Clinical Benefit of Bempedoic Acid in Randomized Clinical Trials.

Bempedoic acid is a selective inhibitor of the adenosine triphosphate citrate lyase that reduces low-density lipoprotein cholesterol (LDLc) levels by 17% to 28%. Although the Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (CLEAR-OUTCOMES) trials demonstrated the efficacy on cardiovascular outcomes there is a controversy related to the possible net clinical benefit. Thereafter, we performed an intention-to-treat meta-analysis in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The primary outcome of the metanalysis was the incidence of major adverse cardiovascular events, defined by each study protocol. Secondary outcomes for the analyses were myocardial infarction, stroke, myocardial revascularization, cardiovascular death, and all-cause death. Results of 4 clinical trials evaluated contained a total of 17,324 patients; 9,236 received bempedoic acid for a median of 46.6 months. The mean baseline LDLc was 129.4 (22.8) mg/100 ml and treatment was associated with a mean LDLc reduction of 26.0 (12.6) mg/100 ml. Treatment with bempedoic acid significantly reduced the incidence of major adverse cardiovascular events (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.81 to 0.96), myocardial infarction (HR 0.76, 95% CI 0.66 to 0.89) and myocardial revascularization (HR 0.82, 95% CI 0.73 to 0.92); the crude incidence of stroke, cardiovascular or all-cause mortality were lower in patients in the bempedoic acid groups although no significant risk reduction was observed. No heterogeneity was observed in any of the end points. In conclusion, the metanalysis of the 4 clinical trials currently available with bempedoic acid provides reliable evidence of its clinical benefit with no signs of heterogeneity or harm.

Cognitive Function with PCSK9 Inhibitors: A 24-Month Follow-Up Observational Prospective Study in the Real World-MEMOGAL Study.

INTRODUCTION: The cognitive safety of monoclonal antibody proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has been established in clinical trials, but not yet in real-world observational studies. We assessed the cognitive function in patients initiating PCSK9i, and differences in cognitive function domains, to analyze subgroups by the low-density lipoprotein cholesterol (LDL-C) achieved, and differences between alirocumab and evolocumab. METHODS: This has a multicenter, quasi-experimental design carried out in 12 Spanish hospitals from May 2020 to February 2023. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). RESULTS: Among 158 patients followed for a median of 99 weeks, 52% were taking evolocumab and 48% alirocumab; the mean change from baseline in MoCA score at follow-up was + 0.28 [95% CI (- 0.17 to 0.73; p = 0.216)]. There were no significant differences in the secondary endpoints-the visuospatial/executive domain + 0.04 (p = 0.651), naming domain - 0.01 (p = 0.671), attention/memory domain + 0.01 (p = 0.945); language domain - 0.10 (p = 0.145), abstraction domain + 0.03 (p = 0.624), and orientation domain - 0.05 (p = 0.224)-but for delayed recall memory the mean change was statistically significant (improvement) + 0.44 (p = 0.001). Neither were there any differences in the three stratified subgroups according to lowest attained LDL-C level-0-54 mg/dL, 55-69 mg/dL and ≥ 70 mg/dL; p = 0.454-or between alirocumab and evolocumab arms. CONCLUSION: We did not find effect of monoclonal antibody PCSK9i on neurocognitive function over 24 months of treatment, either in global MoCA score or different cognitive domains. An improvement in delayed recall memory was shown. The study showed no differences in the cognitive function between the prespecified subgroups, even among patients who achieved very low levels of LDL-C. There were no differences between alirocumab and evolocumab. REGISTRATION: ClinicalTtrials.gov Identifier number NCT04319081.

Effect of dapagliflozin on COVID-19 infection and risk of hospitalization.

BACKGROUND: Dapagliflozin has been proposed as a potential treatment for coronavirus disease 2019 (COVID-19) by reducing cytokine production and inflammation. However, there are limited data on its effectiveness. We aimed to evaluate the impact of dapagliflozin on COVID-19 severity (including hospitalization risk, ICU admission, in-hospital death and progression to severe COVID-19) and its potential on susceptibility to COVID-19 infection. METHODS: We conducted a population-based case-control study. For aim 1, we assessed COVID-19 severity in cases (positive PCR patients requiring hospitalization) and matched controls (negative PCR patients or positive PCR patients not requiring hospitalization). For aim 2, we compared positive PCR cases (hospitalized and non-hospitalized) with controls. Adjusted odds ratios (aORs) were calculated using a generalized linear mixed model. RESULTS: We analysed 86 602 subjects: 3060 were hospitalized cases, 26 757 were non-hospitalized cases and 56 785 were controls. Among the hospitalized COVID-19 patients, 228 were admitted to the ICU and 413 died. Dapagliflozin had no effect on the risk of hospitalization (aOR 0.98; 95% CI 0.65-1.48; P = 0.915), ICU admissions (aOR 1.21; 95% CI 0.34-4.25; P = 0.767) or in-hospital death (aOR 1.33; 95% CI 0.53-3.30; P = 0.543). Dapagliflozin reduced the risk of progression to severe COVID-19 by 35%, but this was not statistically significant (aOR 0.65; 95% CI 0.40-1.06; P = 0.086). Dapagliflozin was associated with a 30% increased risk of susceptibility to COVID-19 infection (aOR 1.31; 95% CI 1.05-1.62; P = 0.015). CONCLUSIONS: Use of dapagliflozin prior to SARS-CoV-2 infection was not associated with an increased risk of hospitalization, ICU admission, mortality or progression to severe COVID-19. However, it was associated with an increased risk of susceptibility to COVID-19 infection.

Differences in weight loss and safety between the glucagon-like peptide-1 receptor agonists: A non-randomized multicenter study from the titration phase.

INTRODUCTION: Obesity increases the risk of type 2 diabetes mellitus and cardiovascular disease (CVD). Weight loss (≥5 %) reduces the risk of CVD. Glucagon-like peptide-1 receptor agonists (GLP1 RA) have shown clinically weight loss. OBJECTIVES: 1) To assess differences in the efficacy of weight loss and HbA1c; 2) to evaluate the safety and adherence during the titration phase. METHODS: It is a multicenter, prospective, and observational study on GLP1 RA naïve patients. The primary end point was the weight loss (≥5 %). Changes in weight, BMI and HbA1c were also calculated as co-primary endpoints. Secondary endpoints were safety, adherence, and tolerance. RESULTS: Among 94 subjects, 42.4 % received dulaglutide, 29,3 % subcutaneous semaglutide, 22,8 % oral semaglutide. 45 % female and the mean age was 62. Baseline characteristics were body weight 99.3 kg, BMI 36.7 kg/m2 and Hba1c 8.2 %. Oral semaglutide achieved the highest reduction: 61.1 % of patients achieving ≥ 5 %, subcutaneous semaglutide 45.8 % and dulaglutide 40.6 %. GLP1 RA significantly reduced body weight (-4.95 kg, p < 0.001) and BMI (-1.86 kg/m2, p < 0.001), without significant differences between groups. Gastrointestinal disorders were the most frequently reported events (74.5 %). 62 % of patients on dulaglutide, 25 % on oral semaglutide and 22 % on subcutaneous semaglutide. CONCLUSIONS: Oral semaglutide achieved the highest proportion of patients that lost ≥ 5 %. GLP1 RA significantly reduced BMI and HbA1c. Most of the reported adverse events were gastrointestinal disorders and they were reported in a major frequency in the dulaglutide group. Oral semaglutide would be a reasonable switch in case of future shortages.

Patients With High Cardiovascular Risk as Candidates to Bempedoic Acid, After Treatment With Statins, Ezetimibe and PCSK9 Inhibitors: An Estimation and Cost-Effectiveness Analysis.

ABSTRACT: Low-density lipoprotein cholesterol (LDLc) is the lead effector of atherosclerosis and main treatment target. Bempedoic acid is a novel oral drug in the therapeutic armamentarium which is able to reduce LDLc. The objectives of this study were (1) to select the potential patients for administering bempedoic acid such as those with a very high cardiovascular risk in which objectives of LDLc were not achieved despite conventional treatment with PCSK9 inhibitors (PCSK9i) and/or statins and ezetimibe and (2) to estimate the cost-effectiveness of bempedoic acid in different scenarios. The methods used were a multicenter and retrospective study of 652 patients initiating treatment with any PCSK9 inhibitor in 17 different hospitals. Before and on-treatment LDLc cholesterol levels, medical treatments, clinical indication, and baseline characteristics were recorded. The results obtained from 443 subjects in secondary prevention were analyzed. The mean (±) LDLc level at baseline was 142.5 ± 46.4 mg/dL and 61.5 ± 40.5 mg/dL in the follow-up, with a reduction of 55.9% ( P < 0.0001); 71.6% of the patients reached the target of LDL < 55 mg/dL or >50% reduction. Of those patients treated with medium-intensity and low-intensity statins plus PCSK9 inhibitors (with or without ezetimibe), only 5.7% of them were able to reduce LDL below 55 mg/dL and the main LDLc reduction in this group was the lowest (42.9% on average). Patients with TG values >135 mg/dL represented 41.6% of the sample, of which approximately 10% of them were using fibrates. Assuming only LDLc reduction and the UK price, the incremental cost-effectiveness ratio was 88,359€; 83,117€; 82,378€; and 79,015€ for different discount rates. In conclusion, one-third of the patients could achieve the target LDL proposed in the 2019 ESC/EAS guidelines. Approximately 10% of them could also benefit from treating hypertriglyceridemia as indicated in the 2021 ESC guidelines on cardiovascular disease prevention. Patients with medium-intensity and low-intensity statins plus PCSK9i and ezetimibe would be the most benefited. Bempedoic acid could be a not cost-efficacy therapy in all the scenarios, but we need to wait for the CLEAR OUTCOMES Trial results.

Semaglutide versus GLP-1 agonists. Effectiveness, safety, and quality of life in patients with diabetes mellitus 2. The SEVERAL study.

OBJECTIVE: The cardiovascular disease is the first cause of deaths in patients  with diabetes mellitus 2. The objective is to evaluate and compare the weight  loss in patients with diabetes treated with the different GLP-1 receptor agonists  for the first time. Secondary endpoints are glycosylated hemoglobin  reduction, changes in quality of life and physical activity and the safety of  these drugs. METHOD: It is a postauthorization, multicenter, non-randomized and  prospective study. 360 Patients that will start treatment for the first time with GLP-1 receptor agonists will be recruited in 10 centers in the National Health System for a period of 6 months and 44 weeks of follow-up.  The primary endpoint will be weight loss achieved with the different GLP-1  receptor agonists and the secondary endpoint will be glycosylated hemoglobin reduction, changes in the quality of life through the EuroQol­5D and changes physical activity through the SF-12 questionnaire, and also the  safety of these drugs. The estimate recruitment period will be 6 months, from  1 December 2021 to 1 May 2022. The follow up will finish in December 2022. DISCUSSION: The SEVERAL study will try to provide information about weight  loss efficacy, changes in quality of life, physical activity and safety of the GLP-1  receptor agonists in patients with diabetes that start treatment with these  drugs in the real life. This study try to compare different GLP-1 receptor  gonists in terms of effectiveness and safety for a better posterior election when  these drugs are used in patients with diabetes mellitus 2 and obesity.

OBJETIVO: La enfermedad cardiovascular es la causa principal de muerte en  pacientes con diabetes mellitus 2. El objetivo principal es evaluar y comparar  prospectivamente la pérdida de peso en pacientes con diabetes mellitus 2  tratados por primera vez con los diferentes análogos de la GLP-1. Como  variables secundarias se estudiará reducción de la hemoglobina glicosilada,  cambios en calidad de vida y actividad física y la seguridad de estos fármacos.Método: Se trata de un estudio postautorización, multicéntrico, no  leatorizado de seguimiento prospectivo. Se reclutarán 360 pacientes que inicien tratamiento por primera vez con análogos de la GLP1 en 10 centros del sistema público durante un período de 6 meses y un seguimiento  de 44 semanas. La variable principal será la pérdida de peso con los  diferentes análogos de la GLP1 y como variable secundaria se valorarán: reducción de hemoglobina glicosilada, cambios en la calidad de vida y actividad  física a través del EuroQol-5D y SF-12 y seguridad. Se ha estimadoun período de reclutamiento de 6 meses, desde el 1 de Diciembre 2021 al 1 de Mayo 2022. El seguimiento finalizará en Diciembre de 2022.Discusión: El estudio intentará aportar información sobre la efectividad en  pérdida de peso, cambios en calidad de vida, actividad física y seguridad de los  análogos de la GLP1 en pacientes con diabetes mellitus 2 que inician  tratamiento con estos fármacos en la vida real. Este trabajo pretende comparar  los diferentes análogos de la GLP1 en términos de eficacia y  eguridad para una posterior mejor elección en la prescripción de estos  fármacos en pacientes con diabetes mellitus 2 y obesidad.

Semaglutida versus agonistas GLP-1. Efectividad, seguridad y calidad de vida en pacientes con diabetes mellitus 2. Estudio SEVERAL / Semaglutide versus GLP-1 agonists. Effectiveness, safety, and quality of life in patients with diabetes mellitus 2. The SEVERAL study

Objetivo: La enfermedad cardiovascular es la causa principal demuerte en pacientes con diabetes mellitus 2. El objetivo principal es evaluar y comparar prospectivamente la pérdida de peso en pacientes condiabetes mellitus 2 tratados por primera vez con los diferentes análogosde la GLP-1. Como variables secundarias se estudiará reducción de lahemoglobina glicosilada, cambios en calidad de vida y actividad física yla seguridad de estos fármacos.Método: Se trata de un estudio postautorización, multicéntrico, no aleatorizado de seguimiento prospectivo. Se reclutarán 360 pacientes queinicien tratamiento por primera vez con análogos de la GLP1 en 10 centros del sistema público durante un período de 6 meses y un seguimientode 44 semanas. La variable principal será la pérdida de peso con los diferentes análogos de la GLP1 y como variable secundaria se valorarán:reducción de hemoglobina glicosilada, cambios en la calidad de vida yactividad física a través del EuroQol-5D y SF-12 y seguridad. Se ha estimado un período de reclutamiento de 6 meses, desde el 1 de Diciembre2021 al 1 de Mayo 2022. El seguimiento finalizará en Diciembre de 2022.Discusión: El estudio intentará aportar información sobre la efectividaden pérdida de peso, cambios en calidad de vida, actividad física y seguridad de los análogos de la GLP1 en pacientes con diabetes mellitus 2que inician tratamiento con estos fármacos en la vida real. Este trabajopretende comparar los diferentes análogos de la GLP1 en términos deeficacia y seguridad para una posterior mejor elección en la prescripciónde estos fármacos en pacientes con diabetes mellitus 2 y obesidad. (AU)

Objective: The cardiovascular disease is the first cause of deaths inpatients with diabetes mellitus 2. The objective is to evaluate and comparethe weight loss in patients with diabetes treated with the different GLP-1receptor agonists for the first time. Secondary endpoints are glycosylatedhemoglobin reduction, changes in quality of life and physical activity andthe safety of these drugs.Method: It is a postauthorization, multicenter, non-randomized and prospective study. 360 Patients that will start treatment for the first time withGLP-1 receptor agonists will be recruited in 10 centers in the NationalHealth System for a period of 6 months and 44 weeks of follow-up. Theprimary endpoint will be weight loss achieved with the different GLP-1receptor agonists and the secondary endpoint will be glycosylated hemoglobin reduction, changes in the quality of life through the EuroQol-5Dand changes physical activity through the SF-12 questionnaire, and alsothe safety of these drugs. The estimate recruitment period will be 6 months,from 1 December 2021 to 1 May 2022. The follow up will finish in December 2022.Discussion: The SEVERAL study will try to provide information aboutweight loss efficacy, changes in quality of life, physical activity and safetyof the GLP-1 receptor agonists in patients with diabetes that start treatmentwith these drugs in the real life. This study try to compare different GLP-1receptor agonists in terms of effectiveness and safety for a better posteriorelection when these drugs are used in patients with diabetes mellitus 2and obesity. (AU)

Impacto de la pandemia por COVID-19 en el control lipídico de pacientes que inician inhibidores de la PCSK9 / Impact of the COVID-19 pandemic in the lipid control of the patients that start PCSK9 inhibitors

Objetivos: El estudio MEMOGAL (NCT04319081) está dirigido a evaluar cambios en la función cognitiva en pacientes tratados con inhibidores de la PCSK9 (iPCSK9). Se realiza primer análisis: 1) discutir el papel de los farmacéuticos hospitalarios durante de la pandemia, así como evaluar el impacto de la misma en el control lipídico; 2) análisis descriptivo; 3) eficacia en reducción de colesterol-LDL (c-LDL) de alirocumab y evolocumab; y 4) reportar seguridad de los iPCSK9. Material y métodos: Se trata de un análisis prospectivo en vida real de pacientes tratados por primera vez con iPCSK9 en la práctica clínica habitual e incluidos en su primera dispensación en las consultas de farmacia de 12 hospitales de Galicia desde mayo de 2020-abril de 2021. Los valores basales de c-LDL son los previos al inicio del tratamiento con iPCSK9 y como seguimiento los valores a los 6 meses. Resultados: Se incluyeron 89 pacientes. El 86,5% con enfermedad cardiovascular y un 53,9% intolerancia a las estatinas. Un 78,8% de los pacientes fueron tratados con estatinas de alta intensidad. Las estatinas más usadas fueron rosuvastatina (34,1%) y atorvastatina (20,5%). El nivel basal de c-LDL fue 148mg/dl y de 71mg/dl al seguimiento. Los pacientes tratados con alirocumab (n=43) presentaban valores basales de 144mg/dl y de 73mg/dl al seguimiento y con evolocumab (n=46) de 151mg/dl basal y 69mg/dl al seguimiento. La reducción de c-LDL fue para evolocumab 51,21% y alirocumab 51,05%. El 43,1% presentaba a los 6 meses valores>70mg/dl, el 19,4% entre 55 y 69mg/dl y el 37,5%<55mg/dl. Los pacientes que obtuvieron una reducción>50% de c-LDL fueron el 58,3%. Los eventos adversos presentados fueron: reacción en el lugar de inyección (n=2), mialgias (n=1), síntomas pseudogripales (n=1) y deterioro neurocognitivo (n=1).(AU)

Objectives: MEMOGAL study (NCT04319081) is aimed at evaluating changes in cognitive function in patients treated with PCSK9 inhibitors (PCSK9i). This is the first analysis: (1) discussion about the role of the Hospital Pharmacists during the pandemic, and also the assessment of the impact of COVID-19 in the lipid control; (2) descriptive analysis; (3) effectiveness in LDL cholesterol (LDL-c) reduction of alirocumab and evolocumab; (4) communicate PCSK9i safety. Material and methods: It is a prospective Real-World Evidence analysis of patients that take PCSK9i for the first time in the usual clinical practice, and they are included after the first dispensation in the public pharmacy consultations of 12 Hospitals in Galicia from May 2020 to April 2021. Baseline values of LDL-c are the previous values before taking PCSK9 and the follow-up values are in 6 months time. Results: 89 patients were included. 86.5% with cardiovascular disease and 53.9% with statin intolerances. 78.8% of the patients were treated with high intensity statins. Statins most used were rosuvastatin (34.1%) and atorvastatin (20.5%). Baseline value of LDL-c was 148mg/dL and the follow-up value was 71mg/dL. The baseline value of patients treated with alirocumab (N=43) was 144mg/dL and 73mg/dL in the follow-up. With evolocumab (N=46) was 151mg/dL in basaline and 69mg/dL in follow-up. The LDLc- reduction was 51.21% with evolocumab and 51.05% with alirocumab. 43.1% of the patients showed values >70mg/dL in six month time; 19.4% between 69mg/dl and 55mg/dL and 37.5% <55mg/dL. 58.3% of the patients achieved a reduction >50% of LDL-c. The adverse events were: injection point reaction (N=2), myalgias (N=1), flu-like symptoms (N=1) and neurocognitive worsening (N=1).(AU)

Effect of PCSK9 inhibitors on remnant cholesterol and lipid residual risk: The LIPID-REAL registry.

BACKGROUND: Monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 55%, regardless of baseline treatments. Nonetheless, the effect of other lipid parameters, such as cholesterol remnants or, the so-called lipid residual risk, is unknown. METHODS: Multicenter and retrospective registry of patients treated with PCSK9 inhibitors from 14 different hospitals in Spain. Before and on-treatment lipid parameters were recorded. Residual lipid risk was estimated by (1) cholesterol remnants, (2) triglycerides/HDLc ratio (TG/HDL), (3) total cholesterol/HDLc (TC/HDL) and (4) the triglycerides-to-glucose index (TGGi). RESULTS: Six hundred fifty-two patients were analysed, mean age of 60.2 (9.63) years, 24.69% women and mean LDLc before treatment 149.24 (49.86) mg/dl. Median time to second blood determination was 187.5 days. On-treatment LDLc was 67.46 (45.78) mg/dl, which represented a 55% reduction. Significant reductions were observed for TG/HDL ratio, cholesterol remnants, TC/HDL ratio and TGGi. As consequence, 34.61% patients had LDLc <55 mg/dl and cholesterol remnants <30 mg/dl; additionally, 31.95% had cholesterol remnants <30 mg/dl but LDLc >55 mg/dl. Patients who had levels of cholesterol remnants >30 mg/dl before initiating the treatment with PCSK9 had higher reductions in cholesterol remnants, TG/HDL ratio, TC/HDL and TGGi. By contrast, no reduction differences were observed according to baseline LDLc (< or > the mean), age, gender or obesity. CONCLUSIONS: This multicenter and retrospective registry of real-world patients treated with PCSK9 inhibitors demonstrates a positive effect on cholesterol remnants and lipid residual risk beyond LDLc reductions.

Impact of the COVID-19 pandemic in the lipid control of the patients that start PCSK9 inhibitors. / Impacto de la pandemia por COVID-19 en el control lipídico de pacientes que inician inhibidores de la PCSK9.

OBJECTIVES: MEMOGAL study (NCT04319081) is aimed at evaluating changes in cognitive function in patients treated with PCSK9 inhibitors (PCSK9i). This is the first analysis: (1) discussion about the role of the Hospital Pharmacists during the pandemic, and also the assessment of the impact of COVID-19 in the lipid control; (2) descriptive analysis; (3) effectiveness in LDL cholesterol (LDL-c) reduction of alirocumab and evolocumab; (4) communicate PCSK9i safety. MATERIAL AND METHODS: It is a prospective Real-World Evidence analysis of patients that take PCSK9i for the first time in the usual clinical practice, and they are included after the first dispensation in the public pharmacy consultations of 12 Hospitals in Galicia from May 2020 to April 2021. Baseline values of LDL-c are the previous values before taking PCSK9 and the follow-up values are in 6 months time. RESULTS: 89 patients were included. 86.5% with cardiovascular disease and 53.9% with statin intolerances. 78.8% of the patients were treated with high intensity statins. Statins most used were rosuvastatin (34.1%) and atorvastatin (20.5%). Baseline value of LDL-c was 148mg/dL and the follow-up value was 71mg/dL. The baseline value of patients treated with alirocumab (N=43) was 144mg/dL and 73mg/dL in the follow-up. With evolocumab (N=46) was 151mg/dL in basaline and 69mg/dL in follow-up. The LDLc- reduction was 51.21% with evolocumab and 51.05% with alirocumab. 43.1% of the patients showed values >70mg/dL in six month time; 19.4% between 69mg/dl and 55mg/dL and 37.5% <55mg/dL. 58.3% of the patients achieved a reduction >50% of LDL-c. The adverse events were: injection point reaction (N=2), myalgias (N=1), flu-like symptoms (N=1) and neurocognitive worsening (N=1). CONCLUSIONS: (1) Despite the number of prescriptions was reduced because of the pandemic, the lipid control was not affected. (2) Half of the patients treated with PSCK9i is due to statins intolerance and the 86% is for secondary prevention. (2) The reduction results were similar to pivotal clinical trials. Despite this, 39% of the total of the patients and 60% of patients with dual teraphy did not reach the goal of ESC/EAS guidelines (<55mg/dL and/or reduction>50%). There were not significant differences between evolocumab and alirocumab: 51.21% vs 51.05% (P=.972). (3) There were not any adverse events of special interest. The possible neurocognitive worsening will be studied as the primary endpoint once the MEMOGAL study has been completed.

Sex Differences in Low-Density Lipoprotein Cholesterol Reduction With PCSK9 Inhibitors in Real-world Patients: The LIPID-REAL Registry.

BACKGROUND: Previous evidence supports that monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 50%-65%, regardless of baseline treatments. We tested possible sex differences in a multicentre registry of real-world patients treated with PCSK9 inhibitors. METHODS: This is a multicentre and retrospective study of 652 patients initiating treatment with any PCSK9 inhibitor in 18 different hospitals. Before-treatment and on-treatment LDLc and medical treatments, clinical indication, and clinical features were recorded. RESULTS: Women represented 24.69% of the cohort. The use of statins was similar in both sexes, but women were receiving most frequently ezetimibe. Before-treatment median LDLc was 135 (interquartile range 115-166) mg, and it was higher in women. The median on-treatment LDLc was 57 (interquartile range 38-84) mg/dL, which represented a mean 54.5% reduction. On-treatment LDLc was higher in women, and the mean LDLc reduction was lower in women (47.4% vs. 56.9%; P = 0.0002) receiving evolocumab or alirocumab. The percentage of patients who achieved ≥50% LDLc reduction was higher in men (71.36% vs. 57.62%; P = 0.002). According to LDLc before-treatment quartiles, LDLc reduction was statistically lower in women in the 2 highest and a significant interaction of women and baseline LDLc >135 mg/dL was observed. Women were negatively associated with lower rates of LDLc treatment target achievement (odds ratio: 0.31). Differences were also observed in women with body mas index >25 kg/m2. Only 14 patients (2.14%) presented side effects. CONCLUSIONS: This multicentre and retrospective registry of real-world patients treated with PCSK9 inhibitors highlights significant gender differences in LDLc reduction.

Observational multicentre prospective study to assess changes in cognitive function in patients treated with PCSK9i. Study protocol.

OBJECTIVE: PCSK9 inhibitors have been shown to reduce LDLc by up to about 60% and 85% when used with high doses of statins and ezetimibe (2019 ESC/EAS Guidelines). These therapies may lead to very low levels of LDLc and have been associated with possible cognitive deterioration. No significant differences were found in the only specific  study (EBBINGHAUS). The objective is to prospectively evaluate cognitive  deterioration and its repercussion on quality of life and changes in LDLc in  patients starting treatment with PCKS9 inhibitors. METHOD: It is a postauthorization, multicentre, non-randomized, prospective study. Patients starting treatment for the first time with PCSK9 inhibitors will be recruited in 11 Galician Hospitals over a period of 12 months and with 24 months of follow-up. The primary outcome will be to evaluate changes in cognitive function using the Montreal  Cognitive Assessment (MOCA) questionnaire. The secondary outcome will be to evaluate changes in quality of life using the EuroQol-5D. Changes in LDLc will be assessed. The sample size will be 275 patients, taking into account a loss to follow-up of no more than 10%. The primary outcome  will be studied through the dichotomous variable cognitive deterioration (0/1). Cognitive changes over the follow-up period will be analysed using  the McNemar test. In addition, an analytical approach using logistic regression will be followed to identify patients at risk of cognitive deterioration. As a result, this analysis will obtain a frequency measurement: the odds ratio (OR). The specific objectives will be studied  using bivariate analysis. Continuous contrast variables will be studied using the t-test or ANOVA and categorical variables will be studied using the chi- square test. CONCLUSIONS: The MEMOGAL study will provide information on safety in  terms of cognitive deterioration in patients starting treatment with PCSK9 inhibitors.

Objetivo: Los inhibidores de proproteína convertasa subtilisina/kexina de tipo 9 (PCSK9) han demostrado reducir hasta un 60% el colesterol  transportado por lipoproteínas de baja densidad (c-LDL) y hasta el 85%  asociado a estatinas de alta intensidad y ezetimibe (2019 ESC/EAS Guidelines). Estas terapias pueden dar lugar a muy bajos niveles de c-LDL y se ha especulado sobre su posible relación con deterioro cognitivo. En el  único estudio específico, EBBINGHAUS, no se encontraron diferencias  significativas. El objetivo es evaluar prospectivamente el deterioro  cognitivo y la repercusión en términos de calidad de vida y variaciones de  c-LDL en pacientes que inician tratamiento con inhibidores de PCSK9. Método: Se trata de un estudio postautorización, multicéntrico, no aleatorizado de seguimiento prospectivo. Se reclutarán pacientes que  inicien tratamiento por primera vez con iPCSK9 en 11 hospitales gallegos  durante un periodo de 12 meses y un seguimiento de 24 meses. El  endpoint primario será evaluar los cambios en la función cognitiva a través del cuestionario Montreal Cognitive Assessment (MOCA), y como endpoints secundarios se valorarán cambios en la calidad de vida a través del  EuroQol­5D y variación de los niveles de LDL. El tamaño muestral, teniendo en cuenta un porcentaje de pérdidas no superior al 10%, será de  275 individuos. El objetivo general se estudiará a través de la variable  dicotómica deterioro cognitivo (0/1). El estudio del deterioro cognitivo a lo  largo del seguimiento se realizará con el test McNemar. Además, se  pretende realizar un planteamiento analítico con una regresión logística que explore si existe algún perfil de paciente con riesgo de sufrir deterioro cognitivo. Este análisis obtendrá como resultado una medida de  frecuencia, la odds ratio (OR). Los objetivos específicos se estudiarán planteando análisis bivariados. Para las variables de contraste continuas se empleará el test T o el ANOVA, si las variables son de naturaleza  categórica se aplicará el test de chi cuadrado.Conclusiones: El estudio MEMOGAL intentará aportar información sobre  la seguridad en términos de deterioro cognitivo en pacientes que inicien  tratamiento con inhibidores de PCSK9 (real-world evidence).

Estimation of the major cardiovascular events prevention with Inclisiran.

BACKGROUND AND AIMS: The ORION 10-11 trials have reported the efficacy of Inclisiran on low-density lipoprotein cholesterol (LDLc) reduction, and also suggested prevention of major cardiovascular events (MACE) incidence. METHODS: We have performed a meta-analysis of the available studies, involving PCSK9 inhibitors or Inclisiran for >6 months, that reported the incidence of MACE. The primary endpoint was MACE incidence, as reported in outcomes-based randomized clinical trials (OB-RCT) and non OB-RCT. Analyses were performed using fixed effect models and fractional polynomial regression. RESULTS: The meta-analysis included a total of 57,431 patients, 1592 treated with Inclisiran and 28,259 with PSCK9 inhibitors (17,244 with evolocumab and 11,015 with alirocumab). Baseline mean LDLc was 104.1 (12.9) mg globally. On-treatment mean LDLc was 40.1 (7.8) mg/dl and mean absolute LDLc reduction was 60.6 (10.3) mg/dl. A total of 5389 MACE were reported, 2482 in patients receiving the study drug and 2907 in patients assigned to placebo. Treatment was associated with OB-RCT and no heterogeneity was observed. The estimation of MACE reduction associated with LDLc reduction, adjusted by age, diabetes, hypertension and baseline LDLc, provided a linear trend in the risk of MACE and LDLc reduction that was linear and all studies fitted properly. CONCLUSIONS: The results of the ORION 10-11 trials are in concordance with results of trials involving treatment with PCSK9 inhibitors. The results of the ORION-4 trial will provide definite evidence on the effects of Inclisiran on MACE reduction.

Prevention of myocardial infarction and stroke with PCSK9 inhibitors treatment: a metanalysis of recent randomized clinical trials.

PURPOSE: Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors treatment induce large reductions in low-density lipoprotein cholesterol (LDLc) and major cardiovascular events. Clinical trials might have been underpowered to test the effect of PSCK9 inhibitors treatment on myocardial infarction and stroke, two of the most relevant cardiovascular events, since all analyzed a combined endpoint. METHODS: we performed a meta-analysis, with currently available studies involving PCSK9 inhibitors and event rate adjudication, with the aim of assessing treatment effects on myocardial infarction and stroke. RESULTS: We included 81,700 patients, 41,979 treated with a PSCK9 inhibitors: 17,244 with evolocumab; 13,720 with bococizumab and 11,015 with alirocumab. A total of 1,319 cases of myocardial infarctions were registered in the treatment group vs. 1,608 in controls, resulting in 19.0% reduction associated with PCSK9 treatment (RR: 0.81, 95% CI 0.76-0.87). Similarly, PCSK9 inhibitors treatment resulted in a 25% reduction of stroke (RR: 0.75, 95% CI 0.65-0.85) when all studies were analyzed together and the statistically significant heterogeneity was not observed in the analysis restricted to end-point based clinical trials. PCSK9 inhibitors treatment had no effect on mortality (RR: 0.95, 95% CI 0.86-1.04). CONCLUSIONS: PCSK9 inhibitors reduce the incidence of myocardial infarction by 19% and stroke by 25%.

La fracción de eyección intermedia no permite estratificar el riesgo de los pacientes hospitalizados por insuficiencia cardiaca / Mid-range ejection fraction does not permit risk stratification among patients hospitalized for heart failure

Introducción y objetivos: La guía de insuficiencia cardiaca de la Sociedad Europea de Cardiología define un nuevo grupo de pacientes con fracción de eyección del ventrículo izquierdo intermedia (40-49%) (ICFEi) cuyas características y pronóstico no están bien definidos. Nuestro objetivo es analizar este grupo en pacientes hospitalizados por insuficiencia cardiaca (Registro REDINSCOR II). Métodos: Estudio observacional prospectivo de 1.420 pacientes clasificados según la fracción de eyección: deprimida (ICFEd), < 40%; intermedia (ICFEi), 40-49% y conservada (ICFEc), ≥ 50%. Se comparan entre los 3 grupos las características clínicas, la mortalidad y sus causas y los ingresos por insuficiencia cardiaca al mes, a los 6 meses y al año. Se obtuvo la puntuación de propensión emparejando según grupo de fracción de eyección. Resultados: La distribución de pacientes fue: 583 (41%) con ICFEd, 227 (16%) con ICFEi y 610 (43%) con ICFEc. El grupo con ICFEi se parece más al de ICFEc en cuanto a edad, prevalencia de hipertensión arterial y fibrilación auricular, aunque comparte con la ICFEd el predominio de varones, la etiología isquémica y el mayor uso de fármacos clase I para ICFEd. Las demás características fueron intermedias. No se detectaron diferencias entre los 3 grupos en la mortalidad total, las causas de muerte y los reingresos por insufiencia cardiaca. Esta similitud en el pronóstico se confirmó en el análisis ajustado por puntuación de propensión. Conclusiones: El grupo de pacientes con ICFEi comparte características con los de ICFEc e ICFEd, aunque está más próximo al de ICFEc. La mortalidad total, las causas de muerte o las rehospitalizaciones por insuficiencia cardiaca eran similares en los 3 grupos (AU)

Introduction and objectives: European Society of Cardiology heart failure guidelines include a new patient category with mid-range (40%-49%) left ventricular ejection fraction (HFmrEF). HFmrEF patient characteristics and prognosis are poorly defined. The aim of this study was to analyze the HFmrEF category in a cohort of hospitalized heart failure patients (REDINSCOR II Registry). Methods: A prospective observational study was conducted with 1420 patients classified according to ejection fraction as follows: HFrEF, < 40%; HFmrEF, 40%-49%; and HFpEF, ≥ 50%. Baseline patient characteristics were examined, and outcome measures were mortality and readmission for heart failure at 1-, 6-, and 12-month follow-up. Propensity score matching was used to compare the HFmrEF group with the other ejection fraction groups. Results: Among the study participants, 583 (41%) had HFrEF, 227 (16%) HFmrEF, and 610 (43%) HFpEF. HFmrEF patients had a clinical profile similar to that of HFpEF patients in terms of age, blood pressure, and atrial fibrillation prevalence, but shared with HFrEF patients a higher proportion of male participants and ischemic etiology, and use of class I drugs targeting HFrEF. All other features were intermediate, and comorbidities were similar among the 3 groups. There were no significant differences in all-cause mortality, cause of death, or heart failure readmission. The similar outcomes were confirmed in the propensity score matched cohorts. Conclusions: The HFmrEF patient group has characteristics between the HFrEF and HFpEF groups, with more similarities to the HFpEF group. No between-group differences were observed in total mortality, cause of death, or heart failure readmission (AU)

Mid-range Ejection Fraction Does Not Permit Risk Stratification Among Patients Hospitalized for Heart Failure.

INTRODUCTION AND OBJECTIVES: European Society of Cardiology heart failure guidelines include a new patient category with mid-range (40%-49%) left ventricular ejection fraction (HFmrEF). HFmrEF patient characteristics and prognosis are poorly defined. The aim of this study was to analyze the HFmrEF category in a cohort of hospitalized heart failure patients (REDINSCOR II Registry). METHODS: A prospective observational study was conducted with 1420 patients classified according to ejection fraction as follows: HFrEF, < 40%; HFmrEF, 40%-49%; and HFpEF, ≥ 50%. Baseline patient characteristics were examined, and outcome measures were mortality and readmission for heart failure at 1-, 6-, and 12-month follow-up. Propensity score matching was used to compare the HFmrEF group with the other ejection fraction groups. RESULTS: Among the study participants, 583 (41%) had HFrEF, 227 (16%) HFmrEF, and 610 (43%) HFpEF. HFmrEF patients had a clinical profile similar to that of HFpEF patients in terms of age, blood pressure, and atrial fibrillation prevalence, but shared with HFrEF patients a higher proportion of male participants and ischemic etiology, and use of class I drugs targeting HFrEF. All other features were intermediate, and comorbidities were similar among the 3 groups. There were no significant differences in all-cause mortality, cause of death, or heart failure readmission. The similar outcomes were confirmed in the propensity score matched cohorts. CONCLUSIONS: The HFmrEF patient group has characteristics between the HFrEF and HFpEF groups, with more similarities to the HFpEF group. No between-group differences were observed in total mortality, cause of death, or heart failure readmission.