Comparable cardiovascular risk reduction with PCSK9 antibodies and statins
Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration
Data from statin trials and studies with PCSK9 antibodies show that the lipid-lowering therapies reduce the risk of major cardiovascular (CV) events. In this analysis, the results of the PCSK9 antibody trials FOURIER (n=27 564) and SPIRE (n=27 438) were compared with the results of the Cholesterol Treatment Trialists (CTT) meta-analysis of statin trials [1-4].
- In the FOURIER trial, treatment with evolocumab reduced the risk of the primary outcome by 11.0% (HR: 0.89; 95% CI: 0.84–0.94) per mmol/L reduction LDL-C, whereas there was a 22% reduction in risk (HR: 0.78; 95% CI: 0.76–0.80) per mmol/L reduction LDL-C during treatment with a statin in the CTT meta-analysis (P=1.6x10-5 for primary outcome).
- The SPIRE trials were stopped early due to high rates of neutralizing antidrug antibody development that resulted in an attenuation of the LDL-C-lowering effect of bococizumab over time. Despite that, the SPIRE-2 trial completed a median follow-up of 1 year, which makes the results of the prematurely terminated trial useful for the present comparison: In the SPIRE-2 trial, treatment with bococizumab reduced risk of the primary outcome by 14.5% (HR: 0.85; 95% CI: 0.75–0.98, P=0.19 for primary outcome) per mmol/L reduction in LDL-C, relative to the 22% risk reduction in CTT.
- A more relevant analysis would be to compare the effect of PCSK9 inhibitors with the effect of statins for the same total duration of therapy or during each year of treatment. In a combined analysis of FOURIER and SPIRE-2 trials, treatment with either evolocumab or bococizumab during first year of treatment reduced risk of CV outcomes by 11–16%, which is similar to the 4–16% reduction in risk per mmol/L reduction in LDL-C observed during the first year of treatment in the statin trials.
- In the FOURIER trial, treatment with evolocumab during the second year of the trial reduced the risk of CV outcomes by 18–23% per mmol/L reduction in LDL-C, which is very similar to the 22–25% reduction in risk for the same outcomes observed during the second year of treatment in the statin trials.
- A recent Mendelian randomization study also demonstrated that genetic variants that mimic the effect of PCSK9 inhibitors and statins, have nearly identical effects on cardiovascular disease risk per unit change in LDL-C. These data suggest that inhibition of PCSK9 and HMG-CoA reductase (statins) have biologically equivalent effects on the risk of CV events per unit change in LDL-C, and that pleiotropic effects do not play an essential role in this context .
- Treatment with statins or with PCSK9 inhibitors is associated with a small increase in risk of diabetes mellitus (DM) per unit change in LDL-C, however the beneficial effect of lowering LDL-C by inhibiting either PCSK9 or HMG-CoA reductase far exceeds any potential risk of new onset DM [6,7].
PCSK9 antibodies and statins comparably reduce the risk of CV events and slightly increase risk of DM, proportional to the absolute achieved reduction in LDL-C and the total duration of therapy. These data support the focus on LDL-C targets in the prevention of cardiovascular disease.