The following are key points to remember from an analysis of several clinical trials on the reduction of low-density lipoprotein cholesterol (LDL-C) and cardiovascular events (CVEs) with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins:

1. There is evidence of a relationship between on-treatment decrease in LDL-C and reduction in CVE rates (about a 40 mg/dl or 1 mmol/L decrease in LDL-C results in a 20% reduction in CVEs). The degree to which that holds between various therapies is not clear. The authors sought to compare the efficacy of PCSK9 inhibitors and statins for reducing the risk of CVEs by comparing the results of the FOURIER (evolocumab) and SPIRE (bococizumab) trials with the results of the Cholesterol Treatment Trialists (CTT) meta-analysis of statin trials. The study was made possible in part by the decrease in efficacy of bococizumab due to neutralizing antidrug antibodies that resulted in an attenuation of the LDL-C lowering over time.
2. Importantly, in the CTT meta-analysis, the statin regression line for CVEs is over an average of 5 years and is associated with only a 10–12% reduction in CVEs per mmol/L reduction in LDL-C during the first year of treatment, followed by a 22–24% reduction in risk per mmol/L reduction in LDL-C during each subsequent year of treatment. Therefore, due to the short duration of follow-up for both the FOURIER (2.2 years) and early terminated SPIRE-2 (1 year) trials, the relevant analysis would be to compare the effect of PCSK9 inhibitors with the effect of statins on the risk of CVEs per mmol/L reduction in LDL-C for the same total duration of therapy or during each year of treatment.
3. When the results of the FOURIER and SPIRE-2 trials are plotted on the separate CTT regression lines recalculated for each duration of therapy, they agree very closely with the results observed in the statin trials. Similarly, the PCSK9 inhibitors and statins also appear to have remarkably similar effects on the risk of CVEs during each year of treatment.
4. The results are supported by a recent Mendelian randomization study, which demonstrated that genetic variants that mimic the effect of PCSK9 inhibitors and statins have nearly identical effects on the risk of cardiovascular disease per unit change in LDL-C.
5. The remarkable concordance between the naturally randomized genetic evidence, the results of the CTT meta-analysis of statin trials, and the results of PCSK9 inhibitor cardiovascular outcomes trials demonstrate that PCSK9 inhibitors and statins reduce the risk of CVEs proportional to the absolute achieved reduction in LDL-C and the total duration of therapy.

Keywords: Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Dyslipidemias, Genetics, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Inflammation, Lipoproteins, LDL, Primary Prevention, Proprotein Convertases, Risk

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