How Low Can Cholesterol Go? Safety Not in Limbo for Patients With Very Low LDL on Alirocumab, Study Shows

With clinicians working for decades to reduce their patients’ cardiovascular risk by lowering elevated cholesterol levels, it may seem ironic that they are now grappling with whether it’s possible for a powerful new drug class to go too far. A pooled analysis, however, reassuringly shows that there appears to be no safety signal associated with using a PCSK9 inhibitor even to achieve very low LDL levels.

The US Food and Drug Administration and the European Commission approved the PCSK9 inhibitors alirocumab (Praluent, Sanofi-Aventis/Regeneron) and evolocumab (Repatha, Amgen) in 2015 for use in adult patients with homozygous familial hypercholesterolemia (FH), heterozygous FH, and clinical atherosclerotic cardiovascular disease who require additional LDL-cholesterol lowering on top of maximally tolerated statins. Since then, debate has raged over their cost and long-term safety, as treated patients can reach LDL cholesterol levels below what’s been observed in any of the landmark statin studies. Complicating matters, the drugs are also in the midst of a patent dispute. In January, a US District Court granted Amgen an injunction preventing Sanofi-Aventis/Regeneron from manufacturing, using, selling, or otherwise offering alirocumab in the United States—a decision now under appeal.

For this analysis, published in the January 30, 2017, issue of the Journal of the American College of Cardiology, researchers led by Jennifer Robinson, MD, MPH (University of Iowa, Iowa City), looked at data from 14 trials of alirocumab in the ODYSSEY development program. Over follow-up as long as 104 weeks, 25.1% and 9.4% of patients on the PCSK9 inhibitor had LDL levels of < 25 and < 15 mg/dL, respectively, on at least 2 consecutive measurements.

There were similar adverse event rates in patients with LDL levels of < 25 mg/dL (72.7%) and < 15 mg/dL (71.7%) compared with those who did not achieve LDL < 25 mg/dl (76.6%). There were also no differences in neurological and neurocognitive events among the three groups.

However, in a propensity-score analysis, those with LDL < 25 mg/dL were more likely to report cataracts than those who did not reach very low LDL levels (2.6% vs 0.8%; HR 3.40; 95% CI 1.58-7.35). But this difference was not maintained when comparing the pooled alirocumab cohort and controls.

Robinson told TCTMD that she was not surprised by the fact that so many patients in the study achieved very low LDL levels, because those randomized to alirocumab had lower LDL levels in the first place. “What was surprising is that the people who ended up with LDLs less than 25 mg/dL were . . . older, sicker people, but the rates of adverse events were really very similar” despite the differences in baseline characteristics, she said.

But the results are “more interesting than clinically applicable at this point,” she stressed, because PCSK9 inhibitors are only currently being used in patients with “quite high” cholesterol levels. It is unlikely, she added, that real-world patients will see their LDL levels drop below 25 mg/dL in the near future.

With regard to the increased risk for cataracts in patients with very low LDL levels, Robinson said this finding is only hypothesis-generating. “There’s some biologic plausibility to why you might tip people over with a tendency to get cataracts,” she said, relating this phenomenon to the relationship with statins and diabetes, with the literature suggesting that the former potentially hastens occurrence of the latter.

More Definitive Data Coming Soon

Seth Martin, MD, MHS (Johns Hopkins Medicine, Baltimore, MD), told TCTMD that in the context of past LDL studies, these latest results are “really reassuring.” He expressed surprise over the signal for cataracts but agreed that the data aren’t conclusive on this issue.

Martin also pointed to the “unexpected” finding that there seemed to be a protective effect with regard to musculoskeletal events in patients with LDL levels below 25 mg/dL compared to those with higher levels (HR 0.75; 95% CI 0.59-0.97).

“Frankly, we were hoping that there wouldn't be an excess of musculoskeletal effects with more intensive LDL-lowering PCSK9 inhibitors, but we weren't necessarily predicting that we would actually protect people from musculoskeletal effects,” he said. “So on the one hand, it's a very encouraging signal. And on the other hand, the fact that they are finding multiple signals like this, it makes me wonder [that if] the increased cataracts could be due to confounding in the nonrandomized subgroup, [is it] the same thing for the musculoskeletal effects as well?”

In an accompanying editorial, Brendan Everett, MD, MPH (Brigham and Women’s Hospital, Boston, MA), said these data “although reassuring, represent only the beginning of our understanding of the safety of this novel class of medications. The ongoing cardiovascular endpoint trials of alirocumab should provide not only a sense of the true cardiovascular benefit of these drugs but also a more accurate and nuanced understanding of their risks.”

Fortunately, physicians will not have to wait too long for more definitive results, as 5-year findings from the FOURIER trial of more than 27,000 patients with dyslipidemia randomized to evolocumab or placebo will be presented at the upcoming American College of Cardiology meeting in March. Additionally, results from the ODYSSEY Outcomes study on alirocumab are expected in 2018.

“If there’s any safety signal for very low LDL levels, it should come out in FOURIER, because everyone is getting the maximum dose,” Robinson said. “It may be totally reassuring and then you don't have to worry about it.”

In the meantime, she said, clinicians should not worry about this issue. “If you have a patient who's on a PCSK9 inhibitor and their LDL is less than 25, don’t panic,” she said. “What you need to do is just to continue to treat them and follow them, and we’ll wait until these outcomes data are presented and then you ought to have pretty clear guidance on what to do for those patients. But never down titrate on a statin.”