RESUMO
Low-density lipoprotein (LDL) receptors on the surface of liver hepatocytes are the primary way that humans regulate serum LDL cholesterol levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a proteolytic enzyme that indirectly regulates serum LDL cholesterol (LDL-C) by causing the destruction of LDL receptors. Less LDL receptors result in increased LDL-C in the bloodstream but inhibiting or binding the circulating PCSK9 results in increased LDL receptors with the resultant decrease in serum LDL-C. Two PCSK9 inhibitors are currently approved for use: alirocumab and evolocumab. Both are fully human monoclonal antibodies that bind free PCSK9. Herein we discuss the mechanism of action, efficacy, and safety of PCSK9 inhibitors. clinical problem.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Inibidores de PCSK9 , Inibidores de Serina Proteinase/uso terapêutico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacocinética , Biomarcadores/sangue , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/enzimologia , Humanos , Pró-Proteína Convertase 9/metabolismo , Inibidores de Serina Proteinase/efeitos adversos , Inibidores de Serina Proteinase/farmacocinética , Resultado do TratamentoRESUMO
BACKGROUND: The effect of alirocumab on potentially atherogenic lipoprotein subfractions was assessed in a post hoc analysis using the vertical auto profile (VAP) method. METHODS: Patients from three Phase II studies with low-density lipoprotein cholesterol (LDL-C) ≥ 2.59 mmol/L (100 mg/dL) at baseline on stable statin therapy were randomised to receive subcutaneous alirocumab 50-150 mg every 2 weeks (Q2W) or 150-300 mg every 4 weeks (according to study) or placebo for 8-12 weeks. Samples from patients treated with alirocumab 150 mg Q2W (n = 74; dose common to all three trials) or placebo (n = 71) were analysed by VAP. Percent change in lipoprotein subfractions with alirocumab vs. placebo was analysed at Weeks 6, 8 or 12 using analysis of covariance. RESULTS: Alirocumab significantly reduced LDL-C and the cholesterol content of subfractions LDL1, LDL2 and LDL3+4. Significant reductions were also observed in triglycerides, apolipoproteins CII and CIII and the cholesterol content of very low-density, intermediate-density, and remnant lipoproteins. CONCLUSION: Alirocumab achieved reductions across a spectrum of atherogenic lipoproteins in patients receiving background statin therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT01288443, NCT01288469, NCT01266876.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Lipoproteínas/sangue , Adulto , Anticorpos Monoclonais Humanizados , LDL-Colesterol , Método Duplo-Cego , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas HDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Triglicerídeos/sangueRESUMO
BACKGROUND: Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing the degradation of LDL receptors and reducing the rate at which LDL cholesterol is removed from the circulation. REGN727/SAR236553 (designated here as SAR236553), a fully human PCSK9 monoclonal antibody, increases the recycling of LDL receptors and reduces LDL cholesterol levels. METHODS: We performed a phase 2, multicenter, double-blind, placebo-controlled trial involving 92 patients who had LDL cholesterol levels of 100 mg per deciliter (2.6 mmol per liter) or higher after treatment with 10 mg of atorvastatin for at least 7 weeks. Patients were randomly assigned to receive 8 weeks of treatment with 80 mg of atorvastatin daily plus SAR236553 once every 2 weeks, 10 mg of atorvastatin daily plus SAR236553 once every 2 weeks, or 80 mg of atorvastatin daily plus placebo once every 2 weeks and were followed for an additional 8 weeks after treatment. RESULTS: The least-squares mean (±SE) percent reduction from baseline in LDL cholesterol was 73.2±3.5 with 80 mg of atorvastatin plus SAR236553, as compared with 17.3±3.5 with 80 mg of atorvastatin plus placebo (P<0.001) and 66.2±3.5 with 10 mg of atorvastatin plus SAR236553. All the patients who received SAR236553, as compared with 52% of those who received 80 mg of atorvastatin plus placebo, attained an LDL cholesterol level of less than 100 mg per deciliter, and at least 90% of the patients who received SAR236553, as compared with 17% who received 80 mg of atorvastatin plus placebo, attained LDL cholesterol levels of less than 70 mg per deciliter (1.8 mmol per liter). CONCLUSIONS: In a randomized trial involving patients with primary hypercholesterolemia, adding SAR236553 to either 10 mg of atorvastatin or 80 mg of atorvastatin resulted in a significantly greater reduction in LDL cholesterol than that attained with 80 mg of atorvastatin alone. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01288469.).
Assuntos
Anticorpos Monoclonais/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertases/antagonistas & inibidores , Pirróis/uso terapêutico , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Atorvastatina , LDL-Colesterol/sangue , Quimioterapia Combinada , Feminino , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/efeitos adversos , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Serina Endopeptidases , Resultado do TratamentoRESUMO
BACKGROUND: This study examined the effects of a mixture of highly bioavailable omega-3 carboxylic acids (OM3-CA) on nuclear magnetic resonance spectroscopy-assessed lipoprotein particle concentrations and sizes and other cardiovascular risk markers in statin-treated patients with fasting triglycerides (TG) ≥ 2.3 mmol/L (200 mg/dL) and <5.6 mmol/L (500 mg/dL) and at high cardiovascular risk. METHODS: After a diet lead-in and statin-stabilization period, 647 patients were randomly assigned to receive capsules of control (olive oil, OO) 4 g/d, OM3-CA 2 g/d (plus OO 2 g/d), or OM3-CA 4 g/d for 6 weeks. RESULTS: Compared with OO, low-density lipoprotein (LDL) particle size was increased with OM3-CA 2 g/d (p < 0.01) and 4 g/d (p < 0.001), and very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) particle sizes were decreased with both OM3-CA dosages vs. OO (p < 0.001 and p < 0.05 for VLDL and HDL, respectively). Total VLDL/chylomicron remnant particle concentration was reduced by 8.5 and 16.0 % with OM3-CA 2 and 4 g/d, respectively, vs. a 6.9 % reduction with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Total HDL particle concentration was also reduced by 1.5 and 3.2 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.6 % increase with OO (at least p < 0.05 for both comparisons). Changes in total LDL particle concentration were not significantly different for OO vs. OM3-CA at either dosage. Apolipoprotein (Apo) CIII levels decreased by 7.6 and 13.1 % with OM3-CA 2 and 4 g/d, respectively, vs. 3.2 % with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass was reduced by 6.2 and 10.7 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.1 % increase with OO (p < 0.001 for both vs. OO). There were no significant differences between treatments in high-sensitivity C-reactive protein responses. CONCLUSION: OM3-CA were associated with shifts in lipoprotein particle sizes and concentrations, and reductions in Apo CIII and Lp-PLA2, in patients with hypertriglyceridemia while taking a statin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01408303.
Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertrigliceridemia/dietoterapia , Hipertrigliceridemia/tratamento farmacológico , Idoso , Apolipoproteína C-III/sangue , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Remanescentes de Quilomícrons/sangue , Método Duplo-Cego , Feminino , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/patologia , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Azeite de Oliva/administração & dosagem , Fosfolipases A2/sangue , Triglicerídeos/sangueRESUMO
AIMS: Prior trials with monoclonal antibodies to proprotein convertase subtilizin/kexin type 9 (PCSK9) reported robust low density lipoprotein cholesterol (LDL-C) reductions. However, the ability to detect potentially beneficial changes in other lipoproteins such as lipoprotein (a), triglycerides, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein (Apo) A1, and adverse events (AEs) was limited by sample sizes of individual trials. We report a pooled analysis from four phase 2 studies of evolocumab (AMG 145), a monoclonal antibody to PCSK9. METHODS AND RESULTS: The trials randomized 1359 patients to various doses of subcutaneous evolocumab every 2 weeks (Q2W) or 4 weeks (Q4W), placebo, or ezetimibe for 12 weeks; 1252 patients contributed to efficacy and 1314, to safety analyses. Mean percentage (95% CI) reductions in LDL-C vs. placebo ranged from 40.2% (44.6%, 35.8%) to 59.3% (63.7%, 54.8%) among the evolocumab groups (all P < 0.001). Statistically significant reductions in apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides and lipoprotein (a) [Lp(a)], and increases in HDL-C were also observed. Adverse events (AEs) and serious AEs with evolocumab were reported in 56.8 and 2.0% of patients, compared with 49.2% and 1.2% with placebo. Adjudicated cardiac and cerebrovascular events were reported in 0.3 and 0% in the placebo and 0.9 and 0.3% in the evolocumab arms, respectively. CONCLUSION: In addition to LDL-C reduction, evolocumab, dosed either Q2W or Q4W, demonstrated significant and favourable changes in other atherogenic and anti-atherogenic lipoproteins, and was well tolerated over the 12-week treatment period.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Azetidinas/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Ezetimiba , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
AIMS: Co-primary objectives were to evaluate dalcetrapib (JTT-705/RO4607381), which targets cholesteryl ester transfer protein (CETP), effects on high-density lipoprotein cholesterol (HDL-C) in participants with coronary heart disease or risk equivalents and to evaluate potential changes in mesenteric lymph nodes. METHODS AND RESULTS: Double-blind trial with participants randomized (2:1) to dalcetrapib 900 mg/day (higher than 600 mg phase III dose) or placebo, both with atorvastatin, for 24 weeks (n = 135; one without post-baseline efficacy data was excluded from intent-to-treat population); a subset continued for 24-week extension (n = 77). Lipid changes and safety parameters were assessed. Mesenteric lymph nodes were evaluated by magnetic resonance imaging. Dalcetrapib increased HDL-C (33.4%, Week 24; 33.8%, Week 48), decreased CETP activity (-53.5%, Week 24; -56.5%, Week 48), and increased apolipoprotein A-I (11.4%, Week 24; 16.4%, Week 48). Dalcetrapib showed no clinically relevant differences vs. placebo in adverse events, laboratory parameters including aldosterone, electrocardiograms, and vital signs including blood pressure (BP). Dalcetrapib had no measurable, clinically relevant effect on lymph node size. CONCLUSION: Dalcetrapib 900 mg administered for up to 48 weeks showed no clinically relevant changes in lymph nodes, BP, or other safety parameters. Dalcetrapib effectively increased HDL-C over 48 weeks of treatment.
Assuntos
Anticolesterolemiantes/administração & dosagem , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Doença das Coronárias/tratamento farmacológico , Compostos de Sulfidrila/administração & dosagem , Adolescente , Adulto , Idoso , Amidas , Anticolesterolemiantes/efeitos adversos , HDL-Colesterol/metabolismo , Doença das Coronárias/sangue , Método Duplo-Cego , Esquema de Medicação , Ésteres , Feminino , Humanos , Doenças Linfáticas/induzido quimicamente , Masculino , Mesentério , Pessoa de Meia-Idade , Compostos de Sulfidrila/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Fish consumption and fish oils rich in omega-3 fatty acids were reported to be cardioprotective in both retrospective and prospective studies undertaken over the past two to three decades. In the past several years, there is mounting clinical trial data as well as basic science information supporting the use of fish oil supplements in both primary and secondary cardiovascular prevention. In addition, there appear to be additional benefits to the use of fish oil, including lowering significantly elevated triglyceride levels, preventing atrial fibrillation, reducing mortality rates in congestive heart failure patients, and perhaps stabilizing atherosclerotic plaques. These data have led to specific recommendations for use of omega-3 fatty acids in several cardiovascular areas.
Assuntos
Doença das Coronárias/prevenção & controle , Óleos de Peixe/administração & dosagem , Prevenção Secundária/métodos , Doença das Coronárias/sangue , Relação Dose-Resposta a Droga , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/farmacocinética , Óleos de Peixe/farmacocinética , Humanos , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate the efficacy and safety of fixed-dose combinations of rosuvastatin and fenofibric acid (rosuvastatin/fenofibric acid) compared with simvastatin in patients with high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). BACKGROUND: Combination therapy with a statin and a fibrate is one of the treatment options to manage multiple lipid abnormalities in patients with hypercholesterolemia and elevated TGs. METHODS: In this randomized, double-blind study, patients (n = 474) with LDL-C > or =160 mg/dL and < or =240 mg/dL and TG > or =150 mg/dL and <400 mg/dL were treated for 8 weeks with simvastatin 40 mg, rosuvastatin/fenofibric acid 5 mg/135 mg, rosuvastatin/fenofibric acid 10 mg/135 mg, or rosuvastatin/fenofibric acid 20 mg/135 mg. Primary and secondary variables were mean percent changes in LDL-C comparing rosuvastatin/fenofibric acid 20 mg/135 mg with simvastatin 40 mg and rosuvastatin/fenofibric acid 10 mg/135 mg and rosuvastatin/fenofibric acid 5 mg/135 mg with simvastatin 40 mg, respectively. Additional efficacy variables included non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein (Apo) B, HDL-C, TG, and high-sensitivity C-reactive protein (hsCRP). Safety was evaluated based on data collected for adverse events (AEs), physical and electrocardiographic examinations, vital sign measurements, and clinical laboratory tests. RESULTS: Significantly greater reductions in LDL-C levels from baseline values were observed with the combination of rosuvastatin/fenofibric acid 20 mg/135 mg (-47.2%, p < 0.001), rosuvastatin/fenofibric acid 10 mg/135 mg (-46.0%, p < 0.001), and rosuvastatin/fenofibric acid 5 mg/135 mg (-38.9%, p = 0.007) than with simvastatin 40 mg (-32.8%). Significant (p < or = 0.04 for all comparisons) improvements in non-HDL-C, ApoB, HDL-C, TG, and hsCRP levels were also observed with each of the rosuvastatin/fenofibric acid doses as compared with simvastatin 40 mg. Treatment-related AEs and discontinuations due to AEs were similar across groups. The incidence of serious AEs was 0% with simvastatin 40 mg, 3.4% with rosuvastatin/fenofibric acid 5 mg/135 mg, 0.8% with rosuvastatin/fenofibric acid 10 mg/135 mg, and 2.5% with rosuvastatin/fenofibric acid 20 mg/135 mg. No cases of rhabdomyolysis or drug-related myopathy were reported. CONCLUSION: In patients with high LDL-C and TG levels, combination treatment with rosuvastatin/fenofibric acid was well tolerated, and each of the rosuvastatin/fenofibric acid doses produced greater reductions in LDL-C and improvements in other efficacy parameters, compared with simvastatin 40 mg. [Clinical trial is registered at www.clinicaltrials.gov NCT00812955.].
Assuntos
Anticolesterolemiantes/uso terapêutico , Fenofibrato/análogos & derivados , Fluorbenzenos/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Pirimidinas/administração & dosagem , Sinvastatina/uso terapêutico , Sulfonamidas/administração & dosagem , Adulto , Idoso , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Fenofibrato/administração & dosagem , Fenofibrato/efeitos adversos , Fluorbenzenos/efeitos adversos , Humanos , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Rosuvastatina Cálcica , Sinvastatina/efeitos adversos , Sulfonamidas/efeitos adversosRESUMO
BACKGROUND: Patients with mixed dyslipidemia characterized by elevated low-density lipoprotein cholesterol (LDL-C), elevated triglycerides (TG), and reduced high-density lipoprotein cholesterol (HDL-C) often require combination therapy to improve multiple lipid and nonlipid parameters. This phase 3, multicenter, randomized, double-blind study evaluated the efficacy and safety of rosuvastatin 5 mg coadministered with fenofibric acid 135 mg in patients with mixed dyslipidemia. METHODS: A total of 760 patients with TG ≥ 150 mg/dL, HDL-C <40 mg/dL (<50 mg/dL for women), and LDL-C ≥ 130 mg/dL were randomized for a 12-week treatment period to rosuvastatin 5 mg, fenofibric acid 135 mg, or rosuvastatin 5 mg + fenofibric acid 135 mg. The primary efficacy comparisons were mean percentage changes in HDL-C and TG (rosuvastatin + fenofibric acid vs. rosuvastatin monotherapy), and LDL-C (rosuvastatin + fenofibric acid vs. fenofibric acid monotherapy). RESULTS: Treatment with rosuvastatin + fenofibric acid resulted in statistically significant greater improvements in HDL-C (23.0% vs. 12.4%; P < 0.001) and TG (-40.3% vs. -17.5%; P < 0.001), compared with rosuvastatin monotherapy; and LDL-C (-28.7% vs. -4.1%; P < 0.001), compared with fenofibric acid monotherapy. All secondary efficacy variables improved with combination therapy. Combination therapy was generally well tolerated with a safety profile consistent with individual monotherapies. No unexpected muscle, hepatic, or renal safety signals were identified with combination therapy versus individual monotherapies. CONCLUSION: In conclusion, rosuvastatin 5 mg + fenofibric acid 135 mg resulted in comprehensive improvements in the lipid profile of patients with mixed dyslipidemia without unanticipated adverse events.
Assuntos
Anticolesterolemiantes/administração & dosagem , Dislipidemias/tratamento farmacológico , Fenofibrato/análogos & derivados , Fluorbenzenos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Idoso , Anticolesterolemiantes/efeitos adversos , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Método Duplo-Cego , Quimioterapia Combinada , Dislipidemias/metabolismo , Feminino , Fenofibrato/administração & dosagem , Fenofibrato/efeitos adversos , Fluorbenzenos/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Rosuvastatina Cálcica , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: Long-term (>1 year) safety and efficacy studies of combination lipid therapy are lacking. This year 2 study evaluated fenofibric acid 135 mg in combination with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg) in patients with mixed dyslipidaemia. METHODS: This was a phase 3, open-label, year 2 extension study in patients who had completed one of three double-blind, 12-week, controlled studies and the subsequent open-label, year 1 extension study. Patients in this study had mixed dyslipidaemia (high-density lipoprotein cholesterol [HDL-C] <40 mg/dL [<1.02 mmol/L] for men or <50 mg/dL [<1.28 mmol/L] for women, triglycerides [TG] > or =150 mg/dL [> or =1.69 mmol/L], and low-density lipoprotein cholesterol [LDL-C] > or =130 mg/dL [> or =3.37 mmol/L]) at the start of the controlled study, and had completed the year 1 extension study. Treatment was once-daily oral coadministration of fenofibric acid 135 mg and moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg), and was identical to the treatment received in the year 1 study. The year 2 population safety data were summarized for the entire duration of fenofibric acid + statin therapy. Efficacy data were summarized by combination therapy group, as well as pooled across combination therapies, and summarized across the controlled and open-label studies. RESULTS: Of the 310 patients enrolled into the year 2 study, 287 (93%) completed therapy. The mean cumulative exposure to combination therapy was 743 days across the studies. Adverse event rates were similar for all three combination therapy groups. No deaths or treatment-related serious adverse events occurred. The incidence of discontinuation due to adverse events was 2.9% overall. Rhabdomyolysis was not reported in any group. Overall, fenofibric acid + moderate-dose statin for > or =2 years resulted in sustained improvements in HDL-C (+17.4%), TG (-46.4%) and LDL-C (-40.4%). CONCLUSIONS: This long-term study demonstrated that fenofibric acid + moderate-dose statin was generally well tolerated with no new or unexpected safety concerns, and resulted in comprehensive and sustained lipid improvements in patients with mixed dyslipidaemia.
Assuntos
Dislipidemias/tratamento farmacológico , Fenofibrato/análogos & derivados , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Adulto , Idoso , Atorvastatina , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Método Duplo-Cego , Quimioterapia Combinada , Dislipidemias/sangue , Feminino , Fenofibrato/administração & dosagem , Fluorbenzenos/administração & dosagem , Ácidos Heptanoicos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Rosuvastatina Cálcica , Sinvastatina/administração & dosagem , Sulfonamidas/administração & dosagemRESUMO
BACKGROUND: The ODYSSEY CHOICE I study (NCT01926782) evaluated alirocumab 300 mg every 4 weeks (Q4W) in patients with hypercholesterolemia receiving maximally tolerated statin or no statin. OBJECTIVE: The objective of the study was to assess the relationship between alirocumab, proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein cholesterol (LDL-C) concentrations with the CHOICE I alirocumab dosing regimen. METHODS: This analysis included 803 patients (547 statin-treated, 256 without statin) who were randomized to alirocumab 300 mg Q4W, alirocumab 75 mg every 2 weeks (Q2W), or placebo. 300 mg Q4W and 75 mg Q2W doses were adjusted to 150 mg Q2W at Week 12 if Week 8 LDL-C was >70 or >100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was <30% from baseline. RESULTS: Most patients remained on 300 mg Q4W without dose adjustment as they achieved study-defined LDL-C goals at Week 8 (statin-treated: 80.7%; no statin: 85.3%). LDL-C was reduced by 60.5%-71.9% over Weeks 20-24 in patients on 300 mg Q4W and 57.2%-63.0% in patients with dose adjustment from 300 mg Q4W to 150 mg Q2W. Statin-treated patients had higher cardiovascular risk as well as higher free PCSK9 and lower alirocumab concentrations (vs no statin), suggesting increased target-mediated clearance. Regardless of statin status, the most common adverse events in alirocumab-treated patients were injection-site reaction and headache. CONCLUSIONS: Data provide further insight on alirocumab's mode of action in terms of relationship between alirocumab, PCSK9, and LDL-C, and disease severity, and support the use of alirocumab 300 mg Q4W as an efficacious dosing regimen for clinically meaningful LDL-C reductions.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , LDL-Colesterol/metabolismo , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/metabolismo , Feminino , Humanos , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND/RATIONALE: Treatment of severe hypertriglyceridemia is indicated to reduce the risk of pancreatitis in patients with triglyceride (TG) levels > or =500 mg/dL. Hypertriglyceridemia is also a risk factor for atherosclerotic coronary heart disease. Prescription omega-3 fatty acids (P-OM3) and fenofibrate (FENO) are among the most effective lipid-altering agents that reduce TG levels. Given that some patients may not achieve optimal TG levels with a single agent, we hypothesized that concomitant use of P-OM3 or addition of P-OM3 to FENO would result in a TG reduction greater than that with FENO alone. METHODS: This randomized, 8-week, double-blind, placebo-controlled study was designed to compare the safety and efficacy of P-OM3 4 g QD plus concomitant FENO 130 mg with FENO 130 mg QD plus placebo in subjects with very high TG levels (> or =500 mg/dL). Subjects who completed the double-blind study were given the option to continue into an open-label, 8-week extension study, wherein they all received P-OM3 4 g plus FENO 130 mg QD. On completion of the first extension study, subjects were eligible to continue into an open-label 24-month extension of the treatment with P-OM3 4 g plus FENO 130 mg QD. RESULTS: Concomitant P-OM3 + FENO (n = 81) and FENO monotherapy (n = 82) reduced median TG values from 649.5 to 267.5 mg/dL (60.8%) and from 669.3 to 310 mg/dL (53.8%), respectively (P = 0.059). When subjects who had received 8 weeks of stable FENO monotherapy were given P-OM3 during the 8-week, open-label extension study (n = 58), TG levels were reduced 17.5% (P = 0.003) over the course of the extension. The second extension phase was terminated early (n = 93)-not because of a safety signal but because of the lack of a substantial incremental change in the primary endpoint lipid values above that reached in either the original study or the first extension in subjects receiving the combination of fenofibrate and P-OM3. CONCLUSIONS: Both FENO monotherapy and P-OM3 + FENO significantly reduced TGs in subjects with very high TGs, with a trend to greater reduction in the P-OM3 + FENO group. The addition of P-OM3 to stable FENO therapy in the same subjects in an open-label extension study resulted in a statistically significant reduction in TG levels. Subjects who received P-OM3 + FENO for 16 weeks and subjects in which P-OM3 was added to FENO monotherapy during the open-label phase of the study did not differ in their final lipid responses. In the second open-label extension, within the combined group taking P-OM3 and FENO, analysis of change from the second extension baseline to end of treatment revealed no clinically important change.
Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Fenofibrato/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Terapia Combinada/efeitos adversos , Registros de Dieta , Dieta com Restrição de Gorduras , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Ácidos Graxos Ômega-3/efeitos adversos , Feminino , Fenofibrato/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Triglicerídeos/sangue , Adulto JovemRESUMO
Ischemic heart disease and stroke are the leading causes of death in the world currently. Both of these conditions are primarily caused by atherosclerosis, the underlying pathophysiology of which is the deposition of lipid, specifically low-density lipoprotein cholesterol (LDL-C) within the arterial bed. PCSK9, is a proteolytic enzyme, which indirectly increases LDL-C levels by causing the destruction of LDL receptors, the main way that humans regulate their serum LDL-C levels. Inhibitors of PCSK9 in conjunction with statins have allowed achievement of very low LDL-C levels. This review will provide an in-depth efficacy and safety review of alirocumab, a monoclonal antibody inhibitor of PCSK9, including the ODYSSEY OUTCOMES trial.
Assuntos
Anticorpos Monoclonais/farmacocinética , LDL-Colesterol/sangue , Hipercolesterolemia/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Biomarcadores/sangue , Humanos , Hipercolesterolemia/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
CONTEXT: In the ODYSSEY CHOICE I trial, alirocumab 300 mg every 4 weeks (Q4W) was assessed in patients with hypercholesterolemia. Alirocumab efficacy and safety were evaluated in a patient subgroup with type 2 diabetes mellitus (T2DM) and who were receiving maximally tolerated statins with or without other lipid-lowering therapies. METHODS: Participants received either alirocumab 300 mg Q4W (n = 458, including 96 with T2DM) or placebo (n = 230, including 50 with T2DM) for 48 weeks, with alirocumab dose adjustment to 150 mg every 2 weeks at Week (W) 12 if W8 low-density lipoprotein cholesterol (LDL-C) levels were ≥70 mg/dL or ≥ 100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was <30% from baseline. Efficacy end points included percentage change from baseline to W24 for lipids, and time-averaged LDL-C over W21 to W24. RESULTS: In individuals with T2DM, LDL-C reductions from baseline to W24 and the average of W21 to W24 were significantly greater with alirocumab (-61.6% and -68.8%, respectively) vs placebo. At W24, alirocumab significantly reduced levels of non-high-density lipoprotein cholesterol (HDL-C) and other lipids. At W24, 85.9% and 12.5% of individuals in the alirocumab and placebo groups, respectively, reached both non-HDL-C <100 mg/dL and LDL-C <70 mg/dL. At W12, In total, 18% of alirocumab-treated participants received dose adjustment. The most common treatment-emergent adverse events were upper respiratory tract infection and injection-site reaction. No clinically significant changes in fasting plasma glucose and glycated hemoglobin were observed. CONCLUSION: In individuals with T2DM, alirocumab 300 mg Q4W was generally well tolerated and efficacious in reducing atherogenic lipoproteins.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Idoso , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: Changes in PCSK9, alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with alirocumab at doses of 75 or 150 mg every 2 weeks (Q2W). METHODS: Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated alirocumab 75 mg Q2W, with possible dose increase to 150 mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied alirocumab 150 mg Q2W. RESULTS: Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After alirocumab administration, increased alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160 mg/dL) were more likely to have their dose increased. LDL-C reductions with alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as alirocumab 150 mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. CONCLUSIONS: Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production.
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Anticorpos Monoclonais Humanizados/uso terapêutico , LDL-Colesterol/sangue , Pró-Proteína Convertase 9/sangue , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Attainment of blood pressure (BP) goals in patients with diabetes is critical both to reduce the risk of cardiovascular events and to delay the progression of renal disease. While therapeutic guidelines advise initial therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, monotherapy with these agents may not be sufficient to attain target BP. OBJECTIVE: The ADHT (Amlodipine Diabetic Hypertension Efficacy Response Evaluation Trial) evaluated the efficacy and safety of adding amlodipine to the treatment regimen of patients with hypertension and diabetes who were already receiving either quinapril or losartan as monotherapy. METHODS: ADHT was a double-blind, double-dummy, 22-week trial conducted in the US. After a washout period of 7-13 days, patients (aged 30-75 y) with hypertension and diabetes were randomized to receive quinapril 20 mg/day plus placebo or losartan 50 mg/day plus placebo for 4 weeks, titrated to 40 mg or 100 mg (if required), respectively, for an additional 4 weeks to achieve their BP goals (<130/80 mm Hg). At week 8, either amlodipine 5 mg/day or placebo was added for an additional 12 weeks, with titration to 10 mg at week 14 if the BP goal was not achieved. RESULTS: Efficacy of add-on therapy was evaluated in 411 patients (amlodipine 211, placebo 200). BP goal was reached by 27.5% of patients when amlodipine was added to quinapril or losartan monotherapy, compared with 12.5% when placebo was added (OR 2.73; 95% CI 1.61 to 4.64; p < 0.001). When added to quinapril or losartan monotherapy, amlodipine reduced BP by 8.1/5.4 mm Hg, compared with a 1.6/0.7 mm Hg decrease with add-on placebo (p < 0.001). Amlodipine, quinapril, and losartan were well tolerated. CONCLUSIONS: Amlodipine is safe and effective when added to quinapril or losartan monotherapy to help lower BP toward therapeutic targets in patients with hypertension and diabetes.
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Anlodipino/administração & dosagem , Anlodipino/uso terapêutico , Losartan/administração & dosagem , Losartan/uso terapêutico , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Idoso , Anlodipino/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Losartan/efeitos adversos , Masculino , Pessoa de Meia-Idade , Quinapril , Tetra-Hidroisoquinolinas/efeitos adversosRESUMO
INTRODUCTION: Evolocumab is an injectable, fully human monoclonal antibody and a member of the newest class of low density lipoprotein cholesterol (LDL-C) lowering agents called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The PCSK9 inhibitors are the most significant advance in lipid therapy since the introduction of the first statin 30 years ago. Areas covered: The PCSK9 monoclonal antibodies have demonstrated a consistently high LDL-C lowering efficacy with and without statins and/or other lipid lowering therapies (LLT). LDL-C levels achieved with these agents are lower than has ever been possible before. This review will focus on the overall safety of evolocumab including cognitive impairment, very low LDL-C levels, new onset diabetes and glucose abnormalities, effect on vitamin E and steroid hormones, liver and muscle abnormalities, and immunogenicity and injection site reactions. The phase II and III clinical trials had relatively low patient-years of exposure, but the open label extension studies and the recently published outcomes trial, FOURIER, will be the focus of this paper. The safety profile of evolocumab to date is remarkable and extremely encouraging as will be demonstrated. Expert opinion: The PCSK9 inhibitors will be responsible for a new era in lipid therapy that will expand our knowledge of lipid levels and cardiovascular disease (CVD) prevention with an efficacy and safety profile not previously available in clinical practice.
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Anticorpos Monoclonais/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Inibidores de PCSK9 , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/farmacologia , LDL-Colesterol/sangue , Disfunção Cognitiva/induzido quimicamente , HumanosRESUMO
A new class of lipid-lowering drugs, inhibitors of PCSK9 has been generating impressive clinical trial data over the last several years, and alirocumab (Praluent) has become the first to be approved by the US FDA. Alirocumab has been shown to lower low density lipoprotein cholesterol by 45-62% with a safety profile generally comparable to placebo. Alirocumab is a monoclonal antibody to PCSK9 administered subcutaneously and has been evaluated in 16 Phase III clinical trials, the majority of which have been enrolled or completed. This article will be a review of the available Phase III safety and efficacy data of the ODYSSEY studies including a brief description of each of the 16 studies.
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Anticorpos Monoclonais/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Hiperlipidemias/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Aprovação de Drogas , HumanosRESUMO
BACKGROUND AND AIMS: In previous phase III studies, the PCSK9 monoclonal antibody alirocumab was administered at doses of 75 or 150 mg every 2 weeks (Q2W). CHOICE I (NCT01926782) evaluated 300 mg every 4 weeks (Q4W) in patients on either maximally tolerated statin or no statin, both ± other lipid-lowering therapies. METHODS: CHOICE I included patients with hypercholesterolemia at moderate-to-very-high cardiovascular risk. Patients were randomized to alirocumab 300 mg Q4W, 75 mg Q2W (calibrator arm), or placebo for 48 weeks, with dose adjustment for either alirocumab arm to 150 mg Q2W at Week (W) 12 if at W8 LDL-C levels were >70/100 mg/dL (1.8/2.6 mmol/L) depending on cardiovascular risk or LDL-C reduction was <30% from baseline. Co-primary endpoints were percent LDL-C change from baseline to W24, and to time-averaged LDL-C over W21-24. RESULTS: Approximately two-thirds of randomized patients were receiving statins. At W12, 14.7% (no statin) and 19.3% (statin) of patients receiving alirocumab 300 mg Q4W required dose adjustment. At W24, significant LDL-C reductions from baseline were observed with alirocumab 300 mg Q4W: mean differences were -52.7% (no statin; placebo: -0.3%) and -58.8% (statin; placebo: -0.1%). Average LDL-C reductions from baseline to W21-24 were also significantly greater with alirocumab 300 mg Q4W vs. placebo in patients not receiving (-56.9% vs. -1.6%) and receiving statin (-65.8% vs. -0.8%). Treatment-emergent adverse event rates ranged from 61.1 to 75.0% (placebo) and 71.5 to 78.1% (alirocumab 300 mg Q4W). CONCLUSIONS: Alirocumab 300 mg Q4W is a viable additional treatment option in patients requiring LDL-C-lowering.