Two investigational drugs from a new class of lipid lowering agents – the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors – significantly reduce cardiovascular events, new exploratory analyses have shown.

PCSK9 promotes the degradation of low density lipoprotein (LDL) receptors, so blocking its action increases the levels of receptor, which facilitates the clearance of LDL cholesterol.

The studies, reported in the New England Journal of Medicine, investigated the efficacy and safety of two monoclonal antibodies that inhibit PCSK9 and showed that they reduced LDL cholesterol by around 60% more than standard therapy.

In the first study the PCSK9 inhibitor evolocumab was tested in two open label trials in 4465 people with raised cholesterol levels (Sabatine et al., 2015). Patients were randomised to receive evolocumab (given subcutaneously at a dose of either 140 mg every two weeks or 420 mg once a month) plus standard treatment (statin or other lipid lowering treatment) or standard treatment alone. Evolocumab reduced LDL cholesterol by 61%, from a median of 120 mg/dL to 48 mg/dL (P<0.001), compared with standard treatment alone.

A study with a second PCSK9 inhibitor, alirocumab, included 2341 patients at high risk of cardiovascular events who were already receiving maximum tolerated doses of statins (Robinson et al., 2015). Patients randomised to alirocumab (150 mg as a 1 ml subcutaneous injection every two weeks) showed a 62% greater reduction in LDL cholesterol from baseline than the placebo group.

Post hoc analyses in both studies showed nearly 50% reductions in cardiovascular events at 12-18 months. The rate of cardiovascular events at one year was 2.18% in patients on standard treatment, compared with 0.95% in patients randomised to evolocumab (hazard ratio 0.47 (95% confidence interval 0.28 to 0.78; P=0.003)). Patients treated with alirocumab plus statin showed a 48% lower rate of cardiovascular events than those treated with placebo plus statin (1.7% v 3.3%; hazard ratio 0.52 (0.31 to 0.90; nominal P=0.02)).

Neurocognitive adverse events, primarily related to memory, occurred more frequently with the PCSK9 inhibitors (0.9% with evolocumab v 0.3% with standard treatment; 1.2% with alirocumab v 0.5% with statins). Injection site reactions were also more frequent with the investigational agents.

“Much work remains to be done,” said Neil Stone and Donald Lloyd-Jones in an accompanying editorial (Stone & Lloyd-Jones, 2015). “But PCSK9 inhibitors appear on track to become important arrows in our quiver for targeting reduction of cardiovascular events among higher risk patients when statins are not enough.”

References (In Article)

Sabatine, M.S., Giugliano, R.P., Wiviott, S.D., Raal, R.J., Blom, D.J., Robinson, J., Ballantyne, C.M., Somaratne, R., Legg, J., Wasserman, S.M., Scott, R., Koren, M.J., & Stein, E.A. for the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. (2015) Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. The New England Journal of Medicine. DOI: 10.1056/NEJMoa1500858.

Robinson, J.G., Farnier, M., Krempf, M., Bergeron, J., Luc, G., Averna, M., Stroes, E.S., Langslet, G., Raal, F.J., El Shahawy, M., Koren, M.J., Lepor, N.E., Lorenzato, C., Pordy, R., Chaudhari, U. & Kastelein, J.J.P. for the ODYSSEY LONG TERM Investigators. (2015) Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events. The New England Journal of Medicine. DOI: 10.1056/NEJMoa1501031.

Stone. N.J. & Lloyd-Jones, D.M. (2015) Lowering LDL Cholesterol Is Good, but How and in Whom? The New England Journal of Medicine. DOI: 10.1056/NEJMe1502192.