Conclusions Ezetimibe monotherapy ( 10 mg/day ) showed a small ( 7.06 % ) but statistically significant reduction in the plasma levels of Lp(a ) in patients with primary hypercholesterolemia .
According to current literature , this magnitude of reduction seems to have no clinical relevance .
Background and Aims Ezetimibe reduces plasma low-density lipoprotein cholesterol ( LDL-C ) levels by up to 20 % .
However , its effect on plasma lipoprotein(a ) [ Lp(a ) ] concentrations in patients with primary hypercholesterolemia has not been defined .
Objective Therefore , we performed a systematic review and meta- analysis to assess this effect based on the available r and omized controlled trials ( RCTs ) .
Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials
BACKGROUND Elevated lipoprotein(a ) ( Lp[a ] ) is a highly prevalent ( around 20 % of people ) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis , but no approved specific therapy exists to substantially lower Lp(a ) concentrations . We aim ed to assess the efficacy , safety , and tolerability of two unique antisense oligonucleotides design ed to lower Lp(a ) concentrations . METHODS We did two r and omised , double-blind , placebo-controlled trials . In a phase 2 trial ( done in 13 study centres in Canada , the Netherl and s , Germany , Denmark , and the UK ) , we assessed the effect of IONIS-APO(a)Rx , an oligonucleotide targeting apolipoprotein(a ) . Participants with elevated Lp(a ) concentrations ( 125 - 437 nmol/L in cohort A ; ≥438 nmol/L in cohort B ) were r and omly assigned ( in a 1:1 ratio in cohort A and in a 4:1 ratio in cohort B ) with an interactive response system to escalating-dose subcutaneous IONIS-APO(a)Rx ( 100 mg , 200 mg , and then 300 mg , once a week for 4 weeks each ) or injections of saline placebo , once a week , for 12 weeks . Primary endpoints were mean percentage change in fasting plasma Lp(a ) concentration at day 85 or 99 in the per- protocol population ( participants who received more than six doses of study drug ) and safety and tolerability in the safety population . In a phase 1/2a first-in-man trial , we assessed the effect of IONIS-APO(a)-LRx , a lig and -conjugated antisense oligonucleotide design ed to be highly and selectively taken up by hepatocytes , at the BioPharma Services phase 1 unit ( Toronto , ON , Canada ) . Healthy volunteers ( Lp[a ] ≥75 nmol/L ) were r and omly assigned to receive a single dose of 10 - 120 mg IONIS-APO(a)LRx subcutaneously in an ascending-dose design or placebo ( in a 3:1 ratio ; single-ascending-dose phase ) , or multiple doses of 10 mg , 20 mg , or 40 mg IONIS-APO(a)LRx subcutaneously in an ascending-dose design or placebo ( in an 8:2 ratio ) at day 1 , 3 , 5 , 8 , 15 , and 22 ( multiple-ascending-dose phase ) . Primary endpoints were mean percentage change in fasting plasma Lp(a ) concentration , safety , and tolerability at day 30 in the single-ascending-dose phase and day 36 in the multiple-ascending-dose phase in participants who were r and omised and received at least one dose of study drug . In both trials , the r and omised allocation sequence was generated by Ionis Biometrics or external vendor with a permuted-block r and omisation method . Participants , investigators , sponsor personnel , and clinical research organisation staff who analysed the data were all masked to the treatment assignments . Both trials are registered with Clinical Trials.gov , numbers NCT02160899 and NCT02414594 . FINDINGS From June 25 , 2014 , to Nov 18 , 2015 , we enrolled 64 participants to the phase 2 trial ( 51 in cohort A and 13 in cohort B ) . 35 were r and omly assigned to IONIS-APO(a)Rx and 29 to placebo . At day 85/99 , participants assigned to IONIS-APO(a)Rx had mean Lp(a ) reductions of 66·8 % ( SD 20·6 ) in cohort A and 71·6 % ( 13·0 ) in cohort B ( both p<0·0001 vs pooled placebo ) . From April 15 , 2015 , to Jan 11 , 2016 , we enrolled 58 healthy volunteers to the phase 1/2a trial of IONIS-APO(a)-LRx .  Of 28 participants in the single-ascending-dose phase , three were r and omly assigned to 10 mg , three to 20 mg , three to 40 mg , six to 80 mg , six to 120 mg , and seven to placebo . Of 30 participants in the multiple-ascending-dose phase , eight were r and omly assigned to 10 mg , eight to 20 mg , eight to 40 mg , and six to placebo . Significant dose-dependent reductions in mean Lp(a ) concentrations were noted in all single-dose IONIS-APO(a)-LRx groups at day 30 . In the multidose groups , IONIS-APO(a)-LRx result ed in mean reductions in Lp(a ) of 66 % ( SD 21·8 ) in the 10 mg group , 80 % ( SD 13·7 % ) in the 20 mg group , and 92 % ( 6·5 ) in the 40 mg group ( p=0·0007 for all vs placebo ) at day 36 . Both antisense oligonucleotides were safe . There were two serious adverse events ( myocardial infa rct ions ) in the IONIS-APO(a)Rx phase 2 trial , one in the IONIS-APO(a)Rx and one in the placebo group , but neither were thought to be treatment related . 12 % of injections with IONIS-APO(a)Rx were associated with injection-site reactions .  IONIS-APO(a)-LRx was associated with no injection-site reactions .  INTERPRETATION IONIS-APO(a)-LRx is a novel , tolerable , potent therapy to reduce Lp(a ) concentrations . IONIS-APO(a)-LRx might mitigate Lp(a)-mediated cardiovascular risk and is being developed for patients with elevated Lp(a ) concentrations with existing cardiovascular disease or calcific aortic valve stenosis . FUNDING Ionis Pharmaceuticals
Conclusions Ezetimibe monotherapy ( 10 mg/day ) showed a small ( 7.06 % ) but statistically significant reduction in the plasma levels of Lp(a ) in patients with primary hypercholesterolemia .
According to current literature , this magnitude of reduction seems to have no clinical relevance .
Background and Aims Ezetimibe reduces plasma low-density lipoprotein cholesterol ( LDL-C ) levels by up to 20 % .
However , its effect on plasma lipoprotein(a ) [ Lp(a ) ] concentrations in patients with primary hypercholesterolemia has not been defined .
Objective Therefore , we performed a systematic review and meta- analysis to assess this effect based on the available r and omized controlled trials ( RCTs ) .