Real-world safety of PCSK9 inhibitors: A pharmacovigilance study based on spontaneous reports in FAERS

Abstract

Objective: We aimed to evaluate alirocumab- and evolocumab-related adverse events (AEs) in real-world compared with all other drugs, overall and by gender and age subgroups; we also aimed to compare their risks of cognitive impairment, musculoskeletal disorders and diabetes with various statins and ezetimibe.Methods: We retrospectively extracted AE reports from the FDA Adverse Event Reporting System (FAERS) database during July 2015-June 2021. Disproportionality analyses were performed using reporting odds ratios (RORs) to detect AE signals of alirocumab and evolocumab in the overall population and in different age and gender subgroups, respectively.Results: Compared with all other drugs, both alirocumab and evolocumab had a significant signal in “musculoskeletal and connective tissue disorders” (ROR1 = 2.626, 95% CI 2.552–2.702; ROR2 = 2.575, 95% CI 2.538–2.613). The highest ROR value of 2.311 (95% CI 2.272–2.351) was for “injury, poisoning and procedural complications” and was found in patients aged ≥65 years on evolocumab. The most frequent AEs were “general disorders and administration site conditions” and “musculoskeletal and connective tissue disorders” for all subpopulations. At the preferred term level, the most frequent AE signal was myalgia for alirocumab and injection site pain for evolocumab, overall and by subgroups. Compared with statins/ezetimibe, PCSK9 inhibitors exhibited lower ROR values for adverse events associated with SOC “nervous system disorders”, “psychiatric disorders” and “metabolism and nutrition disorders” (all RORs < 1), but mixed results for musculoskeletal disorders. Compared with all other drugs, undocumented AEs, such as acute cardiac event (ROR = 30.0, 95% CI 9.4–95.3) and xanthoma (ROR = 9.3, 95% CI 3.4–25.5), were also reported.Conclusion: Real-world evidence showed that PCSK9 inhibitors were associated with an increased risk of musculoskeletal and connective tissue disorders and general disorders and administration site conditions, overall and by subgroups. Muscle toxicity, injection site reactions, and influenza-like illness were significant AE signals. Compared with various statins and ezetimibe, PCSK9 inhibitors have shown a favorable safety profile in muscle-related events, cognitive impairment and diabetes. Some undocumented AE signals were also reported. Due to the limitations of spontaneous reporting databases, further studies are still needed to establish causality and validate our results.

Adverse Reactions to Evolocumab: Analysis of Real-World Data from EudraVigilance

“…The results of this study, through a disproportionality analysis, focused particularly on injection site reactions and muscle-related adverse events related to evolocumab prescription [ 16 ]. Another study on real-world data, using the same data system, reported similar conclusions about musculoskeletal problems and injection site reactions; however, the authors added influenza-like illness as a significant signal of adverse events to evolocumab [ 17 ]. In patients at extremely high risk for acute coronary syndrome, with elevated low-density lipoprotein cholesterol levels and subjected to percutaneous coronary intervention and treated with 140 mg evolocumab every two weeks, associated with atorvastatin 40 mg/day and ezetimibe 10 mg/day, lipids were decreased, with an improvement in cardiovascular prognosis, without any further adverse reaction.…”

Psychiatric disorders associated with PCSK9 inhibitors: A real‐world, pharmacovigilance study

“…Elderly patients >65 years of age generally had higher ROR values than middle‐aged adults (2.20 vs. 3.60), suggesting that older adults taking PCSK9i may be more susceptible to psychiatric AEs. Another FAERS‐based study also reported that numerous AEs for evolocumab and alirocumab occurred more frequently in older adults >65 years of age, 32 possibly due to age‐related decreases in both drug metabolism and excretory and digestive abilities, which may lead to increased plasma concentrations of PCSK9i 34 . Therefore, caution should be exercised when prescribing PCSK9i to patients >65 years of age.…”

“…Diseases associated with neuromuscular injury also predispose to obstructive sleep apnoea syndrome, progressive respiratory muscle weakness and chronic hypercapnic respiratory failure 31 . Since the pathogenesis of obstructive sleep apnoea syndrome is closely related to neuromuscular injury, and real‐world evidence suggests that the most common adverse effects associated with PCSK9i are muscle toxicity as well as myalgia 32 . Therefore, we hypothesized that obstructive sleep apnoea syndrome after PCSK9i use may be a secondary effect of PCSK9i leading to myotoxicity, and that further studies are needed to investigate the effects of PCSK9i on obstructive sleep apnoea syndrome and the mechanisms underlying this potential association need to be further investigated.…”

Effect of sacubitril/valsartan on lipid metabolism in patients with chronic kidney disease combined with chronic heart failure: a retrospective study

“…However, their use is marred by adverse effects such as rhabdomyolysis and hepatic insufficiency, with limited discernible benefits for patients undergoing dialysis therapy [ 5 ]. Emerging lipid-lowering interventions, such as proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors, may present side effects at the injection site, including allergies and muscle cramps [ 6 ]. The American Heart Association guidelines recommended utilizing omega-3 fatty acids in individuals with heart failure (HF) to mitigate the likelihood of hospitalization and mortality, particularly in those categorized within New York Heart Association (NYHA) classes II-IV [ 7 ].…”