How Low Should LDL Go?


The remarkable reductions of low-density lipoprotein cholesterol levels in several recent phase II trials using antibodies to PCSK9 triggered speculation on how low LDL should go for optimal patient outcomes.

The short answer is that, for secondary prevention of cardiovascular disease, patients may benefit from a goal substantially below the current level of less than 70 mg/dL – perhaps down to below 50 mg/dL and maybe even below 40 mg/dL. The new drug class of antibodies against the PCSK9 human protein that regulates LDL receptors seems capable of safely producing LDL levels that low when used with a potent statin regimen.

Courtesy Wikimedia/Urban/Creative Commons License

The benefit, as well as safety, of serum LDL cholesterol levels so low remains to be proven and won’t be so for a few more years, but those were the some of the LDL levels seen in the phase II anti-PCSK9 data reported earlier this month at the scientific sessions of the American Heart Association in Los Angeles.

The meeting included four reports from phase II studies of the anti-PCSK9 antibody made by Amgen, which involved a total of 981 patients who received some dosage of the drug. When administered on top of maximal dosages of statin or, in a few patients, ezetimibe, the highest antibody dosages – by subcutaneous injection every 2 weeks – produced LDL cuts of as much as 66%. As a result, a large fraction of patients on the antibody reached the sub–70-mg/dL LDL goal.

One AHA report analyzed data from a phase II study with 474 antibody-treated patients in terms of how many fell below 70 mg/dL while on the antibody. The highest dosage tested brought 90% of patients to goal, compared with virtually none at the start. Average LDL fell to 47 mg/dL and some patients dropped as low as 16 mg/dL.

What might LDL levels like these mean? In an invited discussion of the PCSK9 antibody results at the meeting, Dutch lipidologist John Kastelein – who called the results a "triumph of LDL goal attainment" and also marveled at the clean safety performance of the Amgen antibody – presented an analysis of data from more than 38,000 patients who received a statin in eight major statin-efficacy trials reported over the past 18 years. The results showed a steady drop in cardiovascular disease events at lower and lower LDL levels.

Patients reaching an LDL of 70-100 mg/dL, for example, had about a 16% rate of CVD events during follow-up. Among those who reached 50-70 mg/dL, the event rate dropped to about 12%, for those who hit 30-50 mg/dL the rate fell to about 5%, and those who slipped to an LDL level below 30 mg/dL had about a 2.5% event rate during follow-up.

The event rates "go down, down, down," as patients near what has been proposed as the true "physiologic" LDL serum level, about 25 mg/dL, Dr. Kastelein said.

Why was the target LDL goal set at 70 mg/dL? "Guideline writers looked at the evidence available" in 2004, when the Adult Treatment Panel III guideline group set its most aggressive goal of less than 70 mg/dL. "They saw where the intensive statin trials had gotten, mostly with 80-mg/day atorvastatin, to LDLs down to 65, 70, 75 mg/dL , so they picked 70 mg/dL as a reasonable target. But now we can get people into the 40s," Dr. Nihar Desai, a cardiologist at Brigham and Women’s Hospital in Boston, said to me after giving one of the anti-PCSK9 reports at the meeting.

Will driving LDLs levels that low help? Dr. Kastelein’s data from more than 38,000 statin-treated patients show that it could, but now it needs to be proved prospectively. A few days ago, Regeneron, one of the companies developing an anti-PCSK9 antibody, announced that its 18,000-patient, phase III trial had begun enrolling patients. A big trial of the Amgen antibody will probably start early next year. Results from both these studies should answer the question in about 3 years.

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