Side effects of pcsk9 inhibitors
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Side Effects of PCSK9 Inhibitors: A Comprehensive Review
Introduction to PCSK9 Inhibitors
PCSK9 inhibitors are a class of drugs designed to lower low-density lipoprotein (LDL) cholesterol levels, thereby reducing the risk of cardiovascular diseases. While their efficacy in lowering LDL cholesterol is well-documented, understanding their side effects is crucial for long-term patient safety.
Common Side Effects of PCSK9 Inhibitors
Injection-Site Reactions and Flu-like Symptoms
In real-world settings, the most frequently reported side effects of PCSK9 inhibitors include injection-site reactions and influenza-like symptoms. These were observed in 33.8% and 27.9% of patients, respectively, in a hospital registry study5. These side effects are generally mild and resolve in most patients.
Musculoskeletal Pain and Nasopharyngitis
Clinical trials have also identified musculoskeletal pain and nasopharyngitis as common adverse events. These side effects were mild to moderate in severity and did not lead to discontinuation of the treatment2.
Metabolic Side Effects
Increased Risk of Type 2 Diabetes Mellitus (T2DM)
Several studies have indicated a potential link between PCSK9 inhibitors and an increased risk of developing type 2 diabetes mellitus. Genetic analyses and meta-analyses have shown that PCSK9 inhibitors can increase fasting blood glucose and HbA1c levels, although this does not significantly elevate the incidence of diabetes in the short term1 3. The risk appears to be associated with the potency and duration of the treatment3.
Weight and Blood Pressure Changes
Genetic studies have also associated PCSK9 inhibitors with increased body mass index (BMI), waist circumference, and diastolic blood pressure. These findings suggest that long-term use of PCSK9 inhibitors may have broader metabolic implications1.
Neurocognitive Side Effects
No Significant Increase in Neurocognitive Adverse Events
Concerns have been raised about the potential neurocognitive side effects of lipid-lowering therapies, including PCSK9 inhibitors. However, meta-analyses and systematic reviews have found no significant increase in the incidence of neurocognitive adverse events among patients treated with PCSK9 inhibitors compared to control groups7 8. These findings are reassuring but highlight the need for further long-term studies.
Other Potential Side Effects
Depression, Asthma, and Chronic Kidney Disease
Genetic analyses have also suggested nominal associations between PCSK9 inhibitors and conditions such as depression, asthma, chronic kidney disease, and venous thromboembolism. However, these associations were not strong enough to raise substantial concerns about the long-term safety of PCSK9 inhibitors1.
Myalgia
In pharmacovigilance databases, myalgia was reported as a common adverse event, occurring in 12.8% and 8.3% of patients in different datasets. This side effect was more frequently reported in real-world settings compared to clinical trials5.
Conclusion
PCSK9 inhibitors are effective in lowering LDL cholesterol and reducing cardiovascular risk. While they are generally well-tolerated, they are associated with several side effects, including injection-site reactions, flu-like symptoms, musculoskeletal pain, and potential metabolic changes. The risk of neurocognitive adverse events appears to be minimal. Ongoing monitoring and further long-term studies are essential to fully understand the safety profile of these drugs.
Sources and full results
Most relevant research papers on this topic
Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors
Long-term use of PCSK9 inhibitors may increase the risk of type 2 diabetes mellitus, but other potential side effects were not found to raise substantial concerns about their long-term safety.
Observational StudyA Highly Durable RNAi Therapeutic Inhibitor of PCSK9
Inclisiran, a long-acting RNAi inhibitor, effectively reduces PCSK9 and LDL cholesterol levels without serious adverse events for at least 6 months in a phase 1 trial.
RCT
Rigorous Journal
Highly CitedProprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors and Incident Type 2 Diabetes: A Systematic Review and Meta-analysis With Over 96,000 Patient-Years
PCSK9i therapy favors a small but significant increase in plasma glycemia and HbA1c, but does not increase the incidence of type 2 diabetes.
Meta-Analysis
Very Rigorous JournalHighly CitedThe promises of PCSK9 inhibition
PCSK9 inhibition effectively lowers LDL cholesterol levels without severe or serious side effects in clinical trials.
Systematic ReviewAdverse Events Associated With PCSK9 Inhibitors: A Real‐World Experience
PCSK9 inhibitors are well-tolerated in real-world settings with an overall safety profile comparable to randomized clinical trials.
Observational StudyRigorous JournalPCSK9 inhibitors in clinical practice: Delivering on the promise?
PCSK9 inhibitors effectively lower LDL-cholesterol and have a favorable side effects profile in routine outpatient care, maintaining their promise from clinical trials.
Observational StudyExposure to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the association with neurocognitive side effects: a meta-analysis and meta-regression
Exposure to PCSK9 inhibitors is not associated with an increased risk of neurocognitive adverse events.
Meta-AnalysisRigorous JournalProprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk for neurocognitive adverse events: A systematic review, meta-analysis and meta-regression.
PCSK9 inhibitors are not associated with an increased risk of neurocognitive adverse effects.
Meta-AnalysisCardiovascular Efficacy and Safety of PCSK9 Inhibitors: Systematic Review and Meta-analysis Including the ODYSSEY OUTCOMES Trial.
PCSK9 inhibitors reduce nonfatal major adverse cardiovascular events and are well-tolerated, but their effects on mortality remain unclear.
Meta-AnalysisSerious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review
PCSK9 inhibitors did not improve cardiovascular health, but evolocumab increased the risk of all-cause mortality.
Systematic Review