Ultra-low LDL-cholesterol cuts CV risk with no safety concerns
Very aggressive reduction of LDL-cholesterol with the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab was associated with progressively fewer cardiovascular (CV) events without compromising safety in patients with established atherosclerotic disease, according to a secondary analysis of the FOURIER trial (Further Cadiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) presented recently at the European Society of Cardiology Congress 2017 in Barcelona, Spain. [Lancet 2017, doi: 10.1016/S0140-6736(17)32290-0]
Previously, FOURIER showed that evolocumab, when added to background statin therapy with or without ezetimibe, lowered LDL-cholesterol concentrations to a median of 0.8 mmol/L and significantly reduced the risk of CV events vs placebo at 2.2 years. No significant differences were found in major safety events or prospective cognitive function tests between the evolocumab and placebo groups. [N Engl J Med 2017;376:1713-1722; N Engl J Med 2017;377:633-643]
“The LDL-cholesterol concentrations achieved with evolocumab were substantially lower than those in previous trials with lipid-lowering therapies,” said lead author Dr Robert Giugliano from Harvard Medical School, Boston, US, who presented the data. “Our analysis explored the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks of treatment and clinical efficacy and safety, and assessed whether there is a threshold below which there is no added clinical benefit or an increase in adverse events.”
The 25,982 patients included in the analysis were stratified into five groups based on their LDL-cholesterol levels at 4 weeks: (1) <0.5 mmol/L (10 percent); (2) 0.5–1.3 mmol/L (31 percent); (3) 1.3–1.8 mmol/L (13 percent); (4) 1.8–<2.6 mmol/L (29 percent); and (5) ≥2.6 mmol/L (17 percent, referent group).
“We found that the risk of the primary efficacy endpoint – a composite of CV death, MI, stroke, coronary revascularization or unstable angina – declined progressively as LDL-cholesterol levels decreased, with risk reductions ranging from 3 percent for group 4 to 24 percent for group 1 vs the referent group,” said Giugliano. “A similar association was observed for the secondary composite endpoint of CV death, MI and stroke, with risk reductions between 10 and 31 percent.”
No safety issues appeared with lower LDL-cholesterol levels with regard to 10 prespecified safety endpoints, such as serious adverse events, adverse events leading to evolocumab discontinuation, elevation in liver enzymes, new or recurrent cancer, new-onset diabetes, and cataract-related events. Among 1,154 patients who underwent formal cognitive testing, there were no adverse effects on memory or executive function associated with lower LDL-cholesterol levels.
“Importantly, the CV benefit extended down to the bottom first percentile of LDL-cholesterol concentration, as an exploratory analysis in a subgroup of 504 patients with LDL-cholesterol <0.26 mmol/L showed even further reduction in CV events, with no increase in adverse events,” he emphasized. “Although longer follow-up will be important, our findings are unique, representing the first analysis of a large patient cohort to achieve extremely low LDL-cholesterol levels. These data support further LDL-cholesterol lowering to below currently recommended levels in patients with atherosclerotic disease.”