PCSK9 antibodies: another option for treating adult hypercholesterolemia
By Will Boggs MD
Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) are safe and effective for treating adults with hypercholesterolemia, according to a systematic review and meta-analysis of 24 phase 2 and phase 3 randomized controlled trials.
"The management of hypercholesterolemia is gradually entering a new era," Dr. Eliano Pio Navarese, from Heinrich Heine University, Dusseldorf, Germany, told Reuters Health by email. "For patients with hypercholesterolemia, especially those at high cardiovascular risk, PCSK9 antibodies could be considered as additional treatment to a statin in the years to come and implemented in future guideline recommendations."
PCSK9 plays an important role in lipid metabolism by modulating the density of low density lipoprotein (LDL) cholesterol receptors in multiple organs. Inhibition of PCSK9 increases the receptor density on the hepatocyte surface, thereby contributing to LDL cholesterol clearance.
Dr. Navarese and colleagues assessed the safety and efficacy of PCSK9 inhibitors in their review and meta-analysis of 24 studies that enrolled 10,159 adult patients with hypercholesterolemia. The longest follow-up was 104 weeks, and all included trials were funded by industry.
Compared with no-anti-PCSK9 treatment, the use of PCSK9 antibodies was associated with a 55% reduction in all-cause mortality (p=0.015) and a nonsignificant 50% reduction in cardiovascular mortality.
LDL cholesterol levels fell by 47.49% with PCSK9 antibody treatment compared with no such treatment (p<0.001). PCSK9 antibody treatment also compared favorably with placebo treatment and with ezetimibe treatment, according to the April 28 Annals of Internal Medicine online report.
HDL cholesterol levels increased by around 6%, compared with other treatments, and there were significant reductions in total cholesterol and lipoprotein(a) levels.
There were more serious adverse events among patients treated with PCSK9 antibodies (9.26%) than among patients not treated with PCSK9 antibodies (7.73%), but the difference was small and not statistically significant.
Significantly fewer PCSK9 antibody-treated patients had increased creatine kinase levels (1.96% versus 2.31% of those who did not receive PCSK9 antibodies), but again the difference was small.
"What is surprising and strongly encouraging is that the present large meta-analysis including more than 10,000 patients found a reduced all-cause and cardiovascular mortality, a finding that could not be appreciated in currently available trials not powered to assess single clinical outcomes," Dr. Navarese said.
"There are three types of patients with unmanaged hypercholesterolemia who might benefit most from PCSK9 antibodies: those with genetic disorder (homo- or heterozygous familial hypercholesterolemia), at high risk of cardiovascular events, and intolerant to statin therapy," he added.
"Ongoing trials should provide further data on the safety of this innovative strategy and on the relationship of lower LDL cholesterol levels and the rate of cardiovascular events," the researchers conclude.
"Within the past five years, many monoclonal antibodies, including evolocumab, alirocumab, and bococizumab, were developed as PCSK9 inhibitors that disrupt the interaction between PCSK9 and the LDL receptor," write Dr. Eliseo Guallar from Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues in a related editorial. "These inhibitors, which are administered subcutaneously in monthly or semimonthly injections, produced striking reductions in LDL cholesterol when compared with placebo or ezetimibe in randomized, controlled trials."
"If the efficacy and safety profile of PCSK9 inhibitors is confirmed in long-term trials with a larger number of clinical events and if costs are not prohibitive, clinicians will be able to add PCSK9 inhibitors or ezetimibe to statin therapy and achieve additional LDL cholesterol reductions," the editorial concludes.
"Furthermore," they add, "with multiple evidence-based safe therapeutic options, it will be critical to establish the optimal sequence and combination of drugs as well as the LDL cholesterol goals that minimize long-term risk in different patient populations. Studies assessing cardiovascular disease (CVD) outcomes and cost-effectiveness of different lipid-lowering strategies in populations at different risks for CVD will provide answers to these questions."
Dr. Gerald Watts, from the University of Western Australia's Lipid Disorders Clinic, Perth, agreed that the "effects on cardiovascular events and mortality need confirmation in trials."
Dr. Watts told Reuters Health by email that the treatment must also be shown to be cost-effective.
Dr. Raul D. Santos, director of the University of Sao Paulo Medical School's Lipid Clinic, Sao Paulo, Brazil, told Reuters Health by email, "PCSK9 antibodies are potent and apparently very well tolerated medications to reduce LDL-cholesterol and are on the right path to reduce cardiovascular events. However, since studies in this meta-analysis were not designed for cardiovascular events we still need to wait for the results of the mega endpoint driven trials (>60,000 patients)."
"In my point of view they initially will have a role for the treatment of familial hypercholesterolemia patients and other dyslipidemic people that persist with high LDL-cholesterol levels, statin-intolerant individuals, and some very high-risk patients," Dr. Santos said. "It is important to consider the possible costs of those treatments that will be expensive in comparison with generic statins and ezetimibe, and therefore will limit the generalized use of the monoclonal antibodies."
The German Research Council supported this research. One coauthor reported receiving consulting fees from Sanofi; no other coauthors reported any disclosures.
SOURCE: http://bit.ly/1bMomI5 and http://bit.ly/1DuSZHm
Ann Intern Med 2015.
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