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Very low LDL levels with alirocumab not linked to rise in adverse events
Very low levels of LDL in patients assigned alirocumab, a PCSK9 inhibitor, were not associated with adverse events, although there was an association with increased cataract incidence, new data show.
“The safety of these new drugs is critical to patients who have no other means by which to control their life-threatening high cholesterol,” Jennifer Robinson, MD, MPH, director of the Preventive Intervention Center at the University of Iowa, Iowa City, and colleagues wrote. “The long-term effects of very low levels of LDL are under evaluation in ongoing large clinical trials.”
The researchers pooled 14 phase 2 and 3 randomized controlled studies of alirocumab (Praluent, Sanofi/Regeneron) to analyze for adverse events when LDL reaches very low levels. Patients were categorized by whether they achieved two or more consecutive LDL levels of < 25 mg/dL or < 15 mg/dL.
Of the 3,340 patients assigned alirocumab (mean age, 59 years; 62% men), 25.1% (n = 839) achieved LDL < 25 mg/dL on at least two consecutive visits and 9.4% (n = 314) achieved LDL < 15 mg/dL.
Very low cholesterol occurred more frequently in patients with lower baseline mean LDL. The mean baseline LDL of those who achieved LDL < 25 mg/dL was 100.3 mg/dL vs. 134.3 mg/dL for those who did not.
Participants with LDL cholesterol < 25 mg/dL were also more likely to be men, have CVD, type 2 diabetes and higher baseline triglycerides, lower HDL levels and higher HbA1c levels.
Adverse events similar
Overall rates for adverse events, serious adverse events, deaths and discontinuation were similar for patients with LDL < 25 mg/dL vs. those with 25 mg/dL. Adverse events occurred in 72.7% of patients achieving LDL < 25 mg/dL and 71.7% of patients achieving < 15 mg/dL compared with 76.6% of those who did not achieve very low levels, Robinson and colleagues wrote.
Neurological and neurocognitive events were also similar across LDL levels, the researchers wrote.
In an analysis of patients matched by a propensity score, the rate of cataracts was higher in patients with LDL < 25 mg/dL vs. 25 mg/dL (HR = 3.4; 95% CI, 1.58-7.35). However, there was no difference in cataract incidence between pooled alirocumab and control groups.
“Low levels of LDL (< 25 mg/dL) appear to be generally well tolerated over 18 months of alirocumab therapy,” the researchers wrote. “The increased incidence of cataracts in those with LDL cholesterol < 25 mg/dL may be due to confounding in this comparison of nonrandomized subgroups. Although the consequences of very low of LDL were not identified in these trials, the long-term effects of very low levels of LDL are unknown.”
Only the beginning
In an accompanying editorial, Brendan M. Everett, MD, MPH, director of the general cardiology inpatient service at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, said: “Alirocumab seems reassuringly safe, although understanding the possible ‘on-target’ physiological effects of lowering LDL to < 25 or < 15 mg/dL will require more patients to receive the drug, each for a more extended period of time. In that context, the data presented here, although reassuring, represent only the beginning of our understanding of the safety of this novel class of medications.” – by Cassie Homer
Disclosure: Robinson reports no relevant financial disclosures. Please see the full study for a list of the other researchers’ relevant financial disclosures. Everett reports receiving grants from Kowa and Novartis and consulting for Abbott and Roche.