What are the differences in the usage of different lipid-lowering drugs?🔠🔠🔠

Among people who die from diseases in the world, deaths caused by atherosclerotic cardiovascular disease rank at the forefront. One of the important pathogenic risk factors in the development of atherosclerotic cardiovascular disease is dyslipidemia. Therefore, lipid-lowering drugs play an important role in preventing and controlling atherosclerotic cardiovascular disease.

What are the items in the blood lipid examination?

Name	Abbreviation	Normal range values
Total Cholesterol	TC	3.4-6.1mmol/L
Triglycerides	TG	0.57-1.7mmol/L
Low density lipoprotein cholesterol	LDL-C	2.7-3.1mmol/L
Apolipoprotein B	ApoB	0.8-1.1g/L
Lipoprotein(a)	Lp(a)	0-300mg/L
High density lipoprotein cholesterol	HDL-C	1.16-1.55mmol/L
Apolipoprotein A1	ApoA1	1.2-1.6g/L

Atherosclerotic cardiovascular disease is positively correlated with TC, TG, LDL-C, ApoB, and Lp(a), and negatively correlated with HDL-C and ApoA1.

What types of lipid-lowering drugs are there?

Lipid-lowering drugs generally reduce LDL-C through the absorption, synthesis and elimination of cholesterol.

Drugs that inhibit cholesterol absorption: such as ezetimibe.

Drugs that inhibit cholesterol synthesis: HMG-CoA reductase inhibitors such as atorvastatin. ATP-citrate lyase inhibitors such as bempedoic acid.

Drugs that promote cholesterol degradation: PCSK9 inhibitors such as evolocumab and alirocumab. PCSK9 synthesis inhibitors such as inclisiran.

Angiopoietin-like protein 3 inhibitor: such as evinacumab.

Apolipoprotein B synthesis inhibitors: such as mipomexan.

Microsomal triglyceride transfer protein inhibitor: such as lomitapide.

How strong are commonly used lipid-lowering drugs?

HMG-CoA reductase inhibitors are the clinically preferred lipid-lowering drugs. When HMG-CoA reductase inhibitors fail to reduce LDL-C to the target value at tolerable doses, it may be considered to add ezetimibe or/and PCSK9 inhibitors. 

	Reduce the average LDL-C level.
Ezetimibe	About 20%.
Moderate-strength HMG-CoA reductase inhibitors (such as simvastatin, pravastatin)	About 30%.
High-strength HMG-CoA reductase inhibitors (such as atorvastatin, rosuvastatin)	About 50%.
PCSK9 inhibitors	About 60%.
High-strength HMG-CoA reductase inhibitors + Ezetimibe	About 65%.
High-strength HMG-CoA reductase inhibitors + PCSK9 inhibitors	About 75%.
High-strength HMG-CoA reductase inhibitors + PCSK9 inhibitors + Ezetimibe	About 85%.

Drugs that inhibit cholesterol absorption.

The absorption of cholesterol in the small intestine is inhibited by this type of drug, thereby reducing blood cholesterol levels. They can reduce ApoB, LDL-C and TC in patients.

• Ezetimibe: Ezetimibe is rapidly absorbed when taken orally. It is extensively conjugated in the body to the pharmacologically active ezetimibe-glucuronide. Ezetimibe-glucuronide has significant enterohepatic circulation. Its half-life is 22 hours. Its recommended dose is 10 mg once daily. It can be taken at any time throughout the day. Ezetimibe can be taken on an empty stomach or with food.

Drugs that inhibit cholesterol synthesis.

Acetyl coenzyme A, a common metabolite of sugar and fat, is the raw material for cholesterol synthesis. 

• HMG-CoA reductase inhibitors directly prevent cholesterol synthesis by inhibiting HMG-CoA reductase. This type of drug is the most widely used lipid-lowering drug in clinical practice. Their main adverse reactions include hepatotoxicity, myotoxicity and increased risk of new-onset diabetes in patients.

1. Moderate-potency HMG-CoA reductase inhibitors: They lower a patient's LDL-C by approximately 30%. Commonly used clinically are simvastatin and pravastatin. The recommended starting dose of simvastatin is 10 to 20 mg once daily in the evening. The recommended starting dose of pravastatin is 10 to 20 mg once daily before bedtime, with the maximum daily dose being 40 mg.
2. High-intensity HMG-CoA reductase inhibitors: They can lower a patient's LDL-C by approximately 50%. Commonly used clinically are atorvastatin and rosuvastatin. The recommended starting dose of atorvastatin is 10 mg once daily, with a maximum daily dose of 80 mg. The recommended starting dose of rosuvastatin is 5 mg once daily, with a maximum daily dose of 20 mg. Both atorvastatin and rosuvastatin can be taken once daily at any time and are not affected by food.

• Bempedoic acid: It reduces patients' LDL-C levels by about 30%. Its half-life is 21 hours. The recommended dose is 180mg taken once daily, on an empty stomach or after a meal. Common adverse reactions include upper respiratory tract infection, muscle cramps, hyperuricemia, anemia, and elevated liver enzymes. It is less myotoxic than HMG-CoA reductase inhibitors.

Drugs that promote cholesterol degradation.

The LDL receptor on the surface of liver cells binds to LDL-C and transports it to the liver cells for elimination. Therefore, the number of LDL receptors on the surface of liver cells affects the level of LDL-C in the blood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that binds to the LDL receptor. The combination of the two will degrade the LDL receptor and reduce its number.

• PCSK9 Inhibitors: They bind to PCSK9 and inhibit the binding of LDL receptors to PCSK9. It lowers LDL-C levels by increasing the number of LDL receptors. PCSK9 monotherapy can reduce patients' LDL-C by approximately 60%. Evolocumab: The recommended dose is subcutaneous injection of 140 mg once every 2 weeks or 420 mg once monthly. Alircumab: The recommended dose is subcutaneous injection of 75 mg once every 2 weeks.
• PCSK9 synthesis inhibitors: Inclisiran is a chemically modified double-stranded RNA. The synthesis of PCSK9 in the liver is directly inhibited by it. It can reduce patients' LDL-C by about 50%. Its recommended dose is 284 mg as a subcutaneous injection, with a second dose after three months and then every six months.

Angiopoietin-like protein 3 inhibitor.

Lipoprotein lipase and endothelial lipase are inhibited by angiopoietin-like protein 3. It will increase the levels of HDL-C, LDL-C and TG. 

• Evinacumab: It is a human angiopoietin-like protein 3 monoclonal antibody. Angiopoietin-like protein 3 binds to it and inhibits its activity. The levels of HDL-C, LDL-C and TG will be reduced as a result. The main cause of homozygous familial hypercholesterolemia (HoFH) is that they lack the gene that expresses low density lipoprotein receptor. It reduces the liver's ability to clear LDL-C. Since the lipid-lowering effect of evinacumab does not depend on the activity of LDL receptors, it can significantly reduce blood lipid levels in patients with HoFH. Evinacumab is used as an adjuvant treatment with other LDL-C lowering therapies. It is approved for the treatment of patients aged 12 years and older with homozygous familial hypercholesterolemia. Its recommended dose is 140 mg subcutaneously every two weeks or 420 mg subcutaneously once monthly.

Apolipoprotein B synthesis inhibitors.

• Mipomexan: It is an antisense nucleotide that binds to and degrades the messenger RNA of ApoB-100. The synthesis and transport of apolipoprotein B are therefore inhibited. Mipomexan is approved for the treatment of patients with homozygous familial hypercholesterolemia, either alone or in combination with other lipid-lowering drugs. Its recommended dose is 200 mg subcutaneously once weekly.

Microsomal triglyceride transfer protein inhibitor.

Microsomal triglyceride transfer protein exist in the microsomal lumen of liver cells and intestinal cells. It is involved in the transport of triglycerides and the assembly of very low-density lipoproteins. 

• Lomitapide: It is a microsomal triglyceride transfer protein inhibitor. It can significantly reduces the levels of LDL-C and apolipoprotein B. Its recommended starting dose is 5 mg taken orally once daily. It should not be taken with food.

Read More