Lipid lowering therapies

Lowering LDL cholesterol

LDL cholesterol is at the base of atherosclerosis development and is causally associated with cardiovascular disease. Numerous blinded randomized trials have demonstrated that LDL cholesterol lowering drugs compared to placebo reduce the risk of cardiovascular disease. There are multiple LDL cholesterol lowering therapies available at the moment, including statins, ezetimibe, bempedoic acid (although currently not reimbursed in the Netherlands), and proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors. These drugs all have different working mechanisms, but all have shown to lower LDL cholesterol levels and reduce cardiovascular disease. Large meta-analyses have demonstrated that for every 1 mmol/L LDL cholesterol lowering, a risk reduction in cardiovascular disease of 20% is observed during a median follow-up time of 5 years. This is true, regardless of how or with which drug LDL cholesterol is lowered. The LDL cholesterol reduction that can be achieved with different combinations of drugs can be calculated via the LDL calculator.


Statins lower LDL cholesterol by inhibiting HMG-CoA reductase, which is an enzyme involved in the intracellular production of cholesterol molecules. When less cholesterol is synthesized in the liver cells, the production of LDL receptors that take up the cholesterol-rich LDL particles from the bloodstream is upregulated. In this way, the LDL cholesterol level in the bloodstream is reduced.

There are different types of statins available, including simvastatin, atorvastatin, and rosuvastatin, all with different efficacy. Guidelines recommend to lower the LDL cholesterol by 50% in patients carrying a high cardiovascular risk, which is only achievable with the newer statins (atorvastatin 40 mg or 80 mg and rosuvastatin 20 mg or 40 mg). More than a hundred thousand patients have been enrolled in randomized controlled trials evaluating the efficacy of different statins. Meta-analyses of these trials have consistently demonstrated that statin use results in reduction of cardiovascular disease risk, even in different subgroups of patients, including men and women, diabetic patients and the elderly (> 70 years of age). Some of these patients (7-29%) do experience side effects, with muscle aches occurring most common. In a large part of patients, this can be remedied by switching to a different type of statin.

Key points

  • Lowering LDL cholesterol is a cornerstone in cardiovascular risk management.
  • LDL cholesterol lowering can be achieved with statins, ezetimibe, PCSK9 inhibitors, and bempedoic acid, all of which have been shown to reduce cardiovascular risk.
  • Regardless of which drug is used to lower LDL cholesterol, every 1 mmol/L reduction in LDL cholesterol results in a 20% reduction in cardiovascular disease risk.
Mechanisms of action of lipid lowering therapies

Bempedoic acid

Bempedoic acid inhibits an enzyme called ATP-citrate lyase. This enzyme is, similar to HMG CoA reductase, involved in intracellular cholesterol synthesis. Inhibition of this enzyme results in more expression of LDL receptors on hepatocytes, which in turn leads to more LDL particles being captured from the bloodstream. Bempedoic acid enables lowering of LDL cholesterol by approximately 20%.

Bempedoic acid is a pro-drug that is converted into its active form in liver cells but not in muscle cells. Therefore, unlike with statins, its use is not associated with muscle pain and myopathy. However, use of bempedoic acid can increase uric acid levels in the bloodstream resulting in a slightly increased risk for more frequent gout attacks in patients already familiar with gout.

In the Netherlands, use of bempedoic acid has been approved although it is currently not reimbursed. In the near future, bempedoic acid will likely be used in patients with a high cardiovascular risk and statin intolerance.


Ezetimibe inhibits the absorption of cholesterol from the diet through NPC1L1 transporter in enterocytes. This way, less cholesterol enters the circulation via chylomicrons. Ezetimibe enables LDL cholesterol lowering of approximately 20% when combined with a statin. Its use has also been shown to reduce cardiovascular disease risk in secondary prevention patients. Adding ezetimibe to the treatment regimen is recommended in patients not reaching their LDL cholesterol targets with statin monotherapy.

PCSK9 inhibitors

Recently, drugs inhibiting the function of the PCSK9 protein have become available. PCSK9 inhibits the reuse of LDL receptors in the liver by breaking them down intracellularly. By inhibiting PCSK9, more LDL receptors become available on hepatocytes, resulting in the reduction of circulating LDL cholesterol. There are currently three PCSK9 inhibitors available that are administered via subcutaneous injection: evolocumab, alirocumab, and inclisiran.

Evolocumab and alirocumab are antibodies targeting the PCSK9 protein, causing it to lose its function. These antibodies lead to more than 50% lowering in LDL cholesterol levels and a significant reduction in cardiovascular disease risk. Inclisiran is a slightly newer drug that inhibits the synthesis of the PCSK9 protein at an mRNA level in hepatocytes. Inclisiran is administered only twice a year and also leads to more than 50% reduction in LDL cholesterol levels. Use of inclisiran is thought to increase medication adherence, as it has a much lower administration frequency.