1. In patients on maximal statin treatment and with LDL levels over 70mg/dL, the addition of alirocumab reduced LDL levels from baseline by about 62% compared to placebo.
2. No increase in adverse events was noted with alirocumab compared to placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: People in the general population with mutations in the proprotein convertase subtilisin-kexin type 9 (PCSK9) enzyme have been found to have lower LDL levels and better cardiovascular outcomes. Hence, monoclonal antibodies against PCSK9 are being explored as a treatment for elevated LDL levels. Prior phase 2 trials had demonstrated that alirocumab, a monoclonal antibody against the protein PCSK9, could lower LDL cholesterol by up to 70% over 8 to 12 weeks. ODYSSEY LONG TERM is a phase 3 study to examine the efficacy and safety of alirocumab over 78 weeks.
The primary outcome was the percentage change in LDL levels at 24 weeks. At baseline, the study participants had LDL levels of about 120mg/dl on average. At 24 weeks, the participants receiving alirocumab had an average LDL level of 48mg/dl, a 61% decrease. 79.3% of patients in the alirocumab group were able to reach their goal LDL level of <70mg/dl, compared to only 8% in the placebo group.
In terms of safety, alirocumab was not associated with increase in severe adverse events. Prominent side effects included myalgias and injection-site reactions. Some patients on alirocumab reached LDL levels of below 25mg/dl. There are no high-quality data on the long-term safety of having such low LDL levels.
Alirocumab offers promise for reaching LDL goals in people already on maximal statin therapy, though further data, and appropriately powered trials, are necessary to show that this leads to improved outcomes.
In-Depth [randomized controlled trial]: This was a multicenter, multinational trial of 2341 patients randomized in a 2:1 ratio to alirocumab or placebo. Alirocumab is a monoclonal antibody against proprotein covertase subtilisin-kexin type 9 (PCSK9).
The effect of alirocumab was relatively rapid and sustained. By 4 weeks, the LDL levels of the participants receiving alirocumab had already reached their lowest point. At week 24, the difference between the alirocumab and placebo groups in terms of percentage change from baseline LDL was -62% (P<0.001). From 24 weeks to 78 weeks, the change in LDL level from baseline diminished from 62% to 52%, mostly due to discontinuation of the study drug. Among those still using the drug at 78 weeks, the LDL change from baseline was -58%.
No firm conclusions can yet be made as to whether reaching lower LDL targets with alirocumab improves cardiovascular outcomes, though the post-hoc analysis done in this study suggests there may be a benefit. The ongoing ODYSSEY OUTCOMES trial looks at cardiovascular events as a primary outcome, and will provide better data to answer this important question.
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