BACKGROUND: Despite the availability of effective drug therapies that reduce 
low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) 
remains an important cause of mortality and morbidity. Therefore, additional 
LDL-C reduction may be warranted, especially for patients who are unresponsive 
to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the 
proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal 
antibodies (PCSK9 inhibitors) may further reduce LDL-C, potentially reducing CVD 
risk as well.
OBJECTIVES: Primary To quantify short-term (24 weeks), medium-term (one year), 
and long-term (five years) effects of PCSK9 inhibitors on lipid parameters and 
on the incidence of CVD. Secondary To quantify the safety of PCSK9 inhibitors, 
with specific focus on the incidence of type 2 diabetes, cognitive function, and 
cancer. Additionally, to determine if specific patient subgroups were more or 
less likely to benefit from the use of PCSK9 inhibitors.
SEARCH METHODS: We identified studies by systematically searching the Cochrane 
Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of 
Science. We also searched Clinicaltrials.gov and the International Clinical 
Trials Registry Platform and screened the reference lists of included studies. 
We identified the studies included in this review through electronic literature 
searches conducted up to May 2016, and added three large trials published in 
March 2017.
SELECTION CRITERIA: All parallel-group and factorial randomised controlled 
trials (RCTs) with a follow-up time of at least 24 weeks were eligible.
DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and 
extracted data. When data were available, we calculated pooled effect estimates.
MAIN RESULTS: We included 20 studies with data on 67,237 participants (median 
age 61 years; range 52 to 64 years). Twelve trials randomised participants to 
alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. 
Owing to the small number of trials using agents other than alirocumab, we did 
not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 
inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and 
statins (five RCTs).Compared with placebo, PCSK9 inhibitors decreased LDL-C by 
53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 
participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 
inhibitors decreased LDL-C by 30.20% (95% CI 34.18 to 26.23; two studies; 823 
participants; GRADE: moderate), and compared with ezetimibe and statins, PCSK9 
inhibitors decreased LDL-C by 39.20% (95% CI 56.15 to 22.26; five studies; 5376 
participants; GRADE: moderate).Compared with placebo, PCSK9 inhibitors decreased 
the risk of CVD events, with a risk difference (RD) of 0.91% (odds ratio (OR) of 
0.86, 95% CI 0.80 to 0.92; eight studies; 59,294 participants; GRADE: moderate). 
Compared with ezetimibe and statins, PCSK9 inhibitors appeared to have a 
stronger protective effect on CVD risk, although with considerable uncertainty 
(RD 1.06%, OR 0.45, 95% CI 0.27 to 0.75; three studies; 4770 participants; 
GRADE: very low). No data were available for the ezetimibe only comparison. 
Compared with placebo, PCSK9 probably had little or no effect on mortality (RD 
0.03%, OR 1.02, 95% CI 0.91 to 1.14; 12 studies; 60,684 participants; GRADE: 
moderate). Compared with placebo, PCSK9 inhibitors increased the risk of any 
adverse events (RD 1.54%, OR 1.08, 95% CI 1.04 to 1.12; 13 studies; 54,204 
participants; GRADE: low). Similar effects were observed for the comparison of 
ezetimibe and statins: RD 3.70%, OR 1.18, 95% CI 1.05 to 1.34; four studies; 
5376 participants; GRADE: low. Clinical event data were unavailable for the 
ezetimibe only comparison.
AUTHORS' CONCLUSIONS: Over short-term to medium-term follow-up, PCSK9 inhibitors 
reduced LDL-C. Studies with medium-term follow-up time (longest median follow-up 
recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) 
decreased CVD risk but may have increased the risk of any adverse events (driven 
by SPIRE-1 and -2 trials). Available evidence suggests that PCSK9 inhibitor use 
probably leads to little or no difference in mortality. Evidence on relative 
efficacy and safety when PCSK9 inhibitors were compared with active treatments 
was of low to very low quality (GRADE); follow-up times were short and events 
were few. Large trials with longer follow-up are needed to evaluate PCSK9 
inhibitors versus active treatments as well as placebo. Owing to the predominant 
inclusion of high-risk patients in these studies, applicability of results to 
primary prevention is limited. Finally, estimated risk differences indicate that 
PCSK9 inhibitors only modestly change absolute risks (often to less than 1%).