Summary of Key Points
This article discusses the evolution of medications for treating high cholesterol levels, starting with the limitations of statins. It explains the mechanism of action of PCSK9, a so-called “miracle lipid-lowering target,” and the development of drugs targeting this target. Early injectable PCSK9 antibodies were not as successful in sales as expected due to their inconvenience. Later, long-acting RNAi drugs (injections every six months) were introduced. In 2026, Merck’s oral PCSK9 inhibitor, enlicitide, was approved, addressing the issue of convenience, although it still faces challenges such as a lack of clinical data demonstrating cardiovascular benefits.
Detailed Explanation
1. Why are statins not enough? – The need for new targets drives innovation
Statins are currently the most commonly used lipid-lowering drugs, but they have two major drawbacks:
- Limited effectiveness: Low doses of statins can only reduce bad cholesterol (LDL) by 20-30%. For example, if someone’s LDL level is 240mg/dL (a risky value), reducing it by 30% would only bring it down to 168mg/dL, which is still far from the ideal level of 100mg/dL. Higher doses can lower LDL more, but they come with more side effects (muscle and liver damage) and are not effective for everyone.
- Inability to cover all patients: Some people have a genetic predisposition to high cholesterol that cannot be controlled even with statins.
Therefore, the medical community needs more powerful and flexible lipid-lowering drugs, and the PCSK9 target was discovered in response to this need.
2. What is PCSK9? – The “key regulator” of blood lipids
Simply put, PCSK9 is a protein that plays a destructive role:
- The liver has receptors specifically designed to remove bad cholesterol (LDL) from the bloodstream, acting like “garbage collectors.”
- PCSK9 binds to these receptors and marks them for destruction, effectively “ruining” the garbage collection process, allowing LDL to accumulate in the blood.
- If PCSK9 can be inhibited, the receptor function can be restored, leading to a significant reduction in LDL levels.
Even more intriguingly, people with naturally inactive PCSK9 genes have very low LDL levels and are less likely to develop cardiovascular diseases, indicating that PCSK9 is a promising target for lipid-lowering therapy.
3. Early PCSK9 antibodies: Powerful but not popular
In 2015, companies like Amgen and Sanofi introduced PCSK9 antibodies that could reduce LDL by 50-70%. However, their sales were disappointing:
- Inconvenience of use: These drugs require injections every 2-4 weeks, which is less convenient than oral medications.
- Subpar sales: Amgen’s Repatha generated only $3 billion in sales in 2025, and Sanofi’s Praluent sold for just $500 million—far from the expectations of these “pharmaceutical giants.”
The problem lay not with the target itself but with the method of administration; patients prefer oral medications.
4. New PCSK9 drugs: Longer-acting or oral options
To improve convenience, pharmaceutical companies have developed two new approaches:
- Long-acting RNAi drugs (inclisiran): Approved in 2021, these drugs interfere with the production of PCSK9, preventing its formation altogether. They are as effective as antibodies but require injections only every six months.
- Oral PCSK9 inhibitors (enlicitide): Developed by Merck, this cyclic peptide drug was approved in 2026 and is the world’s first oral PCSK9 medication. It needs to be taken daily and can reduce LDL by 56-59%, similar to the effects of antibodies, at a much lower cost (about $10 per dose compared to the monthly costs of $500-600 for antibodies).
5. The opportunities and challenges of enlicitide
Merck is betting heavily on enlicitide, as its blockbuster drug Keytruda’s patent will expire in 2028, and they need a new revenue source. However, enlicitide faces several challenges:
- Lack of solid clinical data: Currently, the drug’s effectiveness is only proven in reducing LDL levels; there is no evidence showing it can lower the risk of cardiovascular diseases. This may make doctors and insurance companies hesitant.
- Competitive pressure: There are other options available, such as inclisiran (injections every six months) and other oral PCSK9 drugs still in clinical trials from companies like AstraZeneca.
- Patient preferences: Patients may prefer daily oral medications over monthly injections. The success of long-acting drugs in the HIV treatment field suggests that some patients are willing to accept fewer injections.
Nevertheless, having more oral options available for high cholesterol patients is a positive development, as it can encourage more people to adhere to their treatment regimens.
Conclusion
The development of PCSK9 drugs focuses on balancing effectiveness and convenience. From injectable to oral formulations, and from frequent to long-acting treatments, pharmaceutical companies are continuously working to improve the patient experience. Whether enlicitide will become the new “pharmaceutical champion” is still uncertain, but its introduction certainly brings hope for patients with high cholesterol levels.