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Safety of Very Low LDL-C Levels With Alirocumab
Study Questions:
A low-density lipoprotein cholesterol (LDL-C) <30 mg/dl was shown in the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial to be associated with increasing adverse events including diabetes, hematuria, hepatobiliary disorders, and insomnia. Are very low levels of LDL-C (<25 mg/dl and <15 mg/dl) obtained with proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies added to baseline lipid-lowering therapy safe?
Methods:
Pooled data from 14 trials lasting up to 2 years (median exposure, 78 weeks) were analyzed (double-blind treatment, 8-104 weeks; n = 3,340 alirocumab, 1,894 control [placebo/ezetimibe]; representing 4,029 [alirocumab] and 2,114 [control] double-blind patient-years’ exposure).
Results:
The median time to the first LDL-C value <25 mg/dl was 6.1 weeks (among patients who achieved two consecutive LDL-C <25 mg/dl), with a median duration at LDL-C <25 mg/dl of 43.3 weeks. In alirocumab-treated patients, 839 (25.1%) achieved two consecutive LDL-C <25 mg/dl, and 314 (9.4%) achieved <15 mg/dl. Baseline LDL-C was lower (mean 100.3 vs. 134.3 mg/dl) in those with LDL-C < versus ≥25 mg/dl. Similar rates of adverse events occurred in patients achieving LDL-C <25 and <15 mg/dl (72.7% and 71.7%, respectively), versus 76.6% in those who did not achieve LDL-C <25 mg/dl. Neurological and neurocognitive events were similar among the three groups. In a propensity-score analysis, the rate of cataracts was higher in patients with LDL-C <25 mg/dl (2.6%) versus ≥25 mg/dl (0.8%; hazard ratio, 3.40; 95% confidence interval, 1.58-7.35). However, no difference in cataract incidence was observed between pooled alirocumab and control groups. Alirocumab had no clinically meaningful effect on levels of cortisol or gonadal hormones, or levels of fat-soluble vitamins A, D, and K.
Conclusions:
LDL-C levels <25 or <15 mg/dl on alirocumab were not associated with an increase in overall treatment-emergent adverse event rates or neurocognitive events, although cataract incidence appeared to be increased in the LDL-C <25 mg/dl group.
Perspective:
This analysis adds to the safety record of very low levels of LDL-C, but, as the authors stated, the number of patients with very low levels was relatively small, and the duration of treatment and number of events was low in my opinion, particularly in relationship with neurocognitive impairment and peripheral neuropathy. The initial signal of loss of memory with both the approved PCSK9 antibodies has triggered more clinical rigorous and longer-term studies of cognitive function. Fortunately, the long-term outcome trials of both alirocumab and evolocumab will be available soon. Until then, physicians considering a PCSK9 inhibitor for approved indications should include a statement that the effect on memory and other neurologic parameters is not clear.
Keywords: Atherosclerosis, Cholesterol, VLDL, Cholesterol, LDL, Antibodies, Monoclonal, Cataract, Cognition, Diabetes Mellitus, Dyslipidemias, Gonadal Hormones, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Memory, Peripheral Nervous System Diseases, Primary Prevention, Proprotein Convertases, Subtilisins, Vitamins
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