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International Journal of Cardiology Jul 2024The effects of bempedoic acid on mortality in the secondary prevention setting have not been examined.
BACKGROUND
The effects of bempedoic acid on mortality in the secondary prevention setting have not been examined.
METHODS
We used data from the overall and primary prevention reports of CLEAR - Outcomes to reconstruct data for the secondary prevention population. A Bayesian analyses was employed to calculate the posterior probability of benefit or harm for the outcomes of all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE). Relative effect sizes are presented as risk ratios (RR) with 95% credible intervals (CrI), which represent the intervals that true effect sizes are expected to fall in with 95% probability, given the priors and model.
RESULTS
In primary prevention, the posterior probability of bempedoic acid decreasing all-cause and cardiovascular mortality was 99.4% (RR: 0.70; 95% CrI: 0.51 to 0.92) and 99.7% (RR: 0.58; 95% CrI: 0.38 to 0.86) respectively. In secondary prevention, the posterior probability of bempedoic acid increasing all-cause and cardiovascular mortality was 96.6% (RR: 1.15; 95% CrI: 0.99 to 1.33) and 97.2% (RR: 1.21; 95% CrI: 1.00 to 1.45) respectively. The probability of bemepdoic acid reducing MACE in the primary and secondary prevention settings was 99.9% (RR: 0.70; 95% CrI: 0.54 to 0.88) and 95.8% (RR: 0.92; 95% CrI: 0.84 to 1.01) respectively.
CONCLUSION
In contrast to its effect in the primary prevention subgroup of CLEAR - Outcomes, bempedoic acid resulted in a more modest MACE reduction and a potential increase in mortality in the secondary prevention subgroup. Whether these findings represent true treatment effect heterogeneity or the play of chance requires further evidence.
Topics: Aged; Female; Humans; Male; Middle Aged; Cardiovascular Diseases; Dicarboxylic Acids; Double-Blind Method; Fatty Acids; Primary Prevention; Secondary Prevention; Treatment Outcome
PubMed: 38643794
DOI: 10.1016/j.ijcard.2024.132074 -
Blood Aug 2023Targeted therapies for cutaneous T-cell lymphoma (CTCL) are limited and curative approaches are lacking. Furthermore, relapses and drug induced side effects are major...
Targeted therapies for cutaneous T-cell lymphoma (CTCL) are limited and curative approaches are lacking. Furthermore, relapses and drug induced side effects are major challenges in the therapeutic management of patients with CTCL, creating an urgent need for new and effective therapies. Pathologic constitutive NF-κB activity leads to apoptosis resistance in CTCL cells and, thus, represents a promising therapeutic target in CTCL. In a preclinical study we showed the potential of dimethyl fumarate (DMF) to block NF-κB and, specifically, kill CTCL cells. To translate these findings to applications in a clinical setting, we performed a multicentric phase 2 study evaluating oral DMF therapy in 25 patients with CTCL stages Ib to IV over 24 weeks (EudraCT number 2014-000924-11/NCT number NCT02546440). End points were safety and efficacy. We evaluated skin involvement (using a modified severity weighted assessment tool [mSWAT]), pruritus, quality of life, and blood involvement, if applicable, as well as translational data. Upon skin analysis, 7 of 23 (30.4%) patients showed a response with >50% reduction in the mSWAT score. Patients with high tumor burden in the skin and blood responded best to DMF therapy. Although not generally significant, DMF also improved pruritus in several patients. Response in the blood was mixed, but we confirmed the NF-κB-inhibiting mechanism of DMF in the blood. The overall tolerability of the DMF therapy was very favorable, with mostly mild side effects. In conclusion, our study presents DMF as an effective and excellently tolerable therapeutic option in CTCL to be further evaluated in a phase 3 study or real-life patient care as well as in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT02546440.
Topics: Humans; Dimethyl Fumarate; NF-kappa B; Quality of Life; Skin Neoplasms; Neoplasm Recurrence, Local; Lymphoma, T-Cell, Cutaneous; Pruritus
PubMed: 37217183
DOI: 10.1182/blood.2022018669 -
Actas Urologicas Espanolas 2024Nephrolithiasis is a globally prevalent urologic condition associated with significant morbidity and patient discomfort. Current management of kidney stones includes... (Review)
Review
Nephrolithiasis is a globally prevalent urologic condition associated with significant morbidity and patient discomfort. Current management of kidney stones includes both surgical and pharmacologic interventions. Though surgery may be necessary under certain circumstances, pharmacologic treatment is a more affordable, readily available, and a less invasive option for patients. A comprehensive scoping review was conducted to summarize the available literature on the pharmacologic strategies for managing the predominant stone types including calcium oxalate, calcium phosphate, uric acid, struvite, and cystine stones. Central to these therapeutic approaches is the regulation of factors such as urine pH, stone crystallization, and patient metabolics that precipitate stone development and growth. This review highlights the pharmacological options available for treating each kidney stone type, emphasizing the importance of patient tailored medical management that should be considered by every physician.
Topics: Humans; Kidney Calculi; Calcium Oxalate; Uric Acid; Hydrogen-Ion Concentration
PubMed: 38043680
DOI: 10.1016/j.acuroe.2023.11.008 -
Frontiers in Immunology 2023Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity...
BACKGROUND AND OBJECTIVE
Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity in the clinical practice. With this aim, we studied the immunophenotypic and transcriptomic changes produced by DMF in peripheral blood mononuclear cells (PBMCs) and its association with clinical response.
MATERIAL AND METHODS
PBMCs were obtained from 22 RRMS patients at baseline and 12 months of DMF treatment. Lymphocyte and monocyte subsets, and gene expression were assessed by flow cytometry and next-generation RNA sequencing, respectively. Clinical response was evaluated using the composite measure "no evidence of disease activity" NEDA-3 or "evidence of disease activity" EDA-3 at 2 years, classifying patients into responders (n=15) or non-responders (n=7), respectively.
RESULTS
In the whole cohort, DMF produced a decrease in effector (TEM) and central (TCM) memory T cells in both the CD4+ and CD8+ compartments, followed by an increase in CD4+ naïve T cells. Responder patients presented a greater decrease in TEM lymphocytes. In addition, responder patients showed an increase in NK cells and were resistant to the decrease in the intermediate monocytes shown by non-responders. Responder patients also presented differences in 3 subpopulations (NK bright, NK dim and CD8 TCM) at baseline and 4 subpopulations (intermediate monocytes, regulatory T cells, CD4 TCM and CD4 TEMRA) at 12 months. DMF induced a mild transcriptional effect, with only 328 differentially expressed genes (DEGs) after 12 months of treatment. The overall effect was a downregulation of pro-inflammatory genes, chemokines, and activators of the NF-kB pathway. At baseline, no DEGs were found between responders and non-responders. During DMF treatment a differential transcriptomic response was observed, with responders presenting a higher number of DEGs (902 genes) compared to non-responders (189 genes).
CONCLUSIONS
Responder patients to DMF exhibit differences in monocyte and lymphocyte subpopulations and a distinguishable transcriptomic response compared to non-responders that should be further studied for the validation of biomarkers of treatment response to DMF.
Topics: Humans; Dimethyl Fumarate; Multiple Sclerosis; Immunosuppressive Agents; Leukocytes, Mononuclear; Killer Cells, Natural; Biomarkers
PubMed: 37483622
DOI: 10.3389/fimmu.2023.1209923 -
PloS One 2024Bempedoic acid, an innovative oral medication, has garnered significant interest in recent times due to its potential as a therapeutic intervention for... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Bempedoic acid, an innovative oral medication, has garnered significant interest in recent times due to its potential as a therapeutic intervention for hypercholesterolemia. Nonetheless, the outcomes of the initial investigations might have been more definitive and coherent. Our objective was to perform a quantitative meta-analysis in order to evaluate bempedoic acid's safety and effectiveness.
METHODS
A search was conducted on ClinicalTrials.gov, and PubMed from the time of inception until September 28, 2023. Randomized controlled trials comparing the safety and efficacy of bempedoic acid among patients with statin intolerance and those without were included in our analysis. The trial outcomes were summarized using a random effects model and were provided as mean differences or odds ratios (ORs) with a confidence interval of 95%. Additionally, trial heterogeneity and the possibility of bias were evaluated and investigated.
RESULTS
Bempedoic acid treatment reduced low-density lipoprotein cholesterol levels more than placebo (mean difference -2.97%, 95% CI -5.89% to -0.05%), according to a pooled analysis of 16 eligible trials. The risk of death (OR 1.18, 95% CI 0.70 to 1.98) and muscle-associated occurrences (OR 1.00, 95% CI 0.77 to 1.31) was not impacted by bempedoic acid. In contrast, discontinuation of treatment was more frequently caused by adverse events in the bempedoic acid group (OR 1.13, 95% CI 1.01 to 1.27).
CONCLUSIONS
In patients with statin intolerance as well as those without, bempedoic acid is a safe and efficacious lipid-lowering agent, according to findings from randomized controlled trials.
Topics: Humans; Dicarboxylic Acids; Fatty Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Randomized Controlled Trials as Topic
PubMed: 38277431
DOI: 10.1371/journal.pone.0297854 -
The Journal of Clinical Investigation Apr 2024Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an...
Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for nine weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized by many tissues. In tissues expressing the "a" isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.
PubMed: 38687608
DOI: 10.1172/JCI174186 -
Redox Biology Feb 2024Acute kidney injury (AKI), often experienced at the intensive care units, is associated with high morbidity/mortality where ischemia-reperfusion injury is a main...
BACKGROUND
Acute kidney injury (AKI), often experienced at the intensive care units, is associated with high morbidity/mortality where ischemia-reperfusion injury is a main causative factor. Succinate accumulation during ischemia contributes to the excessive generation of reactive oxygen species at reperfusion. Inhibition of succinate dehydrogenase has been associated with protective outcome in cardiac ischemia-reperfusion after 24h, but the effects on kidney and mitochondrial functions are less well studied.
AIM
To investigate the therapeutic potential of succinate dehydrogenase inhibition, by using dimethyl malonate (DMM), on kidney and mitochondria functions in a mouse model of AKI.
METHODS
Male C57BL/6J mice were pre-treated with DMM or placebo, i.p. 30min prior to bilateral renal ischemia (20min). After 3-days of reperfusion, glomerular filtration rate (GFR) was calculated from plasma clearance of FITC-inulin. Kidney mitochondria was isolated and mass specific and intrinsic mitochondrial function were evaluated by high resolution respirometry. Kidney sections were stained (i.e., hematoxylin-eosin and TUNEL) and analyzed for histopathological evaluation of injuries and apotosis, respectively. NADPH oxidase activity in kidney and human proximal tubular cell-line (HK2) were measured luminometrically.
RESULTS
DMM treatment improved GFR (p < 0.05) and reduced levels of blood urea nitrogen (p < 0.01) compared to untreated animals, which was associated with lower degree of ischemia-reperfusion-induced tubular injuries (P < 0.001) and apoptosis (P < 0.01). These therapeutic renal effects were linked with improved mitochondrial function, both mass-specific and intrinsic. Finally, DMM treatment prevented ischemia-reperfusion-induced NADPH oxidase activity in the kidney (p < 0.001), which was showed also in HK2 cells exposed to hypoxia and reoxygenation (P < 0.01).
CONCLUSION
Inhibition of succinate dehydrogenase with DMM, in conjunction with the ischemia-reperfusion phase, significantly improved both renal and mitochondrial functions. These findings may have clinical implications for future therapeutic strategies to prevent development of AKI and associated adverse complications, especially in high risk hospitalized patients.
Topics: Mice; Animals; Humans; Male; Succinate Dehydrogenase; Mice, Inbred C57BL; Kidney; Ischemia; Mitochondria; Reperfusion Injury; Acute Kidney Injury; Reperfusion; NADPH Oxidases; Malonates
PubMed: 38061207
DOI: 10.1016/j.redox.2023.102984 -
Nutrition Journal Nov 2023The inconsistent relationship between Vitamin B12 (B12), methylmalonic acid (MMA, marker of B12 deficiency) and mortality was poorly understood, especially in patients...
BACKGROUND
The inconsistent relationship between Vitamin B12 (B12), methylmalonic acid (MMA, marker of B12 deficiency) and mortality was poorly understood, especially in patients with coronary heart disease (CHD). This study aims to investigate the association of serum MMA, and B12-related biomarkers (serum level, dietary intake, supplement use, and sensibility to B12) with all-cause and cardiovascular mortality in adults with CHD.
METHODS
The data of this study were from a subcohort within the US National Health and Nutrition Examination Survey (NHANES). We included adults with preexisting CHD with serum MMA and B12, and dietary B12 intake measurements at recruitment. All participants were followed up until 31 December 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CI of mortality risk.
RESULTS
Overall, 1755 individuals (weighted mean [SE] age, 65.2 [0.5] years; 1047 men [weighted 58.5%]) with CHD were included, with geometric mean levels of serum MMA 182.4 nmol/L, serum B12 494.5 pg/ml, and dietary B12 intake 4.42 mg/day, and percentage of B12 supplements use 39.1%. During a median follow-up of 7.92 years, 980 patients died. Serum B12 concentration, dietary B12 intake and supplements use were not significantly associated with mortality risk (each p ≥ 0.388). In contrast, individuals in the top tertile of MMA had multivariable-adjusted HRs (95% CIs) of 1.70 (1.31-2.20) for all-cause mortality, and 2.00 (1.39-2.89) for cardiovascular mortality (both p trend < 0.001) compared to those in the bottom tertile of MMA. MMA-related mortality risk was particularly higher among participants with sufficient serum B12 (p < 0.001). CHD patients with increased levels of both MMA and B12 had a doubled mortality risk compared to those with lower MMA and B12 (p < 0.001).
CONCLUSION
MMA accumulation but not serum or dietary vitamin B12 was associated with increased cardiovascular mortality risk among patients with CHD. This paradox may be related to decreased response to vitamin B12.
Topics: Adult; Male; Humans; Aged; Vitamin B 12; Methylmalonic Acid; Nutrition Surveys; Vitamin B 12 Deficiency; Prospective Studies; Cardiovascular Diseases
PubMed: 38017447
DOI: 10.1186/s12937-023-00900-6 -
Applied Microbiology and Biotechnology Oct 2023Acyl-CoA-thioesterases, which hydrolyze acyl-CoA-esters and thereby release the respective acid, have essential functions in cellular metabolism and have also been used...
Acyl-CoA-thioesterases, which hydrolyze acyl-CoA-esters and thereby release the respective acid, have essential functions in cellular metabolism and have also been used to produce valuable compounds in biotechnological processes. Thioesterase YciA originating from Haemophilus influenzae has been previously used to produce specific dicarboxylic acids from CoA-bound intermediates of the ethylmalonyl CoA pathway (EMCP) in Methylorubrum extorquens. In order to identify variants of the YciA enzyme with the capability to hydrolyze so far inaccessible CoA-esters of the EMCP or with improved productivity, we engineered the substrate-binding region of the enzyme. Screening a small semi-rational mutant library directly in M. extorquens yielded the F35L variant which showed a drastic product level increase for mesaconic acid (6.4-fold) and 2-methylsuccinic acid (4.4-fold) compared to the unaltered YciA enzyme. Unexpectedly, in vitro enzyme assays using respective M. extorquens cell extracts or recombinantly produced thioesterases could not deliver congruent data, as the F35L variant showed strongly reduced activity in these experiments. However, applied in an Escherichia coli production strain, the protein variant again outperformed the wild-type enzyme by allowing threefold increased 3-hydroxybutyric acid product titers. Saturation mutagenesis of the codon for position 35 led to the identification of another highly efficient YciA variant and enabled structure-function interpretations. Our work describes an important module for dicarboxylic acid production with M. extorquens and can guide future thioesterase improvement approaches. KEY POINTS: • Substitutions at position F35 of YciAHI changed the productivity of YciA-based release of carboxylic acid products in M. extorquens AM1 and E. coli. • YciAHI F35N and F35L are improved variants for dicarboxylic production of 2-methylsuccinic acid and mesaconic acid with M. extorquens AM1. • In vitro enzyme assays did not reveal superior properties of the optimized protein variants.
PubMed: 37572123
DOI: 10.1007/s00253-023-12691-1 -
Frontiers in Immunology 2024Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell's metabolic activity to provide energy... (Review)
Review
Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell's metabolic activity to provide energy and biomolecules for inflammatory and proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns and cytokines upregulate expression of the enzyme ACOD1 that generates the immune-metabolite itaconate by decarboxylation of the TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well as immunomodulatory activities, which makes it attractive as endogenous effector metabolite fighting infection and restraining inflammation. Here, we first summarize the pathways and stimuli inducing ACOD1 expression in macrophages. The focus of the review then lies on the mechanisms by which itaconate, and its synthetic derivatives and endogenous isomers, modulate immune cell signaling and metabolic pathways. Multiple targets have been revealed, from inhibition of enzymes to the post-translational modification of many proteins at cysteine or lysine residues. The modulation of signaling proteins like STING, SYK, JAK1, RIPK3 and KEAP1, transcription regulators (e.g. Tet2, TFEB) and inflammasome components (NLRP3, GSDMD) provides a biochemical basis for the immune-regulatory effects of the ACOD1-itaconate pathway. While the field has intensely studied control of macrophages by itaconate in infection and inflammation models, neutrophils have now entered the scene as producers and cellular targets of itaconate. Furthermore, regulation of adaptive immune responses by endogenous itaconate, as well as by exogenously added itaconate and derivatives, can be mediated by direct and indirect effects on T cells and antigen-presenting cells, respectively. Taken together, research in ACOD1-itaconate to date has revealed its relevance in diverse immune cell signaling pathways, which now provides opportunities for potential therapeutic or preventive manipulation of host defense and inflammation.
Topics: Humans; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Signal Transduction; Inflammation; Succinates
PubMed: 38487538
DOI: 10.3389/fimmu.2024.1352165