For decades, statins have been the gold-standard, first-line treatment for high cholesterol [1.2.1]. However, a significant portion of patients experience statin intolerance, most commonly characterized by muscle aches and pains, preventing them from taking these crucial medications [1.2.1, 1.2.2]. A 2022 meta-analysis reported the prevalence of statin intolerance at 9.1% [1.6.2]. This has driven the development of new classes of non-statin therapies that offer effective alternatives for lowering low-density lipoprotein (LDL) cholesterol, often called "bad cholesterol."
Understanding Statin Intolerance
Statins work by blocking HMG-CoA reductase, an enzyme the liver uses to produce cholesterol [1.3.5]. While highly effective, this mechanism can sometimes lead to side effects. The most common is muscle pain (myalgia), which can be debilitating for some individuals [1.2.2]. Statin intolerance is medically defined as the inability to tolerate at least two different statins due to adverse effects [1.6.4]. For the 5-30% of patients who report intolerance, finding an alternative is essential for managing cardiovascular risk [1.6.3].
The Rise of New Statin Alternatives
Fortunately, the landscape of cholesterol management is expanding. Several new drugs, working through different mechanisms, have been approved and proven effective. The primary new alternatives include bempedoic acid, PCSK9 inhibitors, and inclisiran [1.2.4].
Bempedoic Acid (Nexletol)
Bempedoic acid is an oral medication that represents a significant advancement for statin-intolerant patients [1.2.5].
- Mechanism of Action: It works by inhibiting adenosine triphosphate-citrate lyase (ACLY), an enzyme in the cholesterol synthesis pathway that is upstream of the statin target [1.3.1, 1.3.5]. A key feature is that bempedoic acid is a prodrug activated by an enzyme found in the liver but not in skeletal muscle, which is why it has a much lower risk of causing muscle-related side effects [1.3.2, 1.3.3].
- Effectiveness: As a monotherapy, bempedoic acid can lower LDL cholesterol by about 17% to 28% [1.2.4]. When combined with another non-statin drug, ezetimibe, it can reduce LDL cholesterol by up to 38% [1.3.5]. A major 2023 study confirmed it reduces the risk of major cardiovascular events like heart attacks and strokes by 13% in statin-intolerant patients [1.2.1].
- Who It's For: It is FDA-approved for adults with established atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia (HeFH) who require additional LDL lowering [1.3.5]. It's a primary choice for those with confirmed statin intolerance [1.2.2].
- Side Effects: The most common side effects include hyperuricemia (which can lead to gout), anemia, and pain in the limbs [1.3.1]. Tendon rupture has been reported as a less common but serious side effect [1.3.1].
PCSK9 Inhibitors (Repatha & Praluent)
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a powerful class of injectable biologic drugs. The two main ones are evolocumab (Repatha) and alirocumab (Praluent) [1.2.4].
- Mechanism of Action: PCSK9 is a protein that degrades LDL receptors on the surface of liver cells. By blocking PCSK9, these inhibitors increase the number of available LDL receptors, allowing the liver to clear more LDL cholesterol from the blood [1.2.4, 1.10.3].
- Effectiveness: These drugs are highly effective, capable of lowering LDL cholesterol by 50% to 70%, even on top of statin therapy [1.2.4, 1.10.3]. Both Repatha and Praluent have been shown in large clinical trials to significantly reduce the risk of cardiovascular events [1.2.4].
- Who It's For: They are typically reserved for patients with genetic conditions causing very high cholesterol (like HeFH or HoFH) or those with established heart disease who cannot reach their LDL goals despite taking maximally tolerated statins and other therapies [1.5.3, 1.10.1].
- Side Effects: The most common side effects are injection site reactions (like itching, swelling, or pain) and flu-like symptoms [1.5.1, 1.5.3, 1.5.4]. Some people report nasopharyngitis and back pain [1.5.1].
Inclisiran (Leqvio)
Inclisiran is the first-in-class small interfering RNA (siRNA) therapy for cholesterol, offering a unique mechanism and a convenient dosing schedule [1.2.4].
- Mechanism of Action: Instead of blocking the PCSK9 protein after it's made, inclisiran uses RNA interference (RNAi) to prevent the liver from producing the PCSK9 protein in the first place [1.4.1, 1.4.4, 1.7.2]. This leads to the same downstream effect as PCSK9 inhibitors: more LDL receptors and lower blood cholesterol [1.4.3].
- Effectiveness: Clinical trials have shown that inclisiran can reduce LDL cholesterol by approximately 50% when used with statins [1.2.4, 1.9.3].
- Who It's For: Like PCSK9 inhibitors, it's approved as an adjunct for adults with clinical ASCVD or HeFH who need additional LDL lowering [1.2.4]. Its twice-yearly dosing, administered by a healthcare professional, makes it a compelling option for those who may have trouble with adherence to more frequently administered medications [1.4.2, 1.9.3].
- Side Effects: The most common adverse reactions are mild-to-moderate injection site reactions, joint pain (arthralgia), and bronchitis [1.4.2].
Comparison of Statin Alternatives
| Feature | Bempedoic Acid (Nexletol) | PCSK9 Inhibitors (Repatha, Praluent) | Inclisiran (Leqvio) |
|---|---|---|---|
| Mechanism | Inhibits ACLY enzyme in the liver [1.3.1] | Monoclonal antibodies that block the PCSK9 protein [1.2.4] | siRNA that prevents PCSK9 protein production [1.4.1] |
| Administration | Once-daily oral pill [1.3.2] | Subcutaneous injection every 2-4 weeks [1.2.4] | Subcutaneous injection by a professional, twice per year (after initial doses) [1.4.2] |
| LDL Reduction | ~17-28% (monotherapy) [1.2.4] | ~50-70% [1.2.4] | ~50% [1.7.2] |
| Common Side Effects | Hyperuricemia (gout), muscle spasms, back pain [1.3.4] | Injection site reactions, flu-like symptoms [1.5.1, 1.5.3] | Injection site reactions, joint pain [1.4.2] |
| Best For | Statin-intolerant patients needing moderate reduction; oral preference [1.2.2] | Very high-risk patients needing significant LDL reduction [1.5.3] | Patients needing significant reduction who prefer infrequent dosing [1.9.3] |
Conclusion
The treatment of high cholesterol has evolved significantly, moving beyond a one-size-fits-all approach. For the nearly one in ten patients who cannot tolerate statins, several powerful new alternatives exist [1.6.2]. Bempedoic acid offers a muscle-pain-sparing oral option, while PCSK9 inhibitors and inclisiran provide potent LDL reduction through injectable routes with varying dosing frequencies. The availability of these therapies allows for more personalized and effective cholesterol management, ultimately helping to reduce the risk of cardiovascular disease in a wider range of patients. As always, a discussion with a healthcare provider is essential to determine the most appropriate treatment plan based on an individual's health profile, risk factors, and preferences.
Authoritative Link: For more in-depth information on non-statin therapies, consult the American College of Cardiology's Expert Consensus Decision Pathway..
