidemia which can increase the risk of coronary artery disease (CAD). Current DM treatment is using oral hypoglycemic drugs, insulin, or a combination of both. Many previous studies have not examined the effect of these therapies on lipid profiles, specifically total cholesterol and triglyceride levels. Objective: To determine the differences in changes in total cholesterol and triglyceride levels between the use of insulin monotherapy and combination therapy of insulin and metformin in patients with type II diabetes mellitus in Sleman Yogyakarta Hospital from January 2010 toJune 2012. Methods: This study was an observational analytic study using a retrospective cohort study method with samples (n = 64). Samples were taken by non-probability consecutive sampling, carried out in DM patients inpatient or outpatient at Sleman Yogyakarta Hospital for the period of January 2010 - June 2012. The samples were divided into two groups, insulin monotherapy group and insulin and metformin combination therapy group. The data taken was the total cholesterol and the first triglyceride level, then the second total cholesterol and triglyceride data were made after four months of getting therapy. Result: Analysis of statistical data using the Mann Whitney test for changes in total cholesterol levels in the two treatment groups showed p = 0.166, whereas for changes in triglyceride levels in the two treatment groups it was found that p = 0.840. Conclusion: There were no significant differences in changes in total cholesterol and triglyceride levels between the two treatment groups.

Half Dose Once-Daily Pemafibrate Effectively Improved Hypertriglyceridemia in Real Practice.

BackgroundHyperlipidemia is a worldwide problem related to cardiovascular disease (CVD) and sudden death. Low-density lipoprotein cholesterol (LDL-C) has been treated well by the use of statins, but hypertriglyceridemia was not the case. Previous fibrates have been shown a certain effect of preventing CVD events, but some remain not enough or even could cause adverse events. Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) with the potential to reduce high triglycerides. To evaluate the clinical effectiveness and safety profile of Pemafibrate, we have started with half dose once-daily administration.MethodsThirty-three patients with hypertriglyceridemia, triglyceride (TG) levels > 150 mg/dL, were treated with Pemafibrate (0.1 mg, once daily) from July 2018 to February 2019. Changes in TG (non-fasting) and LDL-C, high-density lipoprotein cholesterol (HDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), creatinine (Cre), blood glucose (PBG) (postprandial), hemoglobin A1c (HbA1c), and body weight (BW) levels were investigated, compared to the baseline levels of the previous visit.ResultsOf the 33 patients, 11 were using other fibrates before. Nine were given statins along with. Baseline TG was 285.0 (210.5 - 423.0) mg/dL, LDL-C 116.4 ± 33.4 mg/dL, and HDL-C 46.5 ± 12.5 mg/dL. TG changes were statistically significant (-20.8 ± 47.6%; P < 0.01). Patients with TG > 200 mg/dL, who used fibrates for the first time, experienced the most significant changes in TG levels (-34.5 ± 37.2%; P < 0.01). In patients using statins already, TG reduction was relatively less, compared to those not using statins (-25.4 ± 36.1%; P < 0.01). HDL-C increased by 3.9 ± 10.2 mg/dL (P < 0.05). LDL-C increased by 16.6 ± 23.7 mg/dL (P < 0.001) in patients not using statins, while patients using statins did not show such significant change. AST, ALT, CK, Cre, PBG, HbA1c and BW did not significantly change.ConclusionsA selective PPARα modulator, Pemafibrate, effectively improved hypertriglyceridemia without major adverse events in real practice, with half dose once-daily administration. Combined use of statins might be a potent therapeutic maneuver for dyslipidemia.

Pancreas in Trouble… Plasmapheresis to the Rescue

Hypertriglyceridemia (HTG) can cause diseases like Acute Pancreatitis (AP) and is associated with Coronary Artery Disease (CAD). Severe HTG, triglycerides (TG) >1000 mg/dl, is the third most common cause of AP in the United States [HTG-induced pancreatitis (HTGP)]. A rapid reduction of TG to less than 1000 mg/dl is known to improve outcome and prevent recurrence. Current management includes resting the pancreas, fluid resuscitation, pain control, insulin, and heparin drip but their slower mode of action makes them less desirable in medical emergencies. Plasmapheresis (PP) can be used as a therapeutic option in such circumstances. A 47-year-old female, with a past medical history of CAD, IDDM and familial HTG, presented to the hospital with acute-onset, progressively worsening epigastric pain which started in the right upper quadrant, migrated to the epigastrium, radiating to the back, 9/10 in severity, exacerbated with movement and improved with rest. On examination, she was afebrile, HR- 115/min, BP- 194/100 mm Hg, SpO2- 91%. Labs—glucose- 455 mg/dl, serum lipase— 1603 U/L and TG-8464 mg/dl. CT abdomen and pelvis showed AP without definite pancreatic necrosis. With a diagnosis of HTGP complicated by a hyperosmolar hyperglycemic state, she was managed with an insulin drip and aggressive fluid resuscitation which reduced her TG levels to 5268 mg/dl. PP was initiated which improved her TG levels further. On day two her respiratory status began to deteriorate, and she was sent to the ICU. She was managed with fluid restriction, ventilatory and vasopressor support over the next five days, and sent to the floors after being extubated, where the rest of her stay was uncomplicated. The use of PP within 48 hours of diagnosing HTGP improved our patient's condition. PP should be used early, within 24-48 hour intervals, until TG levels are < 500 mg/dl. Previous studies showed shorter hospital stay and decreased hospital readmissions in patients with HTGP (TG > 5000 mg/dl) receiving PP. It is an effective treatment for patients with severe HTGP who are at increased risk of developing complications. Due to lack of standardization of protocol, an optimum number of PP treatments required in addition to standard therapy needs to be worked out in future studies. Randomized controlled studies are warranted to assess the efficacy, timing, cost-benefit ratio, and necessity of PP as a treatment modality for HTGP.1240_A.tif Figure 1: CT Abdomen- AP Without Definite Pancreatic Necrosis And A 1.4 X 0.8 cm Pseudoaneurysm1240_B.tif Figure 2: Change in Triglyceride Levels with Subsequent Plasmapheresis

Epigenome wide association study of SNP\u2013CpG\xa0interactions on changes in triglyceride levels after pharmaceutical intervention: a GAW20 analysis

In the search for an understanding of how genetic variation contributes to the heritability of common human disease, the potential role of epigenetic factors, such as methylation, is being explored with increasing frequency. Although standard analyses test for associations between methylation levels at individual cytosine-phosphate-guanine (CpG) sites and phenotypes of interest, some investigators have begun testing for methylation and how methylation may modulate the effects of genetic polymorphisms on phenotypes. In our analysis, we used both a genome-wide and candidate gene approach to investigate potential single-nucleotide polymorphism (SNP)–CpG interactions on changes in triglyceride levels. Although we were able to identify numerous loci of interest when using an exploratory significance threshold, we did not identify any significant interactions using a strict genome-wide significance threshold. We were also able to identify numerous loci using the candidate gene approach, in which we focused on 18 genes with prior evidence of association of triglyceride levels. In particular, we identified GALNT2 loci as containing potential CpG sites that moderate the impact of genetic polymorphisms on triglyceride levels. Further work is needed to provide clear guidance on analytic strategies for testing SNP–CpG interactions, although leveraging prior biological understanding may be needed to improve statistical power in data sets with smaller sample sizes.

Do changes in DNA methylation mediate or interact with SNP variation? A pharmacoepigenetic analysis

BackgroundIn studies with multi-omics data available, there is an opportunity to investigate interdependent mechanisms of biological causality. The GAW20 data set includes both DNA genotype and methylation measures before and after fenofibrate treatment. Using change in triglyceride (TG) levels pre- to posttreatment as outcome, we present a mediation analysis that incorporates methylation. This approach allows us to simultaneously consider a mediation hypothesis that genotype affects change in TG level by means of its effect on methylation, and an interaction hypothesis that the effect of change in methylation on change in TG levels differs by genotype. We select 322 single-nucleotide polymorphism–cytosine-phosphate-guanine (SNP-CpG) site pairs for mediation analysis on the basis of proximity and marginal genome-wide association study (GWAS) and epigenome-wide association study (EWAS) significance, and present results from the real-data sample of 407 individuals with complete genotype, methylation, TG levels, and covariate data.ResultsWe identified 3 SNP-CpG site pairs with significant interaction effects at a Bonferroni-corrected significance threshold of 1.55E-4. None of the analyzed sites showed significant evidence of mediation. Power analysis by simulation showed that a sample size of at least 19,500 is needed to detect nominally significant indirect effects with true effect sizes equal to the point estimates at the locus with strongest evidence of mediation.ConclusionsThese results suggest that there is stronger evidence for interaction between genotype and methylation on change in triglycerides than for methylation mediating the effect of genotype.

Evaluating the performance of gene-based tests of genetic association when testing for association between methylation and change in triglyceride levels at GAW20

Although methylation data continues to rise in popularity, much is still unknown about how to best analyze methylation data in genome-wide analysis contexts. Given continuing interest in gene-based tests for next-generation sequencing data, we evaluated the performance of novel gene-based test statistics on simulated data from GAW20. Our analysis suggests that most of the gene-based tests are detecting real signals and maintaining the Type I error rate. The minimum p value and threshold-based tests performed well compared to single-marker tests in many cases, especially when the number of variants was relatively large with few true causal variants in the set.