How Nexlizet Works to Reduce Cholesterol Levels
Nexlizet (bempedoic acid and ezetimibe) works through a dual mechanism of action that inhibits both cholesterol synthesis in the liver and cholesterol absorption in the intestine, resulting in approximately 35% reduction in LDL-C levels. 1, 2
Dual Mechanism of Action
Ezetimibe Component
- Intestinal Cholesterol Absorption Inhibition: Ezetimibe targets the Niemann-Pick C1-Like 1 (NPC1L1) protein at the brush border of the small intestine 2
- Blocks absorption of:
- Dietary cholesterol
- Resorption of cholesterol from intestinal cell breakdown
- Cholesterol contained in bile secretions
- This mechanism typically reduces LDL-C by 15-25% when used as monotherapy 1
- Leads to decreased delivery of intestinal cholesterol to the liver
- Results in reduction of hepatic cholesterol stores and upregulation of LDL receptors, enhancing clearance of cholesterol from the blood 2
Bempedoic Acid Component
- Hepatic Cholesterol Synthesis Inhibition: Bempedoic acid is an ATP citrate lyase (ACL) inhibitor 1
- Works upstream from statins in the liver's cholesterol synthesis pathway 1
- Reduces hepatic cholesterol synthesis, typically lowering LDL-C by 15-25% 1
- Important pharmacological advantage: Bempedoic acid is a prodrug that requires activation by very long-chain acyl-CoA synthetase-1 (ACSVL1), an enzyme present in the liver but not in skeletal muscle 3
- This explains why bempedoic acid has low rates of muscle-related adverse effects compared to statins 1
Combined Effect
- When combined in Nexlizet, bempedoic acid and ezetimibe work synergistically to lower LDL-C by approximately 35% 1, 4
- The combination provides complementary mechanisms:
- Reduced cholesterol synthesis (bempedoic acid)
- Reduced cholesterol absorption (ezetimibe)
- This dual approach addresses two different pathways of cholesterol metabolism, making it particularly effective for patients who cannot tolerate statins or need additional LDL-C lowering beyond statin therapy 5, 6
Clinical Benefits
- The CLEAR Outcomes trial demonstrated that bempedoic acid reduced major adverse cardiovascular events (MACE) by 13% compared to placebo 1
- The combination product has shown effectiveness across different patient subgroups, including those on high-intensity statins, other-intensity statins, or no statin therapy 4
- Beyond LDL-C reduction, bempedoic acid also reduces high-sensitivity C-reactive protein (hsCRP), suggesting potential anti-inflammatory effects 4, 6
Clinical Applications
- Particularly valuable for statin-intolerant patients due to the low risk of muscle-related adverse effects 1, 5
- Useful as add-on therapy for patients not achieving LDL-C goals with maximally tolerated statin therapy 1
- Effective option for patients with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease requiring additional LDL-C reduction 7
Nexlizet represents an important advancement in lipid-lowering therapy by combining two complementary mechanisms to effectively reduce LDL-C levels while maintaining a favorable side effect profile, especially for patients who cannot tolerate statins.