How Low is Too Low?: Safety and Tolerability of Extremely Low LDL Examined
Data from 14 phase 2 and 3 studies were pooled to assess the safety of lowering LDL cholesterol with alirocumab.
Extremely low levels of low-density lipoprotein cholesterol (LDL-C) in patients taking alirocumab were not linked to increased rates of adverse events or neurocognitive events, according to research published in the Journal of the American College of Cardiology.1
Jennifer G. Robinson, MD, MPH, from the departments of epidemiology and medicine, the College of Public Health at the University of Iowa, and colleagues, assessed the safety of alirocumab in 2 groups of patients (LDL-C level <25 mg/dL and LDL-C level <15 mg/dL) in a prospectively defined, pooled, individual-level analysis. Data were collected from 14 phase 2 and phase 3 double-blind studies between 8 and 104 weeks long.
The analysis included 5234 patients (3340 who received alirocumab). Of those patients, 25.1% achieved LDL-C <25 mg/dL at 2 consecutive visits; 9.4% achieved LDL-C <15 mg/dL at 2 consecutive visits. Both groups were exposed to randomized treatment for a median of 78 weeks (control n = 1894)
The investigators found that LDL-C <25 mg/dL or <15 mg/dL was more frequent in those patients with a lower baseline mean LDL-C, especially among those starting alirocumab therapy. Patients with LDL-C <25 mg/dL were 75% men, and were more likely to have cardiovascular disease (76.9%) or type 2 diabetes (37.1%), and higher triglycerides, glycated hemoglobin levels, and lower high-density lipoprotein cholesterol (HDL-C) levels.
Pooled analyses of phase 2 and 3 studies indicated that overall rates of treatment-emergent adverse events (TEAEs), serious TEAEs, deaths, and discontinuations were similar across all LDL-C groups. TEAEs were similar in patients with <15 mg/dL when compared with the overall pooled control and alirocumab populations. TEAE rates were also similar for neurocognitive, neurological, musculoskeletal, ophthalmological, and hepatic events in patients with LDL-C <25 mg/dL or <15 mg/dL vs patients who did not reach those LDL-C levels.
“Low levels of LDL-C (<25 mg/dL) appear to be generally well tolerated over 18 months of alirocumab therapy,” the researchers concluded. “Although the consequences of very low LDL-C were [not] identified in these trials, the long-term effects of very low levels of LDL-C are unknown.”
The investigators noted that data from “large, ongoing cardiovascular outcomes trials” should be used to gather important information related to cardiovascular event reduction benefits and the “adverse effects of long-term exposure to pharmacologically induced low LDL-C levels.”
In an accompanying editorial,2 Brendan M. Everett, MD, MPH, of the divisions of cardiovascular and preventive medicine at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts noted that, “[A]lirocumab seems reassuringly safe, although understanding the possible ‘on-target' physiological effects of lowering LDL-C 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,” Dr Everett concluded.
- The analysis included comparisons of post-randomization subgroups that were confounded by characteristics predisposing patients to low LDL-C levels.
- Sample size and “relatively short” treatment duration were additional limitations.
- Finally, assessment of diabetes as well as neurological and neurocognitive TEAEs was limited by the small number of events reported.
This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Dr Robinson reports receiving research funding from Amarin, Amgen, AstraZeneca, Eli Lilly, Esai, GlaxoSmithKline, Merck, Pfizer, Regeneron Pharmaceuticals, Inc./Sanofi, and Takeda; and has acted as a consultant and/or advisory panel member for Akcea/Ionis, Amgen, Eli Lilly, Esperion, Merck, Pfizer, and Regeneron/Sanofi. Dr Rosenson reports receiving research funding from Akcea, Amgen, AstraZeneca, Catabasis, The Medicines Company, Regeneron Pharmaceuticals, Inc., and Sanofi; and has acted as a consultant and/or advisory board panel member for Akcea, Amgen, AstraZeneca, Eli Lilly, Regeneron Pharmaceuticals, Inc., and Sanofi. Dr Farnier reports receiving research support from Amgen, Merck, and Sanofi and honoraria from Abbott, Eli Lilly, and Pfizer and acting as a consultant and/or advisory panel member for Amgen, Akcea/Ionis, AstraZeneca, Roche, Kowa, Merck, Mylan, Pfizer, Sanofi/Regeneron Pharmaceuticals, Inc., and Servier. Drs Chaudhari and Merlet are stockholders and employees of Sanofi. Drs Sasiela and Miller are stockholders and employees of Regeneron Pharmaceuticals, Inc. Dr Kastelein reports receiving consulting fees from Cerenis, The Medicines Company, CSL Behring, Amgen, Regeneron Pharmaceuticals, Inc., Eli Lilly, Esperion, AstraZeneca, Catabasis, UniQure, Novaritis, Merck, Ionis Pharmaceuticals, Kowa, and Pfizer.
- Robinson JG, Rosenson RS, Farmier M, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab. J Am Coll Cardiol. 2017;69(5):471-482. doi: 10.1016/j.jacc.2016.11.037
- Everett BM. Low-density lipoprotein cholesterol and the on-target effects of therapy. J Am Coll Cardiol. 2017;69(5):483-485. doi: 10.1016/j.jacc.2016.11.036