Statins have long been the first-line defense against high cholesterol, but they are not a one-size-fits-all solution. A significant number of patients experience muscle-related side effects, leading many to discontinue their medication and remain at risk for cardiovascular events. This treatment gap has driven innovation, bringing newer non-statin drugs to the market that work in different ways to lower low-density lipoprotein cholesterol (LDL-C), often referred to as 'bad' cholesterol. Two prominent recent additions are the oral medication bempedoic acid and the long-acting injectable inclisiran.
Bempedoic Acid (Nexletol): A New Oral Alternative
Approved by the FDA in 2020, bempedoic acid is an oral, once-daily medication available under the brand name Nexletol, or in a combination pill (Nexlizet) with ezetimibe. It provides a new option for patients who are unable to tolerate statins or need additional LDL-C reduction. Bempedoic acid is particularly noteworthy because its mechanism of action minimizes the muscle side effects commonly associated with statins.
Bempedoic acid is a prodrug, meaning it must be activated by an enzyme in the liver. Crucially, this activating enzyme is not present in skeletal muscle, which is thought to be the reason it causes less muscle pain than statins. It works by inhibiting a different enzyme in the cholesterol synthesis pathway, adenosine triphosphate-citrate lyase (ACL), which is located upstream of the enzyme targeted by statins. This blockage leads to increased LDL receptor expression on the liver's surface, enhancing the removal of LDL-C from the blood. Clinical trials have shown that bempedoic acid can reduce LDL-C by approximately 15–25% when used alone and has been shown to reduce cardiovascular events in statin-intolerant patients. However, it does have a distinct side effect profile, including an increased risk of gout and tendon rupture in rare cases.
Inclisiran (Leqvio): The Innovative Injectable
Inclisiran is another key player in the newer generation of non-statin therapies, offering a unique and convenient dosing schedule. It belongs to a class of drugs known as small interfering RNA (siRNA). While older PCSK9 inhibitors are monoclonal antibodies that bind to the PCSK9 protein, inclisiran takes a different approach by preventing the protein's production entirely.
The PCSK9 protein normally binds to LDL receptors on liver cells, leading to their degradation and reducing the liver's ability to clear LDL-C from the bloodstream. Inclisiran works by interfering with the messenger RNA (mRNA) that instructs cells to produce the PCSK9 protein. By halting this production, inclisiran ensures a higher number of LDL receptors remain available on the liver's surface, significantly increasing LDL-C clearance. This mechanism allows for a remarkable dosing schedule: after two initial injections, inclisiran is only required twice a year. The most common side effect is mild, transient injection site reactions.
Comparing New Non-Statin Options
| Feature | Bempedoic Acid (Nexletol) | Inclisiran (Leqvio) | Statins |
|---|---|---|---|
| Mechanism of Action | Inhibits ACL, an enzyme in the cholesterol production pathway. | Uses siRNA to prevent the liver from producing the PCSK9 protein. | Inhibits HMG-CoA reductase, another enzyme in the cholesterol production pathway. |
| Administration | Oral tablet, once daily. | Subcutaneous injection, twice yearly (after initial doses). | Oral tablet, once daily. |
| Efficacy | Lowers LDL-C by ~15–25% as monotherapy; more with ezetimibe. | Lowers LDL-C by up to 50% or more, often used with statins. | Can lower LDL-C by 50%+, depending on dose and type. |
| Target Patient | Statin-intolerant, or those needing additional LDL-C lowering. | High-risk patients needing more LDL-C reduction despite maximum statin use. | First-line therapy for most patients with high cholesterol. |
| Common Side Effects | Muscle spasms, back pain, increased uric acid (gout risk). | Injection site reactions, joint pain, diarrhea. | Muscle pain, fatigue, potential liver enzyme elevation. |
Expanding the Treatment Landscape
The availability of these new non-statin drugs is revolutionizing the management of high cholesterol. They are indicated for patients who fall into several key groups:
- Statin-intolerant patients: These individuals cannot take statins due to adverse side effects and can now be effectively treated with an oral alternative like bempedoic acid.
- Patients requiring additional LDL-C reduction: For those already on maximally tolerated statin therapy but still at high cardiovascular risk, adding a non-statin like inclisiran can achieve significantly lower LDL-C levels.
- Familial hypercholesterolemia (FH): Patients with this genetic disorder, who have extremely high cholesterol levels, often require multiple therapies, including a non-statin, to reach their treatment goals.
The Future of Cholesterol Management
As research continues, the focus is shifting towards achieving optimal LDL-C lowering through a combination of well-tolerated medications, tailored to each patient's needs and risk factors. The emergence of bempedoic acid and inclisiran reinforces the principle that lowering LDL-C, regardless of the drug class used, leads to cardiovascular benefits. These options expand the medical community's ability to help patients who previously had limited treatment choices, ultimately leading to better outcomes for a broader range of individuals at risk for cardiovascular disease. For more detailed information on cardiovascular health, you can consult authoritative resources such as the American Heart Association.
Conclusion
For patients asking, "What is the new cholesterol drug that is not a statin?", the primary oral answer is bempedoic acid (Nexletol), and an innovative injectable option is inclisiran (Leqvio). These new non-statin therapies represent a significant advance in cholesterol management, providing effective alternatives for those who cannot take statins and powerful add-on options for those who need more aggressive LDL-C lowering. Their different mechanisms of action and safety profiles allow for more personalized and comprehensive treatment strategies, improving cardiovascular health for many.
