As guidelines on reducing cardiovascular risk have increasingly focused on lowering LDL cholesterol levels, statins have become the drugs most frequently prescribed for this indication and have been shown to reduce cardiovascular risk across all risk factor categories. Still, says a recent study, "Although statins have acceptable efficacy and safety profiles, more than one half of cardiovascular events are not being prevented by these drugs, owing to either elevated residual cardiovascular risk or statin intolerance."
Enter protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which in recent years have been identified as an innovative lipid-lowering strategy. Now, in a study(annals.org) published online April 28 in Annals of Internal Medicine that examined the effectiveness of antibodies targeting PCSK9, researchers concluded the antibodies appeared to be a safe and effective alternative to statins to treat adults with hypercholesterolemia.
Study Results Show Promise
Specifically, researchers said that treating patients with PCSK9 antibodies produced "profound" reductions in LDL cholesterol and lipoprotein(a) while offering safety and survival benefit levels similar to those of patients who were not treated.
Moreover, a number of phase 3 studies conducted in different settings showed combining PCSK9 antibodies with statins reduced atherogenic lipid fractions in patients with hyperlipidemia or heterozygous familial hypercholesterolemia.
- In a recent meta-analysis, researchers concluded protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors appeared to be a safe and effective alternative to statins to treat adults with hypercholesterolemia.
- Moreover, a number of phase 3 studies showed combining antibodies targeting PCSK9 with statins reduced atherogenic lipid fractions in patients with hyperlipidemia or heterozygous familial hypercholesterolemia.
- The evidence to support use of PCSK9 antibodies still lags behind that for statins, however, and this therapy has not yet been approved by the FDA.
The study authors noted that ongoing trials should provide further data on the safety of PCSK9 antibodies used to lower LDL cholesterol levels and the rate of cardiovascular events. "In particular, these trials should validate or refute the findings on mortality that, if confirmed, could have a profound effect on public health," the study said.
Currently, four of these trials are large cardiovascular outcome studies testing the ability of PCSK9 antibodies to affect clinical outcomes. They are expected to be completed in 2018.
That's particularly important given that the current study counted among its limitations the fact that it derived results from study-level data rather than patient-level data, because clinical-outcome data about PCSK9 antibody use are still lacking.
FP Expert Weighs In
According to Theodore Ganiats, M.D., of the Department of Family Medicine and Community Health in the Miller School of Medicine at the University of Miami, the use of PCSK9 antibodies is associated with a large reduction in LDL cholesterol and an increase in HDL cholesterol.
"This can be over and above the changes found with statins" when used in combination with these drugs, Ganiats told AAFP News, "or they can be used alone. In addition, they seem to be relatively safe, and in the published study, they may show an ability to protect the muscle from statin toxicity."
However, he added, use of PCSK9 antibodies is still new, and although they have been studied in thousands of patients, the evidence to support their use isn't yet as extensive as that supporting statins. Also, it should be noted that the FDA has yet to approve PCSK9 antibody therapy for use in the United States.
Ganiats pointed to the fact that the current study is a meta-analysis of 24 phase 2 and phase 3 randomized, controlled trials that included a total of about 10,000 patients (average of 400 subjects per trial). By contrast, he said, many statin trials have included more than 4,000 subjects.
"In addition, while the study tried to control for biases in meta-analysis, meta-analyses are notoriously difficult to perform," he said. "Errors may be present we won't be aware of until the larger trials are completed."
Still, Ganiats is optimistic about PCSK9 antibody treatment, saying this is a promising category of drug that may
- offer a strong cholesterol-lowering medicine for those who cannot tolerate statins;
- provide additional cholesterol reduction and, more importantly, further event reduction when combined with statins; and
- be relatively safe when used alone or combined with statins.
"However, more data are needed on the safety and their ability to improve clinical endpoints," he said.
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