With LDL-Cholesterol, the Lower it Goes the Better

A secondary analysis of the Fourier study findings indicates that patients with the lowest LDL had best cardiovascular outcomes.

Interviews with Robert P. Giugliano, MD, and Eliot A. Brinton, MD

Getting low density lipoprotein-cholesterol (LDL-C) to very low levels with a combination of an HMG-CoA reductase inhibitor (statin) and a PCSK9 inhibitor, evolocumab (Repatha), produced a progressive reduction in major cardiovascular outcomes, without an appreciable change in adverse effects, regardless of how low the LDL-C fell, according to a secondary analysis of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial.1

Findings from the new analysis were published online in The Lancet and simultaneously presented at the European Society of Cardiology Congress (ESCC).

In a related presentation at the European Association for the Study of Diabetes, researchers reported that the rate of adverse events was similar for patients with and without diabetes who were taking evolocumab or placebo. There was no associated increase in the risk of new-onset diabetes or worsening of glycemia over the median 2.2 years of follow-up,2  published simultaneously in The Lancet Diabetes & Endocrinology.

The lower the LDL the better with a combination of a statin and PSK9-inhibitor.

How Low Do We Dare Push LDL?

In the Fourier trial, more than 27,000 patients who were 40 to 85 years old with stable cardiovascular disease (CVD) received the combination therapy: statin therapy and evolocumab, or a stain with a placebo.1 Those who were given the combination therapy demonstrated a 20% reduction in the composite risk for cardiovascular (CV) death, myocardial infarction (MI, 27%) or stroke (21%).3

In the secondary analysis, ''we looked at patient outcomes according to the level of LDL they reached at four weeks," said lead author Robert P Giugliano, MD, a senior investigator of the TIMI Study Group at Brigham and Women's Hospital in Boston, Massachusetts who also presented the data at the ESCC.

We did the secondary analysis to determine if lower was safe and might offer better results—an ongoing debate, Dr. Guilglano told EndocrineWeb.

Evaluating Outcomes and Safety Data

The primary endpoint for this analysis was a composite risk score for CV death, MI, stroke, coronary revascularization or hospital admission for unstable angina, and key secondary endpoints were singular risk outcomes for CV death, MI or stroke. The risk of CV death, MI, and stroke over 2.2 years declined progressively as the LDL decreased to below 20 mg/dL (0.5 mmol/L). The researchers found that the lower the LDL fell, the better the results for the outcomes endpoints.  

"Compared to the group having LDL-C levels of 100 mg/dL or above, those with an LDL of less than 10 had a 41% reduction in the secondary endpoint with no difference in adverse events," said Dr. Giugliano. "Compared to the group with LDLs of 100 mg/dL or above, those with an LDL under 10 mg/dL (0.26 mmol/L0, had the greatest reduction in the secondary endpoints [cardiovascular death, MI, and stroke] with no differences in adverse events."1

'The research team also looked at 10 safety events, including cognition, new onset diabetes, cataract-related events and non-cardiovascular death," said Dr. Guigliano, "None of the safety type events were increased'' no matter how low the LDL reached, which was a significant finding."

"We think these results are reassuring," he told EndocrineWeb. While the study population was limited to those with cardiovascular disease, he said, lower LDL targets also may be good for those without it.1

A Lipidologist's Reaction to the Fournier Findings

"I think this new analysis is in many ways more important than the original paper," Eliot A. Brinton, MD, FAHA, FNLA, president of the Utah Lipid Center in Salt Lake City.

"I'm not saying the original Fournier study wasn't important," Dr. Brinton added, “However, the new analysis has two striking findings. Efficacy of LDL-lowering really does seem to achieve greater [outcomes] improvement the lower the LDL goes. Also, there was no adverse safety signal, so the other key point is that we did not sacrifice safety.''

Dr. Brinton predicted that these findings could bring the LDL debate to an end.

"This is maybe the final chapter in a long saga,'' he told EndocrineWeb, adding that most lipid specialists probably could have predicted the results of this secondary analysis.  

Yet, Dr. Brinton did not think that these new findings would change the practice of most lipidologists because they are already typically treating hyperlipidemia aggressively.

However, other clinicians, including primary care physicians and endocrinologists, ''have been more tentative about being too aggressive," Dr. Brinton said. The Fournier results may be enough to convince most physicians to change their approach to treating LDL-C. That said, he also pointed out that the best treatment approach ''is one that is individualized to the patient."

Further Insights on Evolocumab and Diabetes

Given that no differences in the rates of adverse events and no increased risk of new-onset diabetes with evolocumab were found from the Fourier-CV outcomes study should allay any lingering concerns,2 said Marc S. Sabatine, MD, chair of the TIMI Study Group and Distinguished Chair in Cardiovascular Medicine at Brigham and Women's Hospital in Boston, Massachusetts.

For endocrinologists, Dr. Sabatine told EndocrineWeb, the message is "Patients with atherosclerotic disease and diabetes are at very high risk for cardiovascular events. We now show they benefit from taking evolocumab to lower LDL-C down to less than 1 mmol/L without any off-putting safety concerns."

In the study, 40% of patients (11,031) had diabetes and 60% (16,533) did not.2 However, among those who did not have diabetes, more than half (10,344) had a diagnosis of prediabetes.

Taking evolocumab reduced LDL-C levels by a mean of 57% in those with diabetes and 60% in those without at 48 weeks, down to .8 mmol/L or 30 mg/dL in both groups,2 Dr. Sabatine said.

About Evolocumab

Evolocumab, a human monoclonal antibody made by Amgen, functions by blocking proprotein convertase subtilisin-kexin 9, PCSK9, which suppresses the liver's ability to remove LDL-C from the blood. The FDA granted approval for evolocumab in 2016 as an adjunct to statins and lifestyle changes aimed to lower LDL in some adults with CVD. The drug is estimated to cost about $14,000 annually.

Funding for the studies was provided by Amgen. Dr. Giugliano has consulted for Amgen as well as other pharmaceutical companies. Drs. Brinton and Sabatine consult for Amgen as well as other pharmaceutical companies.

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