RESUMEN

BACKGROUND: The effect of proprotein convertase subtilisin kexin type (PCSK9) inhibitors on blood lipids and major adverse cardiovascular events (MACEs) is still controversial for acute coronary syndrome (ACS) patients. This study aimed to evaluate the efficacy and safety of PCSK9 inhibitors for ACS patients. METHODS: We searched the following databases until March 2023: PubMed, Embase, Cochrane, Web of Science, CNKI, Chongqing VIP Database and Wan Fang Database. Finally, all randomized controlled trials, retrospective studies and prospective studies were included in the analysis. RESULTS: A total of 20 studies involving 48,621 patients were included in this meta-analysis. The results demonstrated that PCSK9 inhibitors group was more beneficial for ACS patients compared to control group (receiving statins alone or placebo). The meta-analysis showed: there was no significant difference in high density lipoprotein cholesterol between PCSK9 inhibitors group and control group (standard mean difference = 0.17, 95% confidence interval [CI]: -0.02 to 0.36, P = .08), while the level of low density lipoprotein cholesterol in PCSK9 inhibitors group was lower than that in control group (standard mean difference = -2.32, 95% CI: -2.81 to -1.83, P < .00001). Compared with the control group, the PCSK9 inhibitors group also decreased the levels of total cholesterol and triglycerides (mean difference = -1.24, 95% CI: -1.40 to -1.09, P < .00001, mean difference = -0.36, 95% CI: -0.56 to -0.16, P = .0004). Moreover, compared with the control group, PCSK9 inhibitors group could reduce the incidence of MACEs (relative risk [RR] = 0.87, 95% CI: 0.83-0.91; P < .00001). However, this study showed that the incidence of drug-induced adverse events in PCSK9 inhibitors group was higher than that in the control group (RR = 1.15, 95% CI: 1.05-1.25, P < .0001). CONCLUSION: Although this study demonstrates that PCSK9 inhibitors have higher drug-induced adverse events, they can not only reduce low-density lipoprotein cholesterol levels but also reduce the incidence of MACEs simultaneously. However, these findings needed to be further verified through large sample, multicenter, double-blind randomized controlled trials.

Asunto(s)

Síndrome Coronario Agudo , Inhibidores de PCSK9 , Humanos , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/sangre , LDL-Colesterol/sangre , LDL-Colesterol/efectos de los fármacos , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Proproteína Convertasa 9

RESUMEN

Amiodarone is an antiarrhythmic drug which may be associated with thyroid dysfunction. Type I amiodarone-induced thyrotoxicosis (AIT) is treated with thionamides and type II AIT is treated with glucocorticoids. Combined therapy is used in mixed or indeterminate forms. When medical treatment is unsuccessful, radioiodine ablation or thyroidectomy is considered. This report reviews a case of AIT refractory to conventional treatment. Despite high doses of methimazole and prednisone, the patient remained clinically and biochemically thyrotoxic. Cholestyramine, a bile salt sequestrant, was used as an off-label adjunctive treatment resulting in significant improvement and achievement of euthyroidism that may also be in part due to the expected natural timeline of recovery from AIT after several months. The patient subsequently trended towards hypothyroidism with symptomatic weight gain and cold intolerance for which he was initiated on levothyroxine.

Asunto(s)

Amiodarona , Antiarrítmicos , Resina de Colestiramina , Tirotoxicosis , Humanos , Tirotoxicosis/inducido químicamente , Tirotoxicosis/tratamiento farmacológico , Amiodarona/efectos adversos , Resina de Colestiramina/uso terapéutico , Masculino , Antiarrítmicos/efectos adversos , Tiroxina/uso terapéutico , Anticolesterolemiantes/efectos adversos

RESUMEN

Randomized clinical trials (RCTs) of PCSK9 monoclonal antibody(mAb) specifically for Chinese patients have been limited. This multi-center RCT is to clarify the efficacy and safety of a novel mAb, Ebronucimab, in Chinese patients. Patients diagnosed with primary hypercholesterolemia, including Heterozygous Familial Hypercholesterolemia, or mixed dyslipidemia, were categorized by ASCVD risk and randomly assigned at a ratio of 2:1:2:1 to receive Ebronucimab 450 mg or matching placebo every 4 weeks (Q4W), or Ebronucimab 150 mg or matching placebo every 2 weeks (Q2W). The primary outcome was the percentage change of LDL-C from baseline to week 12 for all groups. The least squares mean reduction difference (95 %CI) in LDL-C from baseline to week 12 of Ebronucimab 450 mg Q4W and Ebronucimab 150 mg Q2W groups versus the placebo group was -59.13 (-64.103, -54.153) (Adjusted p<0.0001) and -60.43 (-65.450, -55.416) (Adjusted p<0.0001), respectively. Meanwhile, the Ebronucimab group exhibited notably high rates in reaching LDL-C goals of each cardiovascular risk stratification. In addition, Ebronucimab effectively improved other lipid panel. During the double-blind treatment period, relatively frequently reported adverse events (AEs) were injection site reactions (ISR), urinary tract infection, and hyperuricemia (Incidence rate are 6.9 %, 4.8 % and 3.5 %). Among treatment-associated AEs, only injection site reactions (ISR) occurred more in the dose groups. In conclusion, Ebronucimab, with either 450 mg Q4W or 150 mg Q2W doses, demonstrated significant efficacy in lowering serum LDL-C level with a favorable safety and immunogenicity profile among hypercholesterolemic patients.

Asunto(s)

Anticuerpos Monoclonales Humanizados , LDL-Colesterol , Hipercolesterolemia , Humanos , Masculino , Persona de Mediana Edad , Método Doble Ciego , Femenino , Hipercolesterolemia/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , LDL-Colesterol/sangre , Adulto , Resultado del Tratamiento , Pueblo Asiatico , Anciano , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , China , Pueblos del Este de Asia , Proproteína Convertasa 9

RESUMEN

BACKGROUND: It remains controversial whether adding ezetimibe to low/moderate-intensity statins has a more beneficial impact on the treatment efficacy and safety of patients with existing atherosclerotic cardiovascular disease (ASCVD) compared to high-intensity statin regimens. HYPOTHESIS: A combination of low/moderate-intensity statins plus ezetimibe might be more effective and safer than high-intensity statin monotherapy. METHODS: We searched databases for randomized controlled trials comparing lipid profile alterations, drug-related adverse events, and MACE components between high-intensity statin monotherapy and low/moderate-intensity statin plus ezetimibe combination therapy. Pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (95% CI) were estimated using a random-effects model. RESULTS: Our comprehensive search resulted in 32 studies comprising 6162 patients treated with monotherapy against 5880 patients on combination therapy. Combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels compared to monotherapy (MD = -6.6, 95% CI: -10.6 to -2.5); however, no significant differences were observed in other lipid parameters. Furthermore, the combination therapy group experienced a lower risk of myalgia (RR = 0.27, 95% CI: 0.13-0.57) and discontinuation due to adverse events (RR = 0.61, 95% CI: 0.51-0.74). The occurrence of MACE was similar between the two treatment groups. CONCLUSIONS: Adding ezetimibe to low/moderate-intensity statins resulted in a greater reduction in LDL-C levels, a lower rate of myalgia, and less drug discontinuation compared to high-intensity statin monotherapy in patients with existing cardiovascular disease. However, according to our meta-analysis, the observed reduction in LDL-C levels in the combination group did not correlate with a reduction in MACE compared to the high-intensity statin group.

Asunto(s)

Anticolesterolemiantes , LDL-Colesterol , Quimioterapia Combinada , Ezetimiba , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Ezetimiba/uso terapéutico , Ezetimiba/administración & dosificación , Ezetimiba/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , LDL-Colesterol/sangre , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Resultado del Tratamiento , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/sangre , Biomarcadores/sangre

RESUMEN

INTRODUCTION: Patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) and concomitant multivessel coronary artery disease (CAD) are considered patients with extremely high-risk atherosclerotic cardiovascular disease (ASCVD), and current guidelines specify a lower low-density lipoprotein cholesterol (LDL-C) target for this population. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to effectively reduce LDL-C levels on a statin background. Additionally, several studies have confirmed the role of PCSK9 inhibitors in plaque regression and reducing residual cardiovascular risk in patients with ACS. However, those studies included coronary lesions with a degree of stenosis <50%. Whether the application of PCSK9 inhibitors in patients with NSTE-ACS with non-culprit artery critical lesions (stenosis degree between 50% and 75%) has a similar effect on plaque regression and improvement of cardiovascular outcomes remains unknown, with a lack of relevant research. This study aims to further investigate the safety and efficacy of evolocumab in patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%). METHODS AND ANALYSIS: In this single-centre clinical randomised controlled trial, 122 patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%) will be randomly assigned to either the evolocumab treatment group or the standard treatment group after completing culprit vessel revascularisation. The evolocumab treatment group will receive evolocumab in addition to statin therapy, while the standard treatment group will receive standard statin therapy. At baseline and week 50, patients in the evolocumab treatment group will undergo coronary angiography and OCT imaging to visualise pre-existing non-lesional vessels. The primary end point is the absolute change in average minimum fibrous cap thickness (FCT) from baseline to week 50. Secondary end points include changes in plaque lipid arc, lipid length, macrophage grading, lipid levels and major adverse cardiovascular events during the 1-year follow-up period. ETHICS AND DISSEMINATION: Ethics: this study will adhere to the principles outlined in the Helsinki Declaration and other applicable ethical guidelines. This study protocol has received approval from the Medical Research Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), with approval number 2022-ky214. DISSEMINATION: we plan to disseminate the findings of this study through various channels. This includes publication in peer-reviewed academic journals, presentation at relevant academic conferences and communication to the public, policymakers and healthcare professionals. We will also share updates on the research progress through social media and other online platforms to facilitate the exchange and application of scientific knowledge. Efforts will be made to ensure widespread dissemination of the research results and to have a positive impact on society. TRIAL REGISTRATION NUMBER: ChiCTR2200066675.

Asunto(s)

Síndrome Coronario Agudo , Anticuerpos Monoclonales Humanizados , Enfermedad de la Arteria Coronaria , Inhibidores de PCSK9 , Humanos , Síndrome Coronario Agudo/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , LDL-Colesterol/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/diagnóstico por imagen , Femenino , Masculino , Resultado del Tratamiento , Persona de Mediana Edad , Proproteína Convertasa 9

RESUMEN

BACKGROUND: High-intensity statin therapy is currently recommended initial guideline therapy in ACS treatment. However, only a minority of patients are achieving LDL-C attainment goal at 6 months. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are on recommended guideline therapy post-ACS if LDL-C goal attainment is not achieved after high-intensity statin (4-6 weeks) and after the addition of ezetimibe if guideline goal attainment is not achieved after an additional 4-6 weeks. Thus, it has been recommended that PCSK9 inhibitors be considered earlier post-ACS. However, the efficacy of early PCSK9 inhibitors initiation in ACS patients remains uncertain. METHODS: This systematic review and meta-analysis was conducted following PRISMA guidelines. Randomized controlled trials (RCTs) and observational studies involving ACS patients who received PCSK9 inhibitors within 48 h of hospitalization were included. Common and random effects models were used to evaluate the pooled effect of early PCSK9 inhibitor administration. Nine RCTs and three cohort studies were included. RESULTS: Early PCSK9 inhibitor administration reduced the incidence of MI, ACS hospitalization, and revascularization at 6-18 months post-ACS. Although there was a drift towards reduced stroke, all-cause mortality, and cardiovascular death, no statistically significant reduction was observed. Additionally, PCSK9 inhibitors significantly enhanced lipid control at 4-12 weeks after index hospitalization. CONCLUSION: Early PCSK9 inhibitors initiation in ACS patients reduces MACE and improves lipid profiles. While the results propose promising benefits in terms of stroke and mortality, further research with longer follow-up is required for more decisive evidence.

Asunto(s)

Síndrome Coronario Agudo , Biomarcadores , Inhibidores de PCSK9 , Humanos , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/mortalidad , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/diagnóstico , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/uso terapéutico , Biomarcadores/sangre , LDL-Colesterol/sangre , Esquema de Medicación , Dislipidemias/tratamiento farmacológico , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/mortalidad , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Infarto del Miocardio/mortalidad , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/diagnóstico , Revascularización Miocárdica , Estudios Observacionales como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Inhibidores de Serina Proteinasa/efectos adversos , Inhibidores de Serina Proteinasa/uso terapéutico , Inhibidores de Serina Proteinasa/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

BACKGROUND: Evolocumab and alirocumab are self-injected proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors indicated for low-density lipoprotein cholesterol reduction. Complications in the use or functionality of self-injection devices may precipitate incomplete dosing. OBJECTIVE: This study sought to characterize postmarketing dosing failure reports involving self-injected PCSK9 inhibitors. METHODS: US Food and Drug Administration Adverse Event Reporting System (FAERS) [2016-second quarter of 2023] data were utilized for a disproportionality analysis. Eight self-injected comparator medications served as referents. Medical Dictionary for Regulatory Activities preferred terms indicating explicit or probable failure to administer a complete dose classified cases. Proportional reporting ratios (PRRs) > 2.0 and lower 95% confidence intervals (CIs) > 1.0 indicated disproportionality signals. US FDA Manufacturer and User Facility Device Experience (MAUDE) [2013-2023] data underwent a narrative review. RESULTS: During the study period, 194,781 (evolocumab, n = 152,831; alirocumab, n = 41,950) drug-event pairs and 43,725 (evolocumab, n = 38,489; alirocumab, n = 5236) cases reported to FAERS identified PCSK9 inhibitors. MAUDE contained six evolocumab reports, half describing dose omission, and no alirocumab reports. A potential dosing failure signal was detected for evolocumab (PRR 2.01; 95% CI 1.98-2.03), but not alirocumab (PRR 0.99; 95% CI 0.97-1.02), relative to pooled comparator reports. Across three case term subcategories, incomplete dosing disproportionality signals were further identified for evolocumab patient usage complication terms (PRR 3.44; 95% CI 3.38-3.50) and alirocumab device malfunction terms (PRR 2.09; 95% CI 1.98-2.22). CONCLUSIONS: Proprotein convertase subtilisin kexin type 9 inhibitor incomplete dosing-related complications are frequently reported in the postmarketing setting. Systematic efforts to understand the incidence and mechanisms of dosing failure and associated patient burdens are needed.

Asunto(s)

Sistemas de Registro de Reacción Adversa a Medicamentos , Anticuerpos Monoclonales Humanizados , Inhibidores de PCSK9 , Vigilancia de Productos Comercializados , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Estados Unidos , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , United States Food and Drug Administration , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/uso terapéutico , Femenino , Masculino , LDL-Colesterol/sangre , Persona de Mediana Edad , Proproteína Convertasa 9

RESUMEN

BACKGROUND/AIMS: Achieving rapid reduction of low-density lipoprotein cholesterol (LDL-C) levels below 55 mg/dL in patients with acute myocardial infarction (AMI) can be challenging with statins alone. This single-center, retrospective study aimed to assess the impact of single-dose injection of evolocumab 140 mg on LDL-C levels during the peri-percutaneous coronary intervention (PCI) period in patients with AMI. METHODS: A total of 95 patients with AMI who underwent PCI were divided into the evolocumab (n = 50) and non-evolocumab (n = 45) groups. RESULTS: The percentage change of LDL-C level at 1-3 weeks from baseline was 78.4 ± 13.4% reduction in the evolocumab group versus 45.6 ± 22.6% in the non-evolocumab group, with a mean difference of -33.5% between the groups (95% CI: -42.6 to -24.5%; p < 0.001). The achievement rate of LDL-C levels below 55 mg/dL at 1-3 weeks was significantly higher in the evolocumab group than in the non-evolocumab group (97.7% vs. 60.0%, p < 0.001). CONCLUSION: Patients with AMI who received single-dose injection of evolocumab 140 mg during the peri-PCI period had a significantly greater LDL-C reduction and higher proportion of patients achieved the target LDL-C level in the early phase AMI than those who did not receive evolocumab.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Anticolesterolemiantes , LDL-Colesterol , Infarto del Miocardio , Intervención Coronaria Percutánea , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , LDL-Colesterol/sangre , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/sangre , Infarto del Miocardio/diagnóstico , Factores de Tiempo , Biomarcadores/sangre , Dislipidemias/tratamiento farmacológico , Dislipidemias/sangre , Dislipidemias/diagnóstico , Inhibidores de PCSK9 , Proproteína Convertasa 9

RESUMEN

In this case report, a 31-year-old woman with heterozygous familial hypercholesterolaemia (FH) underwent treatment with statins and PCSK9 inhibitor but had to discontinue due to elevated creatine kinase levels and neurological and muscular side effects. In 2021, the patient received inclisiran therapy, the first known instance of its application in Denmark. No side effects were reported, and LDL cholesterol levels were significantly reduced. This case report highlights the potential of inclisiran as an effective and well-tolerated treatment for individuals with heterozygous FH.

Asunto(s)

Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hiperlipoproteinemia Tipo II , Inhibidores de PCSK9 , Humanos , Femenino , Adulto , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , LDL-Colesterol/sangre , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos

RESUMEN

This is a case report of a 70-year-old woman with possible cholestyramine-induced bowel perforation. She had a prior history of pancreaticoduodenectomy for pancreatic cancer with a daily intake of cholestyramine. She underwent emergency laparotomy for small bowel perforation twice. Subsequent pathology reports showed crystal depositions in the small bowel wall. Leasions spread out on the small bowel and the omentum during the second surgery were thought to be carcinomatosis. However, the pathology report showed no malignant cells but plenty of crystal depositions as seen with cholestyramine intake.

Asunto(s)

Resina de Colestiramina , Perforación Intestinal , Humanos , Anciano , Femenino , Perforación Intestinal/cirugía , Perforación Intestinal/inducido químicamente , Perforación Intestinal/etiología , Resina de Colestiramina/efectos adversos , Intestino Delgado/patología , Intestino Delgado/cirugía , Pancreaticoduodenectomía/efectos adversos , Anticolesterolemiantes/efectos adversos , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología

RESUMEN

BACKGROUND: Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials. METHODS: We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined. RESULTS: We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04). CONCLUSIONS: Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Anticolesterolemiantes , LDL-Colesterol , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , LDL-Colesterol/sangre , Masculino , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Femenino , Resultado del Tratamiento , Persona de Mediana Edad , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/sangre , Inhibidores de PCSK9/uso terapéutico , Anciano , Proproteína Convertasa 9

RESUMEN

BACKGROUND: The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator. METHODS: Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration. RESULTS: We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, p = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, p = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, p < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, p < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, p = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p = 0.03; 12-24 weeks OR 2.12, 95% CI 1.20 to 3.73, p = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, p = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, p = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, p = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, p < 0.01). CONCLUSION: Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Inhibidores de PCSK9 , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Humanos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Femenino , Proproteína Convertasa 9/metabolismo , Masculino , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/epidemiología

RESUMEN

BACKGROUND AND AIMS: Limited evidence exist regarding the association between ongericimab, a novel recombinant humanized anti-PCSK9 monoclonal antibody, and primary hypercholesterolemia and mixed dyslipidemia. This study aimed to evaluate the efficacy and safety of ongericimab administered by prefilled syringe (PFS) or autoinjector (AI) in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia on stable optimized lipid-lowering therapy. METHODS AND RESULTS: A total of 255 patients on stable optimized lipid-lowering therapy were randomized in a 2:1:2:1 ratio to receive PFS for the subcutaneous injection of ongericimab 150 mg every 2 weeks (Q2W) or a matching placebo, or AI for the subcutaneous injection of ongericimab 150 mg Q2W or a matching placebo. The primary efficacy endpoint was the percent change in low-density lipoprotein cholesterol (LDL-C) levels from baseline to week 12. Safety was also evaluated. At week 12, the least squares mean percent changes were -72.7% (3.9%) for PFS and -71.1% (3.8%) for AI (all P < 0.001) compared to respective matching placebo groups. Beneficial effects were also seen for all secondary lipid parameters, notably with robust reduction in Lp (a). Treatment-emergent adverse events (TEAEs) and serious AEs with ongericimab were reported in 46.2% and 2.4% of patients, compared to 44.2% and 3.5% with placebo. CONCLUSION: In Chinese patients with primary hypercholesterolemia and mixed dyslipidemia, a 12-week treatment regimen with ongericimab administered by PFS or AI significantly reduced LDL-C and other lipid parameters, proving to be safe and well tolerated. Patients experienced consistent effects from PFS or AI devices. CLINICAL TRIAL REGISTRATION: CTR20220027; January 11, 2022; http://www.chinadrugtrials.org.cn/index.html.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Biomarcadores , LDL-Colesterol , Hipercolesterolemia , Inhibidores de PCSK9 , Jeringas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/sangre , Hipercolesterolemia/diagnóstico , Resultado del Tratamiento , China , LDL-Colesterol/sangre , Inyecciones Subcutáneas , Anciano , Factores de Tiempo , Biomarcadores/sangre , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Método Doble Ciego , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/administración & dosificación , Adulto , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/diagnóstico , Hiperlipidemias/sangre , Proproteína Convertasa 9

RESUMEN

ABSTRACT: In vitro investigations have established metformin's capacity to downregulate proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (cholesterol-lowering agents alone: atorvastatin ± ezetimibe, n = 38) and Met + CLA groups (metformin plus CLA, n = 33) in a 1:1 ratio. The primary end point was the therapeutic impact of 1-month metformin combination treatment on low-density lipoprotein cholesterol (LDL-C) and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL -1 and 80.54 ng·mL -1 , respectively. After 1 month, metformin significantly reduced LDL-C (-20.81%, P < 0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (-15.03%, P < 0.001) were observed. Moreover, Met + CLA markedly reduced LDL particle number more than CLA alone (-10.65% vs. 1.45%, P = 0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a 1-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR1900026925 (26/10/2019).

Asunto(s)

Biomarcadores , LDL-Colesterol , Enfermedad de la Arteria Coronaria , Quimioterapia Combinada , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Metformina , Inhibidores de PCSK9 , Proproteína Convertasa 9 , Humanos , Metformina/farmacología , Masculino , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/sangre , Persona de Mediana Edad , Femenino , LDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Proproteína Convertasa 9/metabolismo , Anciano , Resultado del Tratamiento , Biomarcadores/sangre , Factores de Tiempo , Atorvastatina/efectos adversos , Atorvastatina/uso terapéutico , Ezetimiba/uso terapéutico , Ezetimiba/efectos adversos , Dislipidemias/tratamiento farmacológico , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/enzimología , Inhibidores de Serina Proteinasa/efectos adversos , Inhibidores de Serina Proteinasa/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/uso terapéutico

RESUMEN

BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH. METHODS: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy. RESULTS: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. CONCLUSIONS: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.

Asunto(s)

LDL-Colesterol , Hiperlipoproteinemia Tipo II , Humanos , Femenino , Masculino , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Adolescente , Adulto , LDL-Colesterol/sangre , Persona de Mediana Edad , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Resultado del Tratamiento , Adulto Joven , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Niño , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Homocigoto

Asunto(s)

Inhibidores de PCSK9 , Humanos , Proproteína Convertasa 9 , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , LDL-Colesterol/sangre

RESUMEN

BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9, as an add-on treatment to optimized lipid-lowering therapy in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia. METHODS AND RESULTS: A total of 806 patients who were receiving stable and optimized lipid-lowering therapy but did not achieve their low-density lipoprotein cholesterol (LDL-C) targets were enrolled and randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks, or ongericimab 300 mg or matching placebo every 4 weeks for 52 weeks. Efficacy and safety were evaluated in 802 patients who received at least 1 dose of ongericimab or placebo. The primary end point was the percentage change in LDL-C from baseline to week 24. Our findings demonstrated that the least-squares mean difference of percentage change in LDL-C from baseline to week 24 was -67.7% (95% CI, -72.5% to -63.0%; P<0.0001) in the ongericimab 150 mg every 2 weeks group compared with the placebo every 2 weeks group, and -61.2% (95% CI, -67.1% to -55.2%; P<0.0001) in the ongericimab 300 mg every 4 weeks group compared with the placebo every 4 weeks group. These reductions were sustained up to week 52. Furthermore, treatment with ongericimab favorably altered other lipid parameters. A similar incidence of adverse events was observed in the ongericimab and placebo groups. CONCLUSIONS: Ongericimab, as an add-on treatment to optimized lipid-lowering therapy, significantly reduced LDL-C and was well-tolerated in Chinese patients with primary hyperlipidemia and mixed dyslipidemia who did not achieve their LDL-C targets. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04781114.

Asunto(s)

LDL-Colesterol , Dislipidemias , Hipercolesterolemia , Inhibidores de PCSK9 , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/administración & dosificación , Pueblo Asiatico , Biomarcadores/sangre , China , LDL-Colesterol/sangre , Método Doble Ciego , Quimioterapia Combinada , Dislipidemias/tratamiento farmacológico , Dislipidemias/sangre , Dislipidemias/diagnóstico , Pueblos del Este de Asia , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/sangre , Hipercolesterolemia/diagnóstico , Inhibidores de PCSK9/uso terapéutico , Proproteína Convertasa 9/inmunología , Proproteína Convertasa 9/metabolismo , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) remain at very high cardiovascular risk despite the best standard of care lipid-lowering treatment. The addition of evinacumab, an angiopoietin-like protein 3 monoclonal antibody, more than halves low-density lipoprotein cholesterol in short-term studies. This study evaluated whether the evinacumab response was durable in the long term and improved cardiovascular outcome. METHODS: The OLE ELIPSE HoFH (Open-Label Extension to Evinacumab Lipid Studies in Patients With HoFH) study included newly diagnosed patients and those completing the ELIPSE HoFH trial, on stable lipid-lowering therapy including lipoprotein apheresis but not lomitapide. All patients received evinacumab (15 mg/kg intravenously) every 4 weeks, with no change in concomitant lipid-lowering treatment during the first 6 months. The primary efficacy end points were the mean absolute and percentage changes in low-density lipoprotein cholesterol from baseline to 6 months. A key secondary end point was cardiovascular event-free survival, which was compared with a control HoFH cohort not treated with evinacumab or lomitapide and matched for age, sex, and lipoprotein apheresis, derived from French Registry of Familial hypercholesterolemia. RESULTS: Twelve patients, 5 women and 7 men (12-57 years), were enrolled in 3 centers in France. At 6 months, the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to 2.8 mmol/L; P<0.0001) and was sustained over the median 3.5-year follow-up. No patients on evinacumab experienced cardiovascular events versus 13 events for 5/21 (24%) over 4 years in the control cohort (likelihood P=0.0267). CONCLUSIONS: Real-life, long-term evinacumab adjunctive to lipid-lowering therapy including lipoprotein apheresis led to sustained low-density lipoprotein cholesterol lowering and improved cardiovascular event-free survival of patients with HoFH.

Asunto(s)

Proteína 3 Similar a la Angiopoyetina , Anticolesterolemiantes , LDL-Colesterol , Homocigoto , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/mortalidad , Masculino , Femenino , LDL-Colesterol/sangre , Adulto , Persona de Mediana Edad , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Eliminación de Componentes Sanguíneos , Biomarcadores/sangre , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Factores de Tiempo , Supervivencia sin Progresión , Adulto Joven , Resultado del Tratamiento , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/epidemiología , Adolescente

RESUMEN

PURPOSE: The objective of this investigation is to examine the benefits and potential risks of these drugs in individuals by varying baseline low-density lipoprotein cholesterol (LDL-C) values, utilizing the concept of the number needed to treat (NNT). METHODS: We extensively searched electronic databases, such as PubMed, EMBASE, Cochrane, and Web of Science, up to 6 August 2023. Baseline LDL-C values were stratified into four categories: < 100, 100-129, 130-159, and ≥ 160 mg/dL. Risk ratios (RRs) and NNT values were computed. RESULTS: This analysis incorporated data from 46 randomized controlled trials (RCTs), encompassing a total of 237,870 participants. The meta-regression analysis demonstrated an incremental diminishing risk of major adverse cardiovascular events (MACE) with increasing baseline LDL-C values. Statins exhibited a significant reduction in MACE [number needed to treat to benefit (NNTB) 31, 95% confidence interval (CI) 25-37], but this effect was observed only in individuals with baseline LDL-C values of 100 mg/dL or higher. Ezetimibe and PCSK9 inhibitors also were effective in reducing MACE (NNTB 18, 95% CI 11-41, and NNTB 18, 95% CI 16-24). Notably, the safety outcomes of statins and ezetimibe did not reach statistical significance, while the incidence of injection-site reactions with PCSK9 inhibitors was statistically significant [number needed to treat to harm (NNTH) 41, 95% CI 80-26]. CONCLUSION: Statins, ezetimibe, and PCSK9 inhibitors demonstrated a substantial capacity to reduce MACE, particularly among individuals whose baseline LDL-C values were relatively higher. The NNT visually demonstrates the gradient between baseline LDL-C and cardiovascular disease (CVD) risk. SYSTEMATIC REVIEW REGISTRATION: Registration: PROSPERO identifier number: CRD42023458630.

Asunto(s)

Enfermedades Cardiovasculares , LDL-Colesterol , Humanos , LDL-Colesterol/sangre , Enfermedades Cardiovasculares/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipolipemiantes/uso terapéutico , Hipolipemiantes/efectos adversos , Números Necesarios a Tratar , Ezetimiba/uso terapéutico , Ezetimiba/efectos adversos , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Inhibidores de PCSK9 , Medición de Riesgo , Adulto

RESUMEN

Safety data on the use of monoclonal antibodies inhibiting proprotein convertase subtilisin/kexin type 9 in pregnancy are scarce. This study queried VigiBase®, the World Health Organization global pharmacovigilance database, to search for signals of disproportionate reporting for pregnancy outcomes with alirocumab and evolocumab. As of November 22, 2023, there were 45 safety reports of exposure to evolocumab (N = 31) and alirocumab (N = 14) in pregnancy. Most of them originated from Europe (N = 25, 55.6%) and were more frequently reported by healthcare professionals (N = 35, 77.8%). Median patient age was 37 years (25th-75th percentiles; 32-41 years). Drug exposure occurred during pregnancy in 36 (80.0%) safety reports, via paternal exposure during pregnancy in four (8.9%), during lactation in three (6.7%), and in two safety reports the time of drug exposure remained unknown. Twenty safety reports (57.8%) merely reported drug exposure, while 19 (42.2%) also reported pregnancy outcomes, however, without specific maternal toxicities or patterns of birth defects. Spontaneous abortion was reported in eight safety reports without representing a signal of disproportionate reporting compared with either the full database (reporting odds ratio, ROR, 0.06 95% confidence interval, CI 0.03-0.12) or statins (ROR 0.16, 95% CI 0.08-0.32). In conclusion, this study showed that, currently, there are no signals of increased reporting of spontaneous abortion with alirocumab and evolocumab compared with the full database and statins in VigiBase®. Notwithstanding, lack of disproportionality is not synonymous with safety and, as disproportionality analyses depend on the number of safety reports that progressively accumulate in VigiBase®, they should be repeated at regular intervals to confirm the results of the present study.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Inhibidores de PCSK9 , Farmacovigilancia , Humanos , Embarazo , Femenino , Anticuerpos Monoclonales Humanizados/efectos adversos , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Bases de Datos Factuales , Resultado del Embarazo/epidemiología , Anticuerpos Monoclonales/efectos adversos , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/inmunología , Anticolesterolemiantes/efectos adversos , Proproteína Convertasa 9/inmunología