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The Changing Landscape of Low-Density Lipoprotein (LDL)-lowering Drugs

The Changing Landscape of Low-Density Lipoprotein (LDL)-lowering Drugs

For the majority of people, statins remain the most effective strategy to reduce dangerous LDL cholesterol. However, two novel medicines may be viable complements or replacements for those with persistently elevated LDL cholesterol levels.

Numerous factors contribute to statins being among the most regularly prescribed medications in the United States. Statins, which were approved in the late 1980s, have a long history of being both effective and safe. These medications not only cut LDL cholesterol but also heart attacks and mortality from heart disease, the nation's leading killer. Additionally, the majority are available in generic form and cost less than $11 per person per year, according to a 2021 American Heart Association statement.

Nonetheless, some persons receiving the highest advised dose of a statin have LDL values that are higher than recommended. Additionally, a small number of persons report intolerance to statins. Until recently, the principal options for decreasing LDL cholesterol were ezetimibe (Zetia) and PCSK9 inhibitors such as alirocumab (Praluent) and evolocumab (Repatha). All three medications have been found to reduce the risk of a heart attack. Two new medications, bempedoic acid (Nexletol) and inclisiran (Leqvio) have been approved by the FDA in the last two years, further expanding the possibilities for decreasing LDL.

However, while these two newer medications may be beneficial for some people, it is unknown whether they will help prevent heart attacks or strokes. In most circumstances, a lower LDL number equates to a lower risk of heart attack, however, this is not always the case. The outcome of clinical trials testing both medications is expected in the next few years.

Who would stand to gain?

For the majority of people, taking a statin can reduce LDL to less than 100 milligrammes per deciliter (mg/dL) — or to less than 70 mg/dL in those with cardiovascular disease or a high risk of developing it (those who have had a heart attack or diabetes, for instance).

However, statins are usually inadequately effective for some individuals, particularly those with familial hypercholesterolemia. This genetic disorder, which affects approximately one in every 250 persons, can result in LDL cholesterol levels of 190 mg/dL or greater. Additionally, some persons report experiencing muscle aches or soreness (myalgias) while taking statins. This intolerance to statins occurs in approximately 5% of persons in clinical trials but up to 15% of people in the real world, despite the fact that these symptoms are frequently not reproducible or directly related to the statin. For patients who are intolerant to statins, doctors may prescribe ezetimibe, which reduces LDL cholesterol by roughly 20%.

The latest non-statin medications have an even larger effect on LDL reduction.

Inclisiran. As with other PCSK9 inhibitors currently available, inclisiran reduces LDL cholesterol levels by approximately 50%. Both types of medicines target a protein called PCSK9, which is produced in the liver and is involved in the regulation of LDL. The initial PCSK9 inhibitors work by binding to and inhibiting PCSK9 after it is synthesised. In comparison, inclisiran disrupts the genetic code of PCSK9, preventing the protein from being produced in the first place. Another distinction is that the first two PCSK9 inhibitors require monthly or bimonthly injections, but inclisiran requires only two injections per year.

Bempedoic acid. Bempedoic acid, like statins, is a medication that acts by interfering with the same cholesterol pathway. However, unlike statins, bempedoic acid is converted to its active form only in the liver, suggesting the possibility of fewer muscle-related adverse effects, though this remains to be verified. Taken alone, bempedoic acid reduces LDL cholesterol by around 25%. Additionally, bempedoic acid is available in a combination with ezetimibe under the brand name Nexlizet. According to studies, this combination can reduce LDL cholesterol by approximately 40%.

Current recommendation

If a patient believes they are unable to tolerate their statin, doctors typically recommend switching to a different statin, frequently at a lower dose. While PCSK9 inhibitors are a well-established alternative, their exorbitant cost has limited their use. Nexlizet may be a viable alternative for those currently on ezetimibe, as it contains ezetimibe. Additionally, it is cheaper than PCSK9 inhibitors, making it more likely that insurers will accept it, but data on the medications' effectiveness to prevent heart attacks are still lacking.


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