Conference Coverage

How Low Can Cholesterol Safely Go?


BARCELONA—Very aggressive reduction of LDL-cholesterol to ultralow levels is associated with progressively fewer cardiovascular events and appears to pose no safety concerns in patients with stable atherosclerotic cardiovascular disease over 2.2 years of follow-up, according to a new analysis. This finding, which was presented at the European Society of Cardiology Congress 2017 and published online ahead of print August 28 in the Lancet, comes from a prespecified secondary analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial. “These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations,” said Robert P. Giugliano, MD, Associate Professor of Cardiovascular Medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston, and his research colleagues.

Robert P. Giugliano, MD

“These findings are unique, in that they represent the first analysis of a large cohort of patients to achieve such very low LDL-cholesterol levels, namely … less than one-third of the most common treatment goal of below 1.8 mmol/L for highest risk patients,” Dr. Giugliano said.

The FOURIER trial randomized patients with stable atherosclerotic cardiovascular disease who were receiving background statin therapy to either placebo or evolocumab, a proprotein convertase subtilisin-kexin type 9 (PCSK9) monoclonal antibody. Initial results from the trial, which was published earlier this year in the New England Journal of Medicine, showed that evolocumab lowered LDL-cholesterol levels to a median of 0.8 mmol/L and significantly reduced the risk of cardiovascular events at a median follow-up of 2.2 years.

The new analysis examined efficacy and safety end points according to degree of LDL-cholesterol reduction at four weeks. In addition, a study known as EBBINGHAUS embedded within the larger analysis explored effects on cognition using a validated tablet-based tool.

A total of 25,982 patients with an LDL-cholesterol assessment at week four who did not experience a primary efficacy or prespecified safety event prior to the week four follow-up visit were included in the analysis. The study showed that the risk of the primary efficacy end point—a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina—declined steadily as LDL-cholesterol levels decreased, with no significant association between LDL-cholesterol level and adverse events.

A similar reduction was observed in the key secondary end point, with 2,669 subjects in the lowest LDL-cholesterol category (< 0.5 mmol/L) at four weeks experiencing the lowest rate for cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio, 0.69), compared with the group with the highest LDL-cholesterol (> 2.6 mmol/L). Exploratory analyses in a subgroup of 504 patients with an LDL-cholesterol level of < 0.25 mmol/L showed further reduction in cardiovascular events with no increase in safety events.

Among 1,154 patients who underwent formal cognitive testing prior to, or on the first day of, study treatment as part of the EBBINGHAUS study, lowered LDL-cholesterol was not associated with adverse effects on memory, executive function, or reaction time.

“Although longer-term follow-up will be important, the totality of evidence to date from trials of intensive lipid lowering supports reduction of LDL-cholesterol in high-risk patients to levels below those currently recommended in cholesterol guidelines,” noted Dr. Giugliano.

This study was sponsored by Amgen.

Important Clinical Implications

The FOURIER secondary analysis, together with a meta-analysis of major statin trials, creates a body of evidence that “heralds the transition from a concept of ‘the lower the better’ towards LDL-cholesterol eradication,” said G. Kees Hovingh, MD, PhD, an internist and vascular medicine specialist at the Academic Medical Center in Amsterdam, and colleagues in an editorial accompanying the published study results.

“For clinicians who prescribe PCSK9 inhibitors, however, the findings from the FOURIER trial, with regard to the potential adverse events, are of even greater importance,” said Dr. Hovingh and colleagues. “Having been trained to first do no harm, many physicians might wonder whether they would infringe on this idea by prescribing PCSK9 inhibitors. Many patients using PCSK9 inhibitors reach extremely low LDL-cholesterol concentrations …, but good safety data for such low LDL-cholesterol values are scarce. In clinical practice, this [situation] often leads to down titration of the dose of conventional lipid-lowering therapy, PCSK9-antibody dose, or both, for fear of potentially unknown side effects.” The results of the FOURIER subanalysis show that “patients achieving very low LDL-cholesterol concentrations are not at increased risk of any of the adverse events assessed.”

Glenn S. Williams

Suggested Reading

Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017 Aug 28 [Epub ahead of print].

Hovingh GK, Boekholdt SM, Stroes ES. Very low LDL-cholesterol concentrations achieved: which target is next? Lancet. 2017 Aug 28 [Epub ahead of print].

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722.

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