Other Lipid-Lowering Agents

These drugs share a goal — lower LDL cholesterol or triglycerides beyond what diet and a statin achieve — but not a mechanism, so each is learned on its own. Three lower LDL: ezetimibe blocks cholesterol absorption in the gut, bempedoic acid blocks cholesterol synthesis in the liver one step upstream of the statin target, and inclisiran silences the gene message for PCSK9. Two mainly lower triglycerides: niacin and icosapent ethyl. Lomitapide blocks the assembly of apo B lipoproteins and is reserved for homozygous familial hypercholesterolemia (HoFH).

WHO stems mark three of them: -imibe (ezetimibe), -siran (small interfering RNA — inclisiran) and -tapide (microsomal triglyceride transfer protein inhibitors — lomitapide).

Ezetimibe acts at the brush border of the small intestine on the sterol transporter NPC1L1, inhibiting absorption of cholesterol and plant sterols. Less intestinal cholesterol reaches the liver, hepatic cholesterol stores fall and LDL receptors increase, clearing cholesterol from the blood. It is glucuronidated and recycled enterohepatically (half-life about 22 hours).

It is usually given with a statin (or with fenofibrate in mixed hyperlipidemia), and it inherits that partner’s contraindications. Consecutive liver-enzyme rises were more frequent with ezetimibe plus a statin than with the statin alone, and most reported rhabdomyolysis occurred with a statin or fibrate.

Bempedoic acid inhibits ATP-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase, cutting cholesterol synthesis in the liver and raising LDL receptors. It is a prodrug activated by an acyl-CoA synthetase (ACSVL1) expressed primarily in the liver. It is used to reduce cardiovascular events in people who cannot take recommended statin therapy, and to lower LDL-C.

Its catches are hyperuricemia and gout (it inhibits the renal tubular transporter OAT2) and tendon rupture. It also raises simvastatin and pravastatin levels.

Inclisiran is a small interfering RNA linked to GalNAc, which steers it into hepatocytes. There it uses RNA interference to break down the mRNA for PCSK9, so more LDL receptors are recycled to the cell surface and LDL-C falls. Unlike the PCSK9 antibodies (separate page), which bind PCSK9 already circulating, inclisiran stops it being made.

A healthcare professional gives it subcutaneously — initially, again at 3 months and then every 6 months. LDL-C falls within 14 days and stays about 53% lower at day 180, even though the drug itself has a plasma half-life of about 9 hours.

Niacin (nicotinic acid) partly inhibits release of free fatty acids from adipose tissue, increases lipoprotein lipase activity and lowers hepatic VLDL and LDL synthesis; it lowers total cholesterol, LDL-C, apo B and triglycerides and raises HDL-C. Its best-known effect is flushing (warmth, redness, itching), and it can injure the liver, raise glucose and uric acid, and add to statin myopathy. Extended-release niacin must never be substituted mg-for-mg for immediate-release or sustained-release niacin — severe liver toxicity has followed such switches. Added to simvastatin, niacin did not reduce cardiovascular events.

Icosapent ethyl is the ethyl ester of the omega-3 fatty acid EPA, from fish oil. EPA reduces hepatic VLDL-triglyceride synthesis and secretion and speeds triglyceride clearance. With a maximally tolerated statin it reduces cardiovascular events in high-risk patients with raised triglycerides — at the cost of more atrial fibrillation and bleeding.

Lomitapide binds and inhibits microsomal triglyceride transfer protein (MTP) in the endoplasmic reticulum, preventing assembly of apo B-containing lipoproteins in enterocytes and hepatocytes. Chylomicron and VLDL synthesis falls, and LDL-C falls with it.

Because the fat stays in the liver and gut, it causes hepatic steatosis and transaminase rises (a boxed warning, with access only through the JUXTAPID REMS), severe gastrointestinal effects unless a very low-fat diet is kept, and reduced absorption of fat-soluble vitamins and essential fatty acids. It is contraindicated in pregnancy and with moderate or strong CYP3A4 inhibitors.