A meta-analysis of 24 clinical trials on monoclonal antibody treatments for hypercholesterolemia pointed to significant reductions in death and MIs, a finding that likely will catch the eye of the FDA as it considers approval for these new drugs. The results were published online April 28 in the Annals of Internal Medicine.
Eliano Pio Navarese, MD, PhD, of Heinrich Heine University in Dusseldorf, Germany, and colleagues reviewed phase 2 and 3 clinical trials assessing monoclonal antibodies that target proprotein convertase subtilisin/kexin type 9 (PCSK9) as a way to lower low-density lipoprotein (LDL) cholesterol. They used PubMed, Google Scholar, conference proceedings and clinicaltrials.gov to identify trials though April 4, 2015 that reported clinical outcomes.
Their analysis focused on 24 studies with more than 10,000 patients who had hypercholesterolemia; in many of these trials, patients were taking statins but not meeting their LDL targets and in two trials patients were statin-intolerant.
Their meta-analysis of all 24 trials found a 47 percent reduction in LDL cholesterol levels for patients treated with PCSK9 inhibitors compared with the control group. They reported a statistically significant reduction in all-cause mortality (0.31 percent vs. 0.53 percent) and a nonstatistically significant reduction in cardiovascular mortality (0.19 percent vs. 0.33 percent). Serious adverse event rates were similar.
Of the 10 trials that reported MI outcomes, PCSK9 inhibitor treatment had a rate of 0.58 percent vs. 1 percent for the controls.
Ten trials also measured total cholesterol; a meta-analysis of these found a 31 percent reduction in total cholesterol with PCSK9 inhibitor treatment compared with no PCSK9 inhibitor treatment. Twelve studies included lipoprotein; in those, total lipoprotein levels were 25 percent lower in the PCSK9 inhibitor group than in the control group.
The clinical benefits remained robust in sensitivity analyses.
“Our large-scale report is the first to show a benefit in mortality with these novel agents,” they wrote. “The finding of lower all-cause mortality, although preliminary, is encouraging. … Moreover, the sensitivity analyses for type and dose of PCSK9 antibody, and the subgroup analyses stratified by placebo or ezetimibe as the control arm and by background statin therapy, all suggest that the overall effect is robust and justified.”
The authors cautioned that the results are based on a small number of events, some with short follow-up periods, and that the meta-analysis relies on study-level and not patient-level data.
They added that four large PCSK9 inhibitor trials are under way to assess clinical outcomes. In the meantime, their preliminary findings signal a potential survival benefit with no safety tradeoff for PCSK9 inhibitors compared to placebo or statins.