What is the effectiveness and safety of PCSK9 inhibitors for cardiovascular disease (CVD) prevention?
Despite the availability of effective medicines (such as statins (which works by blocking a substance your body needs to make cholesterol) or ezetimibe (which stops your body taking in cholesterol from food), or both) that reduce low-density lipoprotein (LDL) cholesterol (LDL-C) (sometimes called 'bad' cholesterol), CVD remains an important cause of death and illness. Additional LDL-C reduction may be needed, especially for people who are unresponsive to, or are unable to use, existing LDL-C-reducing therapies. Medicines called PCSK9 inhibitors are another way of lowering LDL-C and CVD risk.
Review authors identified 23 studies that evaluated the effects of the PCSK9 inhibitors, alirocumab and evolocumab, in people at high risk of CVD. Studies were conducted in outpatient clinics. Review authors identified the studies included in this review through electronic literature searches conducted up to December 2019. This is an update of the review first published in 2017.
Both alirocumab and evolocumab decreased the risk of CVD when added to other LDL-C-lowering medicines (e.g. statins or ezetimibe). Alirocumab additionally showed a decrease in death from any cause; with insufficient evidence for evolocumab. Limited data, often of lower quality, was available comparing these PCSK9 inhibitors against other LDL-C-lowering drugs. Differences in risk between people treated with and without PCSK9 inhibitors suggest the absolute treatment benefit will likely be modest (e.g. less than 1% change in risk).
Quality of evidence
We found high-quality evidence when adding PCSK9 inhibitors to existing LDL-C-lowering treatments and low- to very low-quality evidence when replacing existing LDL-C-reducing medicines with PCSK9 inhibitors.
The evidence for the clinical endpoint effects of evolocumab and alirocumab versus placebo were graded as high. There is a strong evidence base for the benefits of PCSK9 monoclonal antibodies to people who might not be eligible for other lipid-lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials.
The evidence base of PCSK9 inhibitors compared with ezetimibe and statins is much weaker (low very- to low-certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies.
Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.
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 people 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) reduce LDL-C and CVD risk.
To quantify the effects of PCSK9 inhibitors on CVD, all-cause mortality, myocardial infarction, and stroke, compared to placebo or active treatment(s) for primary and secondary prevention.
To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention.
We identified studies by systematically searching CENTRAL, MEDLINE, Embase, and Web of Science in December 2019. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in August 2020 and screened the reference lists of included studies. This is an update of the review first published in 2017.
All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up of at least 24 weeks and adult participants with or without a history of CVD were eligible if they compared PCSK9 inhibitors alirocumab or evolocumab to placebo or active treatments such as statins, ezetimibe, or a combination of these.
Two review authors independently reviewed and extracted data. Where data were available, we calculated pooled effect estimates. We used GRADE to assess certainty of evidence and in 'Summary of findings' tables.
We included 24 studies with data on 60,997 participants. Eighteen trials randomised participants to alirocumab and six to evolocumab. All participants received background lipid-lowering treatment or lifestyle counselling. Six alirocumab studies used an active treatment comparison group (the remaining used placebo), compared to three evolocumab active comparison trials. Follow-up ranged from 6 to 36 months for the comparisons with placebo and from 6 to 12 months for comparisons with active treatment. Most of the available studies preferentially enrolled people with either established CVD or at a high risk already, and evidence in low- to medium-risk settings is minimal.
Alirocumab compared with placebo decreased the risk of CVD events, with an absolute risk difference (RD) of –2% (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.80 to 0.94; 10 studies, 23,868 participants; high-certainty evidence), decreased the risk of mortality (RD –1%; OR 0.83, 95% CI 0.72 to 0.96; 12 studies, 24,797 participants; high-certainty evidence), and MI (RD –2%; OR 0.86, 95% CI 0.79 to 0.94; 9 studies, 23,352 participants; high-certainty evidence) and for any stroke (RD 0%; OR 0.73, 95% CI 0.58 to 0.91; 8 studies, 22,835 participants; high-certainty evidence).
Alirocumab compared with ezetimibe and statins: for CVD, the RD was 1% (OR 1.37, 95% CI 0.65 to 2.87; 3 studies, 1379 participants; low-certainty evidence); for mortality, RD was –1% (OR 0.51, 95% CI 0.18 to 1.40; 5 studies, 1333 participants; low-certainty evidence); for MI, RD was 1% (OR 1.45, 95% CI 0.64 to 3.28, 5 studies, 1734 participants; low-certainty evidence); and for any stroke, RD was less than 1% (OR 0.85, 95% CI 0.13 to 5.61; 5 studies, 1734 participants; low-certainty evidence).
Evolocumab compared with placebo: for CVD, the RD was –2% (OR 0.84, 95% CI 0.78 to 0.91; 3 studies, 29,432 participants; high-certainty evidence); for mortality, RD was less than 1% (OR 1.04, 95% CI 0.91 to 1.19; 3 studies, 29,432 participants; high-certainty evidence); for MI, RD was –1% (OR 0.72, 95% CI 0.64 to 0.82; 3 studies, 29,432 participants; high-certainty evidence); and for any stroke RD was less than –1% (OR 0.79, 95% CI 0.65 to 0.94; 2 studies, 28,531 participants; high-certainty evidence).
Evolocumab compared with ezetimibe and statins: for any CVD event RD was less than –1% (OR 0.66, 95% CI 0.14 to 3.04; 1 study, 218 participants; very low-certainty evidence); for all-cause mortality, the RD was less than 1% (OR 0.43, 95% CI 0.14 to 1.30; 3 studies, 5223 participants; very low-certainty evidence); and for MI, RD was less than 1% (OR 0.66, 95% CI 0.23 to 1.85; 3 studies, 5003 participants; very low-certainty evidence). There were insufficient data on any stroke.