Cholesterol is a waxy, fat-like substance necessary for building healthy cells. However, too much low-density lipoprotein (LDL) cholesterol, often called “bad” cholesterol, can cause plaque buildup in the arteries. This condition, known as hyperlipidemia, significantly increases the risk of heart attacks and strokes. While statins are the most commonly prescribed and highly effective first-line treatment for lowering LDL cholesterol, they are not suitable or sufficient for every patient. Many individuals require alternative or supplementary non-statin medications to achieve target cholesterol levels or due to statin intolerance.
Preventing Absorption in the Gut
Some non-statin drugs focus their action directly in the digestive system, preventing cholesterol from entering the bloodstream. This approach bypasses the liver’s internal cholesterol production pathway, providing a complementary strategy to liver-focused drugs like statins. The two main classes that work this way are cholesterol absorption inhibitors and bile acid sequestrants.
Cholesterol absorption inhibitors, such as Ezetimibe, work by blocking a specific protein in the wall of the small intestine called Niemann-Pick C1-Like 1 (NPC1L1). This protein transports cholesterol from the intestinal lumen into the cells lining the gut. By binding to NPC1L1, Ezetimibe prevents the absorption of both dietary cholesterol and cholesterol secreted in the bile. This action reduces the amount of cholesterol delivered to the liver, prompting the liver to increase the number of LDL receptors on its surface to pull more cholesterol from the circulation.
Bile Acid Sequestrants (e.g., Cholestyramine, Colesevelam) work by binding to bile acids within the small intestine. Bile acids are synthesized in the liver from cholesterol and secreted into the intestine to help digest fats. By sequestering these bile acids, the medication prevents their reabsorption back into the liver. The liver must then use its internal cholesterol stores to produce new bile acids to replace those lost in the feces. This depletion of intracellular cholesterol leads to an upregulation of LDL receptors on the surface of liver cells, which enhances the clearance of LDL cholesterol from the blood.
Biologic Therapies
Biologic therapies represent a newer and highly potent class of non-statin treatments, specifically Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors. The PCSK9 protein, produced primarily by the liver, plays a significant role in regulating the number of LDL receptors on the liver cell surface. When PCSK9 binds to an LDL receptor, the entire complex is internalized by the cell and then tagged for destruction in the lysosome.
This process effectively reduces the number of LDL receptors available to clear cholesterol from the bloodstream, leading to higher circulating LDL levels. PCSK9 inhibitors, such as Evolocumab and Alirocumab, are monoclonal antibodies that bind directly to the circulating PCSK9 protein. By neutralizing PCSK9, these inhibitors prevent it from binding to the LDL receptor.
This inhibition allows the LDL receptors to be recycled back to the liver cell surface instead of being degraded. With more functional LDL receptors present, the liver can efficiently pull a significantly greater amount of LDL cholesterol out of the blood. These therapies are typically administered via subcutaneous injection and are reserved for patients with severe hypercholesterolemia, including those with familial hypercholesterolemia, or those who cannot tolerate or achieve sufficient LDL lowering with maximal oral therapy.
Modifying Liver Lipid Production
Other non-statin medications work by targeting different steps in the liver’s complex process of synthesizing and processing fats. These mechanisms offer distinct ways to reduce cholesterol and triglyceride levels compared to statins, which inhibit the HMG-CoA reductase enzyme. ACL inhibitors, fibrates, and niacin each modulate different pathways to achieve a lipid-lowering effect.
ACL Inhibitors
Adenosine triphosphate citrate lyase (ACL) inhibitors, such as Bempedoic acid, work upstream of the target enzyme for statins in the cholesterol synthesis pathway. This medication is a prodrug that becomes active in the liver, where it inhibits the ACL enzyme. By blocking ACL, Bempedoic acid reduces the production of acetyl-CoA, a precursor molecule needed for cholesterol synthesis. This reduction in internal cholesterol synthesis prompts the cell to increase the expression of LDL receptors, thereby enhancing the clearance of LDL cholesterol from the blood. Because the activation of Bempedoic acid is limited to the liver and is not active in muscle tissue, it offers a distinct advantage for patients who experience muscle-related side effects, or myopathy, with statin therapy.
Fibrates
Fibrates, including Gemfibrozil and Fenofibrate, primarily target high triglyceride levels and low high-density lipoprotein (HDL) cholesterol. Their mechanism involves activating a nuclear receptor called peroxisome proliferator-activated receptor alpha (PPAR \(\alpha\)). Activation of PPAR \(\alpha\) leads to changes in the expression of genes involved in fat metabolism. This action promotes the breakdown of triglycerides by stimulating lipoprotein lipase and reduces the liver’s production of very low-density lipoprotein (VLDL), which is a precursor to LDL. Fibrates also increase the synthesis of apolipoproteins A-I and A-II, which contributes to raising HDL cholesterol levels.
Niacin
Niacin, or nicotinic acid, is a B vitamin that, at pharmacological doses, modifies liver lipid production. Niacin acts to reduce the levels of LDL and VLDL by inhibiting the enzyme diacylglycerol acyltransferase-2 (DGAT-2). This enzyme is necessary for triglyceride synthesis in the liver. Lowering triglyceride synthesis leads to increased degradation of apolipoprotein B, a structural component of VLDL and LDL particles, thus reducing their secretion into the bloodstream. Niacin is also effective at raising HDL cholesterol by decreasing its rate of breakdown in the liver. Its use has declined due to common side effects like flushing and concerns about potential liver toxicity.
Clinical Use of Non-Statin Treatments
Non-statin medications are integrated into therapy based on specific patient needs and the overall lipid profile. The most common reason for using these alternatives is statin intolerance, where patients experience side effects, most often muscle pain, that prevent them from taking the drug. In these cases, non-statin therapies like ACL inhibitors offer an effective pathway to lower LDL cholesterol with a lower risk of myopathy.
These drugs are frequently used in combination with statins to achieve lower LDL targets than a statin alone can reach. For example, Ezetimibe can be added to a statin regimen for a synergistic effect, blocking both cholesterol production and absorption. Fibrates are the primary agents for managing very high triglyceride levels, which can pose a risk for pancreatitis. PCSK9 inhibitors are generally reserved for patients with genetic conditions causing extreme hypercholesterolemia or those with established cardiovascular disease who require substantial further LDL reduction.