Describe the effectiveness and safety of PCSK9 inhibitors for cardiovascular disease prevention.
Despite the availability of effective drug therapies (statins or ezetimibe) that reduce low-density (LDL) cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Additional LDL-C reduction may therefore be warranted, especially for patients who are unresponsive to, or are unable to use, existing LDL-C reducing therapies. PCSK-9 inhibition produced by monoclonal antibodies (PCSK9 inhibitors) may further reduce LDL-C levels and CVD risk.
Review authors identified 20 studies that evaluated the effects of PCSK9 inhibitors in participants at high risk of CVD; studies were conducted in outpatient clinic settings. Review authors 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.
PCSK9 inhibitors constitute a class of drugs that decrease LDL-C and therefore may decrease the incidence of CVD. We examined the results of 20 studies, which showed beneficial effects on blood cholesterol concentrations of PCSK9 inhibitors at both six months and one year of follow-up. Although the magnitude of this beneficial effect differed between studies, all showed beneficial effects. In comparisons of PCSK9 inhibitors versus no PCSK9 inhibitors, current evidence suggests that PCSK9 inhibitors decrease CVD incidence without affecting the incidence of all-cause mortality. In comparisons of PCSK9 inhibitors versus alternative (more established) treatments such as statins or ezetimibe, high-quality evidence is lacking. Differences in risk between people treated with and without PCKS9 inhibitors suggest the absolute treatment benefit will likely be modest (e.g. < 1% change in risk).
Quality of evidence
Most of the included randomised controlled trials (RCTs) were designed to explore biomarker associations; however, as all trials were industry funded, GRADE assessment revealed that the quality of the evidence was moderate. For associations with clinical endpoints (mortality and CVD), the quality of the evidence was moderate (placebo comparison) to very low (ezetimibe and statin comparisons).
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%).
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.
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.
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.
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.
All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up time of at least 24 weeks were eligible.
Two review authors independently reviewed and extracted data. When data were available, we calculated pooled effect estimates.
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.