– The maxim that lower is better for LDL cholesterol continues to hold true, even at jaw-droppingly low levels of less than 10 mg/dL in a new analysis of data from the FOURIER trial.

The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial was the pivotal efficacy and safety study for the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab (Repatha) and enrolled patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of at least 70 mg/dL (N Engl J Med. 2017 May 4;376[18]:1713-22).

Mitchel L. Zoler/Frontline Medical News Dr. Robert P. Giugliano

After a median follow-up of 26 months, the incidence of the study’s primary endpoint (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) dropped by a statistically significant 15% in patients with an achieved LDL cholesterol of 20-49 mg/dL, compared with patients whose 4-week LDL cholesterol was at or above 100 mg/dL (primarily patients randomized to the study’s control arm), by 24% in all patients with LDL cholesterol less than 20 mg/dL, and by 31% in the 2% of patients whose LDL cholesterol levels fell below 10 mg/dL.

These strikingly improved event rates at the lowest levels of LDL cholesterol occurred with no signal of excess adverse events, Robert P. Giugliano, MD, said at the annual congress of the European Society of Cardiology.

In contrast, the 13% of patents whose achieved LDL cholesterol was 50-69 mg/dL had an event rate just 6% below the referent group of 100 mg/dL or more, a nonsignificant difference. Existing cholesterol management guidelines that set LDL cholesterol targets for secondary prevention have used a level below 70 mg/dL as the target, such as the European Society of Cardiology’s 2016 guidelines (Eur Heart J. 2016 Oct 14;37[39]:2999-3058).

“The data suggest that we should target considerably lower LDL cholesterol than is currently recommended for our patients with atherosclerotic cardiovascular disease,” said Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston.

“Lowest is best with LDL. You don’t need a lot of LDL in the serum for normal human function,” he noted during the discussion of his report.

While FOURIER’s event curve continued to drop as LDL cholesterol fell below 10 mg/dL, the study’s wide-ranging safety assessment showed no signal of harm at the lowest levels. This “gives us some reassurance it’s safe,” he said in an interview. “We saw benefit that continued down to the lowest LDL levels, so it’s hard to pick a LDL target. I no longer feel comfortable treating my patients to just less than 70 mg/dL. I’m not sure what is the optimal LDL target, but I think it needs to be lower than that.”

To achieve such ultralow LDL levels, most patients need treatment with a PCSK9 inhibitor plus at least one and perhaps two additional cholesterol-lowering drugs, a statin and ezetimibe, he noted.

The FOURIER analyses Dr. Giugliano reported included data on the incidence during the study of 10 specific types of adverse events: noncardiovascular death, serious adverse events, adverse events leading to study discontinuation, and new onset of diabetes, cancer, cataract, neurocognitive deficit, significant liver enzyme increase, significant creatine kinase increase, and hemorrhagic stroke. The incidence of each of these was similar among the patients in five study subgroups based on achieved levels of LDL cholesterol: less than 20 mg/dL, 20-49 mg/dL, 50-69 mg/dL, 70-99 mg/dL, and 100 mg/dL or higher. In addition, the rates of both serious adverse events and adverse events leading to study discontinuation was roughly the same in the subgroup of patients with an achieved LDL cholesterol of less than 10 mg/dL as in those with an achieved LDL of at least 100 mg/dL.

Concurrently with Dr. Giugliano’s report, the results also appeared in an online article (Lancet. 2017 Aug 28. doi: 10.1016/S0140-6736[17]32290-0).

FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has been a consultant to and has received research funding from Amgen, and he has also been a consultant to Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Merck, and Pfizer.

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