Bempedoic acid

A small molecule that lowers the LDL cholesterol by inhibiting ATP citrate lyase, a key enzyme in the cholesterol biosynthesis pathway that acts upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the target for statins.

Through a mechanism, distinct from that of statins, it inhibits the mevalonate pathway, and produces a depletion of cellular cholesterol, and subsequent upregulation of hepatic LDL receptors to lower circulating LDL cholesterol levels.

An ATP-citrate lyase inhibitor.

Trade name Nexletol.

A pro drug and requires activation by the enzyme very long chain acyl-CoA synthetase 1, which is present in the liver but absent in most peripheral tissues.

This enzyme can activate bempedoic but it is not contained in muscle tissue, which is abundant in the liver.

It has few, if any, muscle related side effects.

It works upstream of statins in the same mechanistic pathway, and reduces the LDL cholesterol level when used alone  or in combination with ezetimbe in statin intolerant patients, or with statins or ezetimbe in patients with familial hypercholesterolemia.

It reduces low density lipoprotein (LDL) cholesterol levels, and is associated with a low incidence of muscle related adverse events.

It is similar to statins, in that it reduces hepatic cholesterol synthesis and raisesLDL receptor expression, thereby increasing clearance of LDL cholesterol from the circulation.

It is differentiated from statins in its liver specific action.

Among statin intolerant patients, treatment with benpedoic acid is associated with low risk of major adverse cardiovascular events.

CLEAR phase 3 trial: A 52 week trial added to maximally tolerated statins therapy did not lead to a higher incidence of adverse events than placebo and lead to significantly lower LDL cholesterol levels.

Its use is not associated with muscle disorders, new onset, diabetes, or worsening hyperglycemia.

Studies suggest, when combined with the statin, there is enhanced occurrence of muscle symptoms.

Patients receiving 180 mg daily of bempedoic acid reduced LDL cholesterol greater than 21% compared to placebo, and the risk of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization eas 13% lower than for placebo over median of 3.4 years.

In a sub group of high risk primary prevention patients, bempedoic acid treatment is associated with reduced major cardiovascular events (Nissen  SE).

It lowers the LDL cholesterol level up to 28% as monotherapy and this effect is attenuated to approximately 16% in patients receiving the maximum tolerated doses of statins.

Associated with increased gout and elevated uric acid, tendon rupture, and reduced glomerular filtration rate.

Bempedoic acid can increase the circulating levels of statins, simvastatin and pravastatin.

It should not be used with fibrates other than fenfibrate because of concerns regarding cholelithiasis.

A daily pill

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