Mechanism of Back Pain with PCSK9 Inhibitors
The exact mechanism by which PCSK9 inhibitors cause back pain remains unknown, but this musculoskeletal adverse event occurs in approximately 17.5% of patients and represents one of the most common side effects reported with both alirocumab and evolocumab. 1, 2
Clinical Evidence of Musculoskeletal Effects
The musculoskeletal adverse event profile of PCSK9 inhibitors is well-documented across multiple data sources:
Real-world pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) demonstrates that both alirocumab and evolocumab have significant signals for "musculoskeletal and connective tissue disorders" compared to all other drugs, with reporting odds ratios of 2.626 and 2.575 respectively. 1
Back pain, along with myalgia and arthralgia, represents one of the most frequently reported adverse events in Phase II and III clinical trials. 3
Data mining of FAERS between 2015-2021 identified muscle-related adverse events (including back pain, myalgia, arthralgia, and muscle spasms) as among the most significant and common reports for PCSK9 inhibitors. 4
Proposed Mechanisms (Theoretical)
While the precise pathophysiology is unclear, several observations are relevant:
PCSK9 inhibitors work by preventing PCSK9 from degrading LDL receptors on hepatocytes, thereby increasing LDL receptor availability. 5 This mechanism is hepatocyte-specific and does not provide an obvious explanation for musculoskeletal symptoms.
The musculoskeletal effects appear to be a class effect, occurring with both alirocumab and evolocumab, suggesting the mechanism relates to PCSK9 inhibition itself rather than antibody-specific properties. 1, 4
Importantly, PCSK9 inhibitors demonstrate a more favorable musculoskeletal safety profile compared to statins and ezetimibe, with lower reporting odds ratios for muscle-related events when directly compared. 1
Clinical Context and Risk Factors
Patients with prior statin or ezetimibe intolerance due to muscle-related adverse events have a substantially higher likelihood of developing muscle-related adverse events with PCSK9 inhibitors. 2
In a veteran population study, statin intolerance ranged from 68.1% to 100% among patients who developed PCSK9 inhibitor-related muscle symptoms. 2
The incidence of muscle-related adverse events (17.5%) in real-world practice aligns with clinical trial data but exceeds the rates reported in prescribing information. 2
Reassuring Safety Data
Despite the occurrence of back pain and other musculoskeletal symptoms:
Large-scale trials including ODYSSEY, PROFICIO, FOURIER, and IMPROVE-IT showed no increase in severe muscle symptoms with PCSK9 inhibitors, even at very low LDL-C levels below 25 mg/dL. 6, 5
The European Heart Journal guidelines note that when PCSK9 inhibitors were compared with standard of care, annualized event rates for muscle symptoms were actually lower (4.7% vs. 8.5% with standard of care). 6
These adverse events are generally mild-to-moderate in severity and do not typically require discontinuation. 3, 7
Clinical Management Approach
When back pain occurs with PCSK9 inhibitor therapy:
Consider dose reduction or switching between alirocumab and evolocumab, as some patients tolerate an alternative PCSK9 inhibitor following initial intolerance. 2
Recognize that injection-site reactions (occurring in <5% of patients) are distinct from systemic musculoskeletal symptoms and are predominantly very mild with no cumulative effect. 5
The benefit-risk profile remains favorable, as PCSK9 inhibitors reduce major cardiovascular events by 15-20% in high-risk patients, which substantially outweighs the risk of mild-to-moderate musculoskeletal symptoms. 5