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BACKGROUND: Olpasiran, a small interfering RNA (siRNA), blocks lipoprotein(a) (Lp(a)) production by preventing translation of apolipoprotein(a) mRNA. In phase 2, higher doses of olpasiran every 12 weeks (Q12W) reduced circulating Lp(a) by >95%. OBJECTIVES: This study sought to assess the timing of return of Lp(a) to baseline after discontinuation of olpasiran, as well as longer-term safety. METHODS: OCEAN(a)-DOSE (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study) was a phase 2, dose-finding trial that enrolled 281 participants with atherosclerotic cardiovascular disease and Lp(a) >150 nmol/L to 1 of 4 active doses of olpasiran vs placebo (10 mg, 75 mg, 225 mg Q12W, or an exploratory dose of 225 mg Q24W given subcutaneously). The last dose of olpasiran was administered at week 36; after week 48, there was an extended off-treatment follow-up period for a minimum of 24 weeks. RESULTS: A total of 276 (98.2%) participants entered the off-treatment follow-up period. The median study exposure (treatment combined with off-treatment phases) was 86 weeks (Q1-Q3: 79-99 weeks). For the 75 mg Q12W dose, the off-treatment placebo-adjusted mean percent change from baseline in Lp(a) was -76.2%, -53.0%, -44.0%, and -27.9% at 60, 72, 84, and 96 weeks, respectively (all P < 0.001). The respective off-treatment changes in Lp(a) for the 225 mg Q12W dose were -84.4%, -61.6%, -52.2%, and -36.4% (all P < 0.001). During the extension follow-up phase, no new safety concerns were identified. CONCLUSIONS: Olpasiran is a potent siRNA with prolonged effects on Lp(a) lowering. Participants receiving doses ≥75 mg Q12W sustained a â¼40% to 50% reduction in Lp(a) levels close to 1 year after the last dose. (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study [OCEAN(a)-DOSE]; NCT04270760).
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Relación Dosis-Respuesta a Droga , Lipoproteína(a) , ARN Interferente Pequeño , Humanos , Lipoproteína(a)/sangre , Masculino , Femenino , Persona de Mediana Edad , ARN Interferente Pequeño/administración & dosificación , Anciano , Resultado del Tratamiento , Método Doble Ciego , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/sangre , Ácidos Dicarboxílicos , Ácidos GrasosRESUMEN
INTRODUCTION: The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations. METHODS: Here, we examined how ancestrally diverse studies could clarify Lp(a)'s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations. RESULTS: Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R2=15% in East Asians) to high (R2=50% in Europeans) accuracy. For all populations, PRS showed promise as a 'rule out' for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%-99.9%) across PRS thresholds (80th-99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10-6), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects. CONCLUSIONS: Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps.
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Enfermedad de la Arteria Coronaria , Isquemia Miocárdica , Humanos , Lipoproteína(a)/genética , Lagunas en las Evidencias , Factores de Riesgo , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genéticaRESUMEN
BACKGROUND: Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS: Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS: Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).
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Anticolesterolemiantes , Aterosclerosis , Hipercolesterolemia , Lipoproteína(a) , ARN Interferente Pequeño , Humanos , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/farmacología , Anticolesterolemiantes/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Método Doble Ciego , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Lipoproteína(a)/análisis , Lipoproteína(a)/antagonistas & inhibidores , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/uso terapéutico , Hígado/efectos de los fármacos , Hígado/metabolismo , Inhibidores de PCSK9/uso terapéutico , Ezetimiba/uso terapéuticoRESUMEN
BACKGROUND: Data support lipoprotein(a) (Lp[Lp(a)]) being a risk factor for atherosclerotic cardiovascular disease (ASCVD). Olpasiran is a small interfering RNA molecule that markedly reduces Lp(a) production in hepatocytes. STUDY DESIGN: The Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study is a multicenter, randomized, double-blind, placebo-controlled dose-finding study in 281 subjects with established ASCVD and Lp(a) > 150 nmol/L. Patients were randomly allocated to one of 4 active subcutaneous doses of olpasiran (10 mg q12 weeks, 75 mg q12 weeks, 225 mg q 12 weeks, or 225 mg q24 weeks) or matched placebo. The primary objective is to evaluate the effects of olpasiran dosed every 12 weeks compared with placebo on the percent change in Lp(a) from baseline at 36 weeks. Enrollment is now complete and follow-up is ongoing. CONCLUSIONS: OCEAN(a)-DOSE trial is assessing the Lp(a)-lowering efficacy and safety of olpasiran. These data will be used to determine optimal dosing and design for a cardiovascular outcomes trial.
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Aterosclerosis , Enfermedades Cardiovasculares , Aterosclerosis/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , Método Doble Ciego , Humanos , Lipoproteína(a) , Factores de Riesgo , Resultado del TratamientoRESUMEN
Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5-8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran (ClinicalTrials.gov: NCT03626662 ), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71-97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9 mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration.
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Lipoproteína(a) , ARN Interferente Pequeño , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Hiperlipidemias/tratamiento farmacológico , Lipoproteína(a)/sangre , Lipoproteína(a)/genética , Macaca fascicularis , Ratones Transgénicos , ARN Interferente Pequeño/genéticaRESUMEN
[This corrects the article DOI: 10.1016/j.ajpc.2020.100091.].
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BACKGROUND: Technological advances in arterial wall imaging permit the opportunity to visualize coronary atherosclerotic plaque with sufficient resolution to characterize both its burden and compositional phenotype. These modalities have been used extensively in clinical trials to evaluate the impact of lipid lowering therapies on serial changes in disease burden. While the findings have unequivocally established that these interventions have the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved, their impact on plaque phenotype is less certain. More recently optical coherence tomography (OCT) has been employed with a number of studies demonstrating favorable effects on both fibrous cap thickness (FCT) and the size of lipid pools within plaque in response to statin treatment. METHODS: The phase 3, multi-center, double-blind HUYGENS study will assess the impact of incremental lipid lowering with the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, evolocumab, on plaque features using serial OCT imaging, in statin-treated patients following an acute coronary syndrome (ACS). Subjects with non-ST-elevation ACS (n=150) will be randomized 1:1 into two groups to receive monthly injections of evolocumab 420 mg or placebo. RESULTS: The primary endpoint is the effect of evolocumab on coronary atherosclerotic plaques will be assessed by OCT at baseline and at week 50. CONCLUSIONS: The HUYGENS study will determine whether intensified lipid lowering therapy with evolocumab in addition to maximally tolerated statin therapy will have incremental benefits on high-risk features of coronary artery plaques. TRIAL REGISTRATION: This study was registered on Clinicaltrials.gov (NCT03570697).
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OBJECTIVES: It is uncertain if long-term levels of low-density lipoprotein-cholesterol (LDL-C) affect cognition in middle age. We examined the association of LDL-C levels over 25 years with cognitive function in a prospective cohort of black and white US adults. METHODS: Lipids were measured at baseline (1985-1986; age: 18-30 years) and at serial examinations conducted over 25 years. Time-averaged cumulative LDL-C was calculated using the area under the curve for 3,328 participants with ≥3 LDL-C measurements and a cognitive function assessment. Cognitive function was assessed at the Year 25 examination with the Digit Symbol Substitution Test [DSST], Rey Auditory Visual Learning Test [RAVLT], and Stroop Test. A brain magnetic resonance imaging (MRI) sub-study (N = 707) was also completed at Year 25 to assess abnormal white matter tissue volume (AWMV) and gray matter cerebral blood flow volume (GM-CBFV) as secondary outcomes. RESULTS: There were 15.6%, 32.9%, 28.9%, and 22.6% participants with time-averaged cumulative LDL-C <100 mg/dL, 101-129 mg/dL, 130-159 mg/dL, and ≥160 mg/dL, respectively. Standardized differences in all cognitive function test scores ranged from 0.16 SD lower to 0.09 SD higher across time-averaged LDL-C categories in comparison to those with LDL-C < 100 mg/dL. After covariate adjustment, participants with higher versus lower time-averaged LDL-C had a lower RAVLT score (p-trend = 0.02) but no differences were present for DSST, Stroop Test, AWMV, or GM-CBFV. CONCLUSION: Cumulative LDL-C was associated with small differences in memory, as assessed by RAVLT scores, but not other cognitive or brain MRI measures over 25 years of follow-up.
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LDL-Colesterol/sangre , Cognición , Adolescente , Adulto , Estudios de Cohortes , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Test de Stroop , Adulto JovenRESUMEN
OBJECTIVE: On-treatment levels of high sensitivity C-reactive protein (hsCRP) in statin-treated patients predict plaque progression and the prospective risk of atherosclerotic cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors produce additional LDL-C lowering, reduce plaque burden and improve cardiovascular outcomes in statin-treated patients. It is unknown whether residual systemic inflammation attenuates their favorable effects on plaque burden. METHODS: GLAGOV compared the effects of treatment for 78 weeks with evolocumab or placebo on progression of coronary atherosclerosis in statin-treated patients with coronary artery disease.Clinical demographics, biochemistry and changes in both the burden (percentage atheroma volume (PAV), total atheroma volume (TAV), n â= â413) and composition (n â= â162) of coronary plaque were evaluated in evolocumab-treated patients according to baseline hsCRP strata (<1, 1-3, >3 âmg/L). RESULTS: The study cohort comprised 413 evolocumab-treated patients (32% low [<1 âmg/L], 41% intermediate [1-3 âmg/L] and 27% high [>3 âmg/L] baseline hsCRP levels). Patients in the highest hsCRP stratum were more likely to be female and had a higher prevalence of diabetes, hypertension, and the metabolic syndrome. LDL-C levels were similar across the groups, however participants with higher hsCRP levels had higher triglyceride and lower HDL-C levels at baseline. At follow-up, the change in PAV from baseline (-0.87% [low] vs. -0.84% [intermediate] vs. -1.22% [high], p â= â0.46) and the proportion of patients experiencing any degree of regression (65.9% vs. 63.5% vs. 63.1%, p â= â0.88) was similar across hsCRP strata and when evaluated by levels of achieved LDL-C. There were no serial differences in plaque composition by hsCRP strata. CONCLUSION: The ability of evolocumab to induce regression in statin-treated patients is not attenuated by the presence of enhanced systemic inflammation. This underscores the potential benefits of intensive lipid lowering, even in the presence of heightened inflammatory states.
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The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.
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Ensayos Clínicos como Asunto , Registros Electrónicos de Salud , Aplicaciones Móviles , Dispositivos Electrónicos Vestibles , Humanos , Proyectos de InvestigaciónRESUMEN
Background Beyond their potent LDL (low-density lipoprotein) cholesterol ( LDL -C)-lowering efficacy (50-60%), PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors also reduce Lp(a) (lipoprotein[a]) levels by 25% to 30%, suggesting a 2:1 response ratio. We aimed to characterize the relationship between LDL -C and Lp(a) lowering by evolocumab, a PCSK 9 inhibitor, in a large clinical trial population and to determine the prevalence of concordant/discordant LDL -C and Lp(a) responses to PCSK 9 inhibition. Methods and Results Data were analyzed from 4 randomized, 12-week, multicenter, phase 3 evolocumab trials. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The main measure was the degree of concordance or discordance of LDL -C and Lp(a) in response to PCSK 9 inhibition; concordant response was defined as LDL -C reduction >35% and Lp(a) reduction >10%. The study cohort comprised 895 patients (438 female; median age: 59.0 years [interquartile range: 51-66 years]). Baseline mean level of LDL -C was 133.6 mg/dL (SE: 1.7) and median Lp(a) level was 46.4 mg/dL (interquartile range: 18.4-82.4 mg/dL). A discordant response was observed in 165 (19.7%) patients. With these cutoffs, the prevalence of discordance was higher when considering baseline Lp(a) concentrations >30 mg/dL (26.5%) or >50 mg/dL (28.6%). Conclusions We demonstrate high prevalence of discordance in LDL -C and Lp(a) reduction in response to evolocumab, particularly when considering higher baseline Lp(a) concentrations, indicating the possibility of alternative pathways beyond LDLR ( LDL receptor)-mediated clearance involved in Lp(a) reduction by evolocumab. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01763827, NCT 01763866, NCT 01763905, NCT 01763918.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , LDL-Colesterol/sangre , Hipercolesterolemia/tratamiento farmacológico , Inhibidores de PCSK9 , Anciano , Anticolesterolemiantes/uso terapéutico , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Hipercolesterolemia/sangre , Masculino , Persona de Mediana Edad , Proproteína Convertasa 9/metabolismo , Resultado del TratamientoRESUMEN
AIMS: Subjects with lipoprotein(a) [Lp(a)] elevation have increased arterial wall inflammation and cardiovascular risk. In patients at increased cardiovascular risk, arterial wall inflammation is reduced following lipid-lowering therapy by statin treatment or lipoprotein apheresis. However, it is unknown whether lipid-lowering treatment in elevated Lp(a) subjects alters arterial wall inflammation. We evaluated whether evolocumab, which lowers both low-density lipoprotein cholesterol (LDL-C) and Lp(a), attenuates arterial wall inflammation in patients with elevated Lp(a). METHODS AND RESULTS: In this multicentre, randomized, double-blind, placebo-controlled study, 129 patients {median [interquartile range (IQR)]: age 60.0 [54.0-67.0] years, Lp(a) 200.0 [155.5-301.5] nmol/L [80.0 (62.5-121.0) mg/dL]; mean [standard deviation (SD)] LDL-C 3.7 [1.0] mmol/L [144.0 (39.7) mg/dL]; National Cholesterol Education Program high risk, 25.6%} were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-C by 60.7% [95% confidence interval (CI) 65.8-55.5] and Lp(a) by 13.9% (95% CI 19.3-8.5). Among evolocumab-treated patients, the Week 16 mean (SD) LDL-C level was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL], and the median (IQR) Lp(a) level was 188.0 (140.0-268.0) nmol/L [75.2 (56.0-107.2) mg/dL]. Arterial wall inflammation [most diseased segment target-to-background ratio (MDS TBR)] in the index vessel (left carotid, right carotid, or thoracic aorta) was assessed by 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography. Week 16 index vessel MDS TBR was not significantly altered with evolocumab (-8.3%) vs. placebo (-5.3%) [treatment difference -3.0% (95% CI -7.4% to 1.4%); P = 0.18]. CONCLUSION: Evolocumab treatment in patients with median baseline Lp(a) 200.0 nmol/L led to a large reduction in LDL-C and a small reduction in Lp(a), resulting in persistent elevated Lp(a) levels. The latter may have contributed to the unaltered arterial wall inflammation.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Arteritis/sangre , Arteritis/tratamiento farmacológico , LDL-Colesterol/antagonistas & inhibidores , Lipoproteína(a)/sangre , Proproteína Convertasa 9/uso terapéutico , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated patients. OBJECTIVES: The purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition. METHODS: A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal. RESULTS: Compared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (-1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (-3.6 mm3 vs. -0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (-3.0 ± 0.6 mm3 vs. -2.4 ± 0.6 mm3; p = 0.49), fibrofatty (-5.0 ± 1.0 mm3 vs. -3.0 ± 1.0 mm3; p = 0.49), and necrotic (-0.6 ± 0.5 mm3 vs. -0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = -0.15; p < 0.001). CONCLUSIONS: The addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422).
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Anticuerpos Monoclonales/administración & dosificación , Enfermedad de la Arteria Coronaria , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de PCSK9 , Placa Aterosclerótica , Ultrasonografía Intervencional/métodos , Anciano , Anticuerpos Monoclonales Humanizados , Anticolesterolemiantes/administración & dosificación , LDL-Colesterol/metabolismo , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/metabolismo , Monitoreo de Drogas/métodos , Quimioterapia Combinada/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Evolocumab significantly lowers low-density lipoprotein cholesterol (LDL-C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously. HYPOTHESIS: LDL-C changes are comparable among different patient subgroups in a pooled analysis of data from phase 3 trials. METHODS: A total of 3146 patients received ≥1 dose of evolocumab or control in four 12-week phase 3 studies. Percent change from baseline in LDL-C for evolocumab 140 mg Q2W or 420 mg QM vs control was reported as the average of week 10 and 12 values. Quantitative and qualitative interactions between treatment group and subgroup by dose regimen were tested. RESULTS: In the pooled analysis, treatment differences vs placebo or ezetimibe were similar for both 140 mg Q2W and 420 mg QM doses across ages (<65 years, ≥65 years); gender; race (Asian, black, white, other); ethnicity (Hispanic, non-Hispanic); region (Europe, North America, Asia Pacific); glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither); National Cholesterol Education Program risk categories (high, moderately high, moderate, low); and European Society of Cardiology/European Atherosclerosis Society risk categories (very high, high, moderate, or low). Certain low-magnitude variations in LDL-C lowering among subgroups led to significant quantitative interaction P values that, when tested by qualitative interaction, were not significant. The incidences of adverse events were similar across groups treated with each evolocumab dosing regimen or control. CONCLUSIONS: Consistent reductions in LDL-C were observed in the evolocumab group regardless of demographic and disease characteristics.
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Anticuerpos Monoclonales/administración & dosificación , LDL-Colesterol/sangre , Hipercolesterolemia/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados , Anticolesterolemiantes/administración & dosificación , Asia/epidemiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/epidemiología , Incidencia , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , América del Norte/epidemiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: To review the efficacy, safety, pharmacology, and pharmacokinetics of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. RECENT FINDINGS: PCSK9 inhibitors are a class of lipid-lowering agents that significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease and hyperlipidemia. Evolocumab is a monoclonal antibody that inhibits PCSK9 and has been evaluated in phase II and III studies as monotherapy, in combination with statins and other lipid-lowering therapies, in patients who are statin intolerant, and in patients with heterozygous and homozygous familial hypercholesterolemia. Data from these studies show that evolocumab significantly reduces LDL-C levels. Treatment with evolocumab also significantly improves levels of other lipid parameters (e.g., apolipoproteins A1 and B, lipoprotein(a), non-high-density lipoprotein cholesterol, and triglycerides). Recent results indicate that LDL-C reduction with evolocumab significantly reduces the risk of cardiovascular events and is also associated with atherosclerotic plaque regression. From a safety standpoint, rates of adverse events (AEs), serious AEs, and AEs leading to discontinuation were similar between evolocumab and controls in clinical trials, and no increase in AEs was observed when evolocumab was used in combination with statins. Patients with elevated LDL-C benefit from evolocumab treatment, suggesting that evolocumab could help meet an unmet medical need in high-risk patient populations with atherosclerotic cardiovascular disease and hyperlipidemia that are unable to reduce LDL-C levels sufficiently with statin therapy alone.
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Anticuerpos Monoclonales/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/farmacología , Humanos , Hiperlipidemias/tratamiento farmacológico , Inhibidores de PCSK9 , Factores de RiesgoRESUMEN
BACKGROUND: Evolocumab, a fully human monoclonal antibody against PCSK9, significantly reduced low-density lipoprotein-cholesterol (LDL-C) levels in Japanese patients by up to 76% when administered with a statin. We evaluated the efficacy and safety of 1 year of evolocumab in a pooled analysis of patients from the 12-week YUKAWA studies who continued into the open-label extension (OLE) OSLER studies.MethodsâandâResults:YUKAWA-1 and YUKAWA-2 were conducted in hypercholesterolemic, high-cardiovascular-risk Japanese patients who were receiving statin therapy. Patients completing these studies were eligible for an OLE study. At OLE entry, patients were re-randomized 2:1 to evolocumab+standard of care (SOC) or SOC alone (OSLER-1: evolocumab 420 mg monthly; OSLER-2: evolocumab 140 mg biweekly or 420 mg monthly). A 1-year analysis was performed on patients enrolled from the YUKAWA studies into OSLER. At parent-study baseline (YUKAWA-1 or YUKAWA-2 patients continuing into OSLER), mean (SD) age was 61 (10) years; 39% were female; mean (SD) baseline LDL-C (on statin) was 119.7 (33.0) mg/dL. Overall rates of adverse events were comparable between evolocumab+SOC and SOC alone. In YUKAWA patients receiving evolocumab+SOC, mean (SE) reductions in LDL-C from parent-study baseline to OLE 1 year were 69.1% (1.2%; OSLER-1) and 65.1% (2.2%; OSLER-2). CONCLUSIONS: In a pooled 1-year analysis of Japanese patients in the ongoing OSLER studies, treatment with evolocumab+SOC was well tolerated and resulted in sustained LDL-C reductions at 1 year.
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Anticuerpos Monoclonales/administración & dosificación , LDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Hipercolesterolemia/sangre , Hipercolesterolemia/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Pueblo Asiatico , Método Doble Ciego , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Japón , Masculino , Persona de Mediana EdadRESUMEN
Importance: The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER-1) evaluated the durability of long-term efficacy and safety during long-term therapy with evolocumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9). Objective: To determine whether LDL-C level reductions with evolocumab persist across different populations. Secondary objectives included assessment of adverse events, antidrug antibodies, and factors contributing to treatment discontinuation. Design, Setting, and Participants: This ongoing, randomized open-label extension trial (OSLER-1) was conducted at 192 sites in 18 countries. A total of 1324 of 1666 patients randomized into 1 of 5 12-week double-blind phase 2 parent studies completed a parent study and chose to participate in OSLER-1; 1255 received 1 or more evolocumab doses. As of August 2016, 812 of 1324 (61%) had 208 weeks of follow-up. This current study was conducted from October 2011 to August 2016, with a data cutoff of August 26, 2016. Interventions: During year 1, patients were randomized to evolocumab, 420 mg, plus standard of care (SOC) or SOC alone. After year 1, all patients continuing the study received evolocumab, 420 mg, plus SOC. Main Outcomes and Measures: Lipids, safety, and tolerability every 12 weeks. A multivariate model identified factors associated with discontinuation of evolocumab. Results: At parent study baseline, the mean (SD) age of the population was 57.1 (11.6) years, with 52.9% being women. The median LDL-C level was 133 mg/dL (to convert to millimoles per liter, multiply by 0.0259). After 52 weeks, evolocumab plus SOC was associated with a significant reduction in LDL-C level by 61% (95% CI, -63% to -60%) vs 2% (95% CI, -5% to -0.2%) with SOC alone (P < .001). At approximately 2, 3, and 4 years of study follow-up, the median LDL-C level was reduced by 59% (95% CI, -60% to -57%), 59% (95% CI, -61% to -58%), and 57% (95% CI, -59% to -55%), respectively, from parent study baseline. For patients receiving statin therapy unchanged from baseline, at week 208, the median LDL-C level reduction was 58%. No neutralizing antibodies to evolocumab were detected. The annualized incidence of new-onset diabetes was 4% in the SOC alone group and, adjusting for duration of evolocumab exposure, 2.8% in the evolocumab plus SOC group. Neurocognitive event rates were 0% (SOC alone) and 0.4% (evolocumab plus SOC). A total of 79% of patients persisted with evolocumab treatment, with a mean exposure duration of 44 months. Conclusions and Relevance: In the longest clinical trial exposure to a PCSK9 inhibitor to date, evolocumab produced sustained reductions in LDL-C levels. The annual frequency of adverse events did not occur more frequently with cumulative exposure during open-label observation. Trial Registration: clinicaltrials.gov Identifier: NCT01439880.
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Anticuerpos Monoclonales/uso terapéutico , Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Hipercolesterolemia/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados , Apolipoproteína A-I/sangre , Apolipoproteínas B/sangre , HDL-Colesterol/sangre , Ensayos Clínicos Fase II como Asunto , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/sangre , Lipoproteína(a)/sangre , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Inhibidores de PCSK9 , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Importance: Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated. Objective: To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients. Design, Setting, and Participants: The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography. Interventions: Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins. Main Outcomes and Measures: The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results: Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, -4.9 mm3 [95% CI, -7.3 to -2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV). Conclusions and Relevance: Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01813422.
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Anticuerpos Monoclonales/uso terapéutico , LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Anticuerpos Monoclonales Humanizados , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Inhibidores de PCSK9 , Efecto Placebo , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/patología , Inducción de Remisión , Factores de Tiempo , UltrasonografíaRESUMEN
BACKGROUND: Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated. AIMS: To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy. METHODS: A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections. CONCLUSIONS: The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422).