Lipid-Lowering Agents

HMG-CoA reductase inhibitors (statins)

These agents inhibit the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase.^{[1, 2, 3]}Note the following:

Low-density lipoprotein (LDL) reduction of 25-60%
Examples include Atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin ^[4]
Contraindications include hypersensitivity, active liver disease, pregnancy, lactation, coadministration with strong CYP3A4 inhibitors (selected statins)

Vitamin B3

Vitamin B3 inhibits very-low-density lipoprotein (VLDL) synthesis. Note the following:

LDL reduction of 10%
High-density lipoprotein (HDL) increase of 20%
Example includes Niacin (nicotinic acid)
Contraindications include hypersensitivity, liver disease, active peptic ulcer, severe hypotension, arterial bleeding

Fibrates

Fibrates enhance lipoprotein lipase, resulting in increased VLDL catabolism, fatty acid oxidation, and triglyceride elimination. They decrease hepatic extraction of free fatty acids. Note the following:

LDL reduction of 15%
Triglyceride reduction of 35%
Examples include Gemfibrozil, fenofibrate, fenofibrate (micronized), fenofibric acid
Contraindications include active liver disease, renal disease, primary biliary cirrhosis, gallbladder disease

2-Azetidiones

These agents inhibit sterol transporter at brush border and, consequently, intestinal absorption of cholesterol.

LDL reduction of 15%
Example includes Ezetimibe
Contraindications include hypersensitivity, coadministration with statins (if active liver disease)

Bile acid sequestrants

These agents lower cholesterol and LDL via bile duct sequestration. Note the following:

LDL reduction of 15%
Examples include Cholestyramine, colesevelam, colestipol
Contraindications include biliary/bowel obstruction, serum triglycerides >300-500 mg/dL, history of hypertriglyceridemia-induced pancreatitis

ACL Inhibitors

Adenosine triphosphate-citrate lyase (ACL) inhibitors lower LDL-C by inhibiting cholesterol synthesis in the liver upstream from that of HMG-CoA reductase inhibitor actions.

LDL reduction (with maximally tolerated statins) averages 18% and 38% (combined with ezetimibe)
Example includes bempedoic acid
Cautions include Elevated uric acid levels and risk of tendon rupture or injury

ANGPTL Inhibitors

Recombinant monoclonal antibody that binds to and inhibits angiopoietin-like 3 (ANGPTL3). Lipoprotein lipase and endothelial lipase are inhibited by ANGPTL3, resulting in reduced lipid metabolism. Inhibition of ANGPTL3 by evinacumab allows increased lipid metabolism, leading to decreased LDLc, HDLc, and trigyclerides (TG).

LDL (relative) reduction: 47.1% compared with placebo
Example includes evinacumab
Contraindications include hypersensitivity to evinacumab

PCSK9 Inhibitors

Monoclonal antibody that binds to PCSK9 (proprotein convertase subtilisin/kexin type 9). LDL-C is cleared from the circulation preferentially through the LDL receptor (LDLR) pathway. PCSK9 is a serine protease that destroys LDLR in the liver, resulting in decreased LDL-C clearance and increased plasma LDL-C.

LDL reduction 20%
Example includes alirocumab, evolocumab
Contraindications include hypersensitivity to PCSK9 inhibitors

Small interfering RNA (siRNA) therapy

Inclisiran is a double-stranded small interfering RNA conjugated on sense strand with triantennary N-acetylgalactosamine to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for proprotein convertase subtilisin kexin type 9 (PCSK9). This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation.

Reduces LDL-C exceeding 50% over 1-2 years ^[5]
Leqvio (inclisiran) is approved as an adjunct to statins for further reductions of LDL cholesterol levels
Side effects: Mild-moderate injection site reaction (eg, pain, redness, rash), joint pain, urinary tract infection, diarrhea, chest cold, pain in legs or arms, and shortness of breath

Apolipoprotein B antisense oligonucleotide

These agents target messenger RNA for apolipoprotein B (apoB)–100, the principal apolipoprotein of LDL and its metabolic precursor, VLDL.^[6]Note the following:

Reduces LDL, ApoB, total cholesterol (TC), and non-HDL cholesterol
Example includes Mipomersen
Contraindications include hypersensitivity, moderate-to-severe hepatic impairment or active liver disease including persistent increased levels of serum transaminases

MTP inhibitor

These agents directly bind and inhibit microsomal triglyceride transfer protein (MTP), thereby preventing ApoB-containing lipoproteins. Note the following:

Reduces LDL, TC, ApoB, and non-HCL cholesterol
Example includes Lomitapide ^[7]
Contraindications include pregnancy, coadministration with strong CYP3A4 inhibitors (lomitapide exposure increased 27-fold), moderate-to-severe hepatic impairment or active liver disease including persistent increased levels of serum transaminases

Omega 3 acids

Omega 3 acid agents inhibit acyl CoA:1,2-diacylglycerol acyltransferase. Note the following:

Reduces non-HCL cholesterol, ratio of total cholesterol to HDL-C, VLDL, Apo-C, phospholipase A2, and arachidonic acid
Examples include omega 3 fatty acids, omega 3 carboxylic acids, icosapent
Contraindications include hypersensitivity or hypersensitivity-related reactions