The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab significantly reduces low-density lipoprotein cholesterol (LDL-C). This study (ODYSSEY EAST) assessed the efficacy and safety of alirocumab vs ezetimibe in high cardiovascular risk patients from Asia. Patients (n = 615) from China, India, and Thailand with hypercholesterolemia at high cardiovascular risk on maximally tolerated statin were randomized (2:1) to alirocumab (75 mg every 2 weeks [Q2W]; with dose increase to 150 mg Q2W at week 12 if week 8 LDL-C was >1.81 mmol/L [>70 mg/dL]) or ezetimibe (10 mg daily) for 24 weeks. The primary efficacy endpoint was percentage change in calculated LDL-C from baseline to week 24. Safety was assessed throughout. Baseline data were similar in both groups. LDL-C levels were reduced from baseline to week 24 by 56.0% and 20.3% in the alirocumab and ezetimibe groups, respectively (P <.0001 vs ezetimibe). Overall, 18.8% of alirocumab-treated patients received a dose increase to 150 mg Q2W. At week 24, 85.1% of alirocumab-treated and 40.5% of ezetimibe-treated patients reached LDL-C <1.81 mmol/L (<70 mg/dL, P <.0001 vs ezetimibe). Treatment-emergent adverse events occurred in 68.5% of alirocumab-treated and 63.1% of ezetimibe-treated patients, with upper respiratory tract infection the most common (alirocumab: 13.3%; ezetimibe: 14.1%). Injection-site reactions occurred more frequently in alirocumab-treated patients (2.7%) than in ezetimibe-treated patients (1.0%). Alirocumab significantly reduced LDL-C vs ezetimibe in high cardiovascular risk patients from Asia and was generally well tolerated. These findings are consistent with previous ODYSSEY studies. • This study evaluated alirocumab in high cardiovascular risk patients from Asia. • Low-density lipoprotein cholesterol (LDL-C) was reduced by 56.0% with alirocumab (P <.0001 vs ezetimibe). • LDL-C <1.81 mmol/L (<70 mg/dL) was reached by 85.1% of alirocumab-treated patients. • Alirocumab was generally well tolerated. • These results are consistent with previous ODYSSEY studies.
<b>BACKGROUND: </b>People living with human immunodeficiency virus (PLHIV) are at increased risk of atherosclerotic cardiovascular disease (ASCVD) and are prone to statin-related adverse events from drug-drug interactions with certain antiretroviral regimens.<b>OBJECTIVES: </b>This study sought to evaluate the efficacy and safety of evolocumab in dyslipidemic PLHIV.<b>METHODS: </b>BEIJERINCK (EvolocumaB Effect on LDL-C Lowering in SubJEcts with Human Immunodeficiency VirRus and INcreased Cardiovascular RisK) is a randomized, double-blind, multinational trial comparing monthly subcutaneous evolocumab 420 mg with placebo in PLHIV with hypercholesterolemia/mixed dyslipidemia taking maximally-tolerated statin therapy. The primary endpoint was the percent change (baseline to week 24) in low-density lipoprotein cholesterol (LDL-C); secondary endpoints included achievement of LDL-C <70 mg/dl and percent change in other plasma lipid and lipoprotein levels. Treatment-emergent adverse events were also examined.<b>RESULTS: </b>A total of 464 patients were analyzed (mean age of 56.4 years, 82.5% male, mean duration with HIV of 17.4 years). ASCVD was documented in 35.6% of patients, and statin intolerance/contraindications to statin use were present in 20.7% of patients. Evolocumab reduced LDL-C by 56.9% (95% confidence interval: 61.6% to 52.3%) from baseline to week 24 versus placebo. An LDL-C level of <70 mg/dl was achieved in 73.3% of patients in the evolocumab group versus 7.9% in the placebo group. Evolocumab also significantly reduced other atherogenic lipid levels, including non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (all p < 0.0001). Evolocumab was well tolerated, and treatment-emergent adverse events patient incidence was similar among evolocumab and placebo groups.<b>CONCLUSIONS: </b>Evolocumab was safe and significantly reduced lipid levels in dyslipidemic PLHIV on maximally-tolerated statin therapy. Evolocumab is an effective therapy for lowering atherogenic lipoproteins in PLHIV with high cardiovascular risk. (Safety, Tolerability & Efficacy on LDL-C of Evolocumab in Subjects With HIV & Hyperlipidemia/Mixed Dyslipidemia; NCT02833844).
<b>BACKGROUND: </b>Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia.<b>METHODS: </b>In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540.<b>RESULTS: </b>The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups.<b>CONCLUSIONS: </b>Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).
BACKGROUND: Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778).
METHODS: In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies.
RESULTS: This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls.
CONCLUSIONS: Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015.
<b>BACKGROUND: </b>Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy.<b>METHODS: </b>We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.<b>RESULTS: </b>The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group).<b>CONCLUSIONS: </b>Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY OUTCOMES ClinicalTrials.gov number, NCT01663402 .).
The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab significantly reduces low-density lipoprotein cholesterol (LDL-C). This study (ODYSSEY EAST) assessed the efficacy and safety of alirocumab vs ezetimibe in high cardiovascular risk patients from Asia. Patients (n = 615) from China, India, and Thailand with hypercholesterolemia at high cardiovascular risk on maximally tolerated statin were randomized (2:1) to alirocumab (75 mg every 2 weeks [Q2W]; with dose increase to 150 mg Q2W at week 12 if week 8 LDL-C was >1.81 mmol/L [>70 mg/dL]) or ezetimibe (10 mg daily) for 24 weeks. The primary efficacy endpoint was percentage change in calculated LDL-C from baseline to week 24. Safety was assessed throughout. Baseline data were similar in both groups. LDL-C levels were reduced from baseline to week 24 by 56.0% and 20.3% in the alirocumab and ezetimibe groups, respectively (P <.0001 vs ezetimibe). Overall, 18.8% of alirocumab-treated patients received a dose increase to 150 mg Q2W. At week 24, 85.1% of alirocumab-treated and 40.5% of ezetimibe-treated patients reached LDL-C <1.81 mmol/L (<70 mg/dL, P <.0001 vs ezetimibe). Treatment-emergent adverse events occurred in 68.5% of alirocumab-treated and 63.1% of ezetimibe-treated patients, with upper respiratory tract infection the most common (alirocumab: 13.3%; ezetimibe: 14.1%). Injection-site reactions occurred more frequently in alirocumab-treated patients (2.7%) than in ezetimibe-treated patients (1.0%). Alirocumab significantly reduced LDL-C vs ezetimibe in high cardiovascular risk patients from Asia and was generally well tolerated. These findings are consistent with previous ODYSSEY studies. • This study evaluated alirocumab in high cardiovascular risk patients from Asia. • Low-density lipoprotein cholesterol (LDL-C) was reduced by 56.0% with alirocumab (P <.0001 vs ezetimibe). • LDL-C <1.81 mmol/L (<70 mg/dL) was reached by 85.1% of alirocumab-treated patients. • Alirocumab was generally well tolerated. • These results are consistent with previous ODYSSEY studies.
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
