Few adverse events of very low LDL-C levels with PCSK9 antibody
Safety of Very Low Low-Density Lipoprotein Cholesterol Levels With Alirocumab: Pooled Data From Randomized Trials
The safety of achieving very low levels of LDL-C with lipid-lowering therapies is debated, since some studies show that cardiovascular risk can be safely reduced in patients achieving LDL-C <50 mg/dl, whereas others reported increases in physician-reported diabetes, haematuria, hepatobiliary disorders, and insomnia in such patients [1,2]. PCSK9 inhibitors decrease LDL-C by an additional 45% to 65% compared with placebo when added to background lipid-lowering therapy, which raised concerns on their effects on metabolic functions such as gonadal hormones, adrenal function, and transport of fat-soluble vitamins [3,4].
In this analysis, data from 14 randomised controlled alirocumab studies with 5 234 patients treated for up to 2 years were pooled, in order to evaluate the occurrence of adverse events and laboratory values in patients who achieved 2 or more consecutive calculated LDL-C values below 25 or 15 mg/dl.
- 25.1% of patients (n=839) achieved an LDL-C <25 mg/dl, 9.4% (n=314) <15 mg/dl.
- LDL-C <25 or <15 mg/dl occurred more frequently in patients with lower baseline mean LDL-C levels, higher baseline triglyceride levels, lower HDL-C levels, higher glycated hemoglobin levels, male gender, and patients with cardiovascular disease or type 2 diabetes.
- The overall rates of treatment-emergent adverse events (TEAEs), serious TEAEs, deaths, and discontinuations were similar for patients with LDL-C <25 mg/dl compared with LDL-C ≥25 mg/dl.
- The overall rates of TEAEs with <15 mg/dl appeared similar in those with LDL-C <25 mg/dl, to the overall pooled alirocumab and to the pooled control population.
- Although there were significant differences in baseline characteristics of patients with LDL-C <25 and ≥25 mg/dl, no imbalances in TEAE rates were noted among patients with LDL-C <25 or <15mg/dl compared with higher LDL-C levels for neurocognitive, neurological (including peripheral neuropathy), musculoskeletal, ophthalmological, and hepatic events.
- A numerically higher incidence of cataracts was observed in patients with LDL-C <25 mg/dl versus those with higher LDL-C values (2.0 vs. 0.6). Also in the propensity analysis controlling for baseline factors predictive of developing LDL-C <25 mg/dl, the rate of cataracts remained higher in patients with LDL-C <25 mg/dl (2.6%) versus ≥25 mg/dl (0.8%, HR 3.40, 95% CI: 1.58 - 7.35).
- Among those without diabetes at baseline, the incidence of TEAEs related to diabetes or diabetes-related complications was slightly higher in those with LDL-C <25 versus ≥25 mg/dl (12.0 vs. 9.2%; HR 1.05, 95% CI: 0.66–1.68), but this difference was lost after controlling for baseline factors in the propensity analyses.
- LDL-C <25 or <15 mg/dl levels were not associated with hepatic enzymes elevations, haemolytic anaemia, impaired renal function or mean glycated haemoglobin levels over time.
In a study of more than 5 000 patients with a median drug exposure of 1.5 years, low levels of LDL-C (<25 mg/dl) were well tolerated. Although the incidence of cataracts was similar between the overall alirocumab and overall control groups, there was an increased incidence of cataracts in those with LDL-C <25 mg/dl. There were no meaningful imbalances between groups in musculoskeletal and neurological conditions (including peripheral neuropathy), neurocognitive events (including those related to memory), and renal or hepatic events. The long-term effects of very low levels of LDL-C are unknown.
In his editorial article , Everett BM discusses the three most important findings in the Robinson et al analysis:
- the increased incidence of cataracts in patients with LDL-C <25 mg/dl is consistent with other studies and may be explained by the cholesterol demands of the ocular lens for the maintenance of the lens structure and clarity
- the relationship of LDL-C-lowering therapy with diabetic-related complications in patients with diabetes at baseline and LDL-C <25 mg/dl
- the fact that although in this analysis the neurocognitive adverse effects did not differ between patients with LDL-C<25 mg/dl and higher LDL-C levels, in the original study, the neurocognitive adverse effects rates were higher in the alirocumab group compared with the placebo group
The author concludes: ‘The data from the ODYSSEY program represent an important first step in understanding the risks of achieving very low LDL-C concentrations with this novel class of medications.’…. ‘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. 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.’