Treatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes .
Although no overall benefit was noted in all-cause or cardiovascular mortality , such benefit may be achievable in patients with higher baseline low-density lipoprotein cholesterol
BACKGROUND We sought to examine the efficacy and safety of 2 PCSK9 ( proprotein convertase subtilisin/kexin type 9 ) inhibitors : alirocumab and evolocumab .
Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial.
CONTEXT An estimated 10 % to 20 % of patients can not tolerate statins or adequate doses to achieve treatment goals . Plasma proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) binds to low-density lipoprotein ( LDL ) receptors , promoting their degradation and increasing LDL cholesterol levels . In phase 1 studies , a human monoclonal antibody to PCSK9 , AMG145 , was well tolerated and reduced LDL cholesterol levels . OBJECTIVE To assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects . DESIGN , SETTING , AND PATIENTS A 12-week , r and omized , double-blind , placebo- and ezetimibe-controlled , dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites . INTERVENTION Patients were r and omized equally to 1 of 5 groups : AMG145 alone at doses of 280 mg , 350 mg , or 420 mg ; AMG145 at 420 mg plus 10 mg of ezetimibe ; or 10 mg of ezetimibe plus placebo . AMG145 or placebo was administered subcutaneously every 4 weeks . MAIN OUTCOME MEASURES The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol . Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe . RESULTS Of 236 patients screened , 160 were r and omized ( mean age , 62 years ; 64 % female ; mean baseline LDL cholesterol , 193 mg/dL ) ; all patients had intolerance to 1 or more statins because of muscle-related events . At week 12 , mean changes in LDL cholesterol levels were -67 mg/dL ( -41 % ; 95 % CI , -49 % to -33 % ) for the AMG145 , 280-mg , group ; -70 mg/dL ( -43 % ; 95 % CI , -51 % to -35 % ) for the 350-mg group ; -91 mg/dL ( -51 % ; 95 % CI , -59 % to -43 % ) for the 420-mg group ; and -110 mg/dL ( -63 % ; 95 % CI , -71 % to -55 % ) for the 420-mg/ezetimibe group compared with -14 mg/dL ( -15 % ; 95 % CI , -23 % to -7.0 % ) for the placebo/ezetimibe group ( P < .001 ) . Four serious adverse events were reported with AMG145 ( coronary artery disease , acute pancreatitis , hip fracture , syncope ) . Myalgia was the most common treatment-emergent adverse event during the study , occurring in 5 patients ( 15.6 % ) in the 280-mg group ( n = 32 ) ; 1 patient ( 3.2 % ) in the 350-mg group ( n = 31 ) , 1 patient ( 3.1 % ) in the 420-mg group ( n = 32 ) , 6 patients ( 20.0 % ) receiving 420-mg AMG145/ezetimibe , and 1 patient ( 3.1 % ) receiving placebo/ezetimibe . CONCLUSION In this phase 2 study in statin-intolerant patients , subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01375764
Treatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes .
Although no overall benefit was noted in all-cause or cardiovascular mortality , such benefit may be achievable in patients with higher baseline low-density lipoprotein cholesterol
BACKGROUND We sought to examine the efficacy and safety of 2 PCSK9 ( proprotein convertase subtilisin/kexin type 9 ) inhibitors : alirocumab and evolocumab .