Kirsten E. Fleischmann, MD, MPH reviewing Robinson JG et al. J Am Coll Cardiol 2017 Feb 7. Khan AR et al. Circ Cardiovasc Qual Outcomes 2017 Jan. Everett BM. J Am Coll Cardiol 2017 Feb 7.

Cataracts and adverse neurocognitive events might be more common with very low LDL cholesterol levels.

The proprotein convertase subtilisin-kexin type 9 (PCSK-9) inhibitors (evolocumab [Repatha] and alirocumab [Praluent]) are potent lipid-lowering agents that can result in very low levels of LDL cholesterol. But can LDL cholesterol be driven so low that adverse events ensue? In two meta-analyses, researchers explore this possibility.

In an industry-sponsored analysis, data from 14 trials in which alirocumab was added to background lipid-lowering therapy were pooled. Treatment duration ranged from 8 to 104 weeks. Among 3340 alirocumab patients, 25% had two consecutive LDL cholesterol measurements <25 mg/dL, and 9% achieved levels of <15 mg/dL. Rates of any reported adverse event were similar in patients with LDL cholesterol levels <15 mg/dL, <25 mg/dL, and ≥25 mg/dL. In propensity-adjusted analyses, rates of specific adverse events, such as diabetes and its complications or neurological and neurocognitive effects, were not significantly different in those with very low LDL cholesterol levels and those with higher levels, but propensity analysis for incident diabetes in those without diabetes at baseline was not presented. Rates of incident cataracts were significantly higher in those with LDL cholesterol levels <25 mg/dL than in those with higher levels (2.6% vs. 0.8%), but overall cataract incidence was similar in the alirocumab and control groups.

A second meta-analysis, which was limited to studies with at least 6 months of follow-up, also showed no significant difference in serious adverse events; however, subgroup analysis of the larger outcome studies suggested excess incidence of neurocognitive adverse events in the very low cholesterol group (odds ratio, 2.85), although the overall incidence was low (<1%).

CITATION(S):

Robinson JG et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: Pooled data from randomized trials. J Am Coll Cardiol 2017 Feb 7; 69:471. 

Khan AR et al. Increased risk of adverse neurocognitive outcomes with proprotein convertase subtilisin-kexin type 9 inhibitors. Circ Cardiovasc Qual Outcomes 2017 Jan; 10:e003153. 

Everett BM.Low-density lipoprotein cholesterol and the on-target effects of therapy: How low is too low? J Am Coll Cardiol 2017 Feb 7; 69:483.

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