When should lipid-lowering drugs be taken?⌚⌚⌚

Dyslipidemia generally refers to elevated levels of cholesterol and/or
triglycerides (TG) in the blood. It is also called hyperlipidemia. At the same time, it also includes various dyslipidemias including low high-density lipoprotein cholesterol (HDL-C). The main clinical lipid-lowering drugs currently include cholesterol absorption inhibitors, HMG-CoA inhibitors (statins), fibrates, anti-lipid peroxidation drugs (probucol), niacin drugs, and PCSK9 inhibitors. , bile acid chelators, high-purity fish oil preparations and other lipid-lowering drugs, etc.

Lipid-lowering drugs can generally be divided into three categories.

1. Drugs that mainly lower cholesterol: Such drugs include statins, cholesterol absorption inhibitors, probucol, bile acid chelators. They reduce cholesterol levels by inhibiting cholesterol synthesis in liver cells, accelerating low-density lipoprotein cholesterol (LDL-C) catabolism, or reducing intestinal cholesterol absorption.
2. Drugs mainly aimed at lowering triglycerides: These drugs include fibrates, niacin and high-purity fish oil preparations. They can lower blood levels of triglycerides in patients.
3. PCSK9-inhibitors: such as evolocumab. It prevents the degradation of LDL-receptors by inhibiting PCSK9, thereby promoting the body's clearance of LDL-C. It reduces blood levels of LDL-C and has a powerful cholesterol-lowering effect.
4. Microsomal triglyceride transfer protein inhibitors: such as lomitapide. It lowers blood levels of LDL-C.
5. Apolipoprotein B-100 synthesis inhibitors: such as mipomexan. It reduces the production and secretion of VLDL. At the same time, it will also reduce the blood level of LDL-C.

The timing of taking lipid-lowering medications.

Drugs that mainly lower cholesterol:

1. Statins: Lovastatin, simvastatin, pravastatin, fluvastatin (tablets) and other statins with short half-lives are recommended to be taken before going to bed. While cholesterol will reach its synthesis peak at night, these drugs will also reach their concentration peak. Statins with long half-lives such as fluvastatin (sustained-release preparation), atorvastatin, rosuvastatin, and pitavastatin can be taken at any time, but it is recommended that patients take them at the same time every day to avoid missing doses. 
2. Cholesterol absorption inhibitors: such as ezetimibe. It inhibits the intestinal absorption of cholesterol. Statins will have a good synergistic effect when combined with it. At the same time, it will not affect the absorption of other drugs and fat-soluble vitamins. Food will not affect its absorption. Therefore, it is generally taken once daily, with or without food.
3. Probucol: It is mainly suitable for hypercholesterolemia. It will enter the core of LDL and affect lipoprotein metabolism. LDL becomes easily eliminated through non-receptor pathways. It can also reduce xanthomas on the skin. Food increases its absorption, so patients are advised to take it with a meal. Generally, it needs to be taken twice a day, with breakfast and dinner.

Drugs mainly aimed at lowering triglycerides: 

1. Fibrates: such as bezafibrate, fenofibrate, gemfibrozil. Bezafibrate generally needs to be taken with or after meals. To reduce stomach upset caused by fenofibrate, it is recommended to take it with food. Gemfibrozil is generally taken twice daily, and it is recommended to take it 30 minutes before breakfast and dinner. Additionally, when they are combined with statins, it is recommended to take fibrates in the morning and statins at bedtime. This reduces the occurrence of drug interactions.
2. Niacin drugs: This type of drugs includes acipimox and niacin extended-release tablets. The usual dose of acipimox is two or three times a day, taken with or after meals. Acipimox dispersible tablets need to be taken after meals. The usual dose of niacin extended-release tablets is once daily, taken before bed.

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What is the difference between the new hypolipidemic agents alirocumab and evolocumab?😵😵😵

A new type of hypolipidemic agent that is a PCSK9 inhibitor developed in
recent years. It is effective in lowering low-density lipoprotein cholesterol (LDL-C) levels alone or in combination with statins. Alirocumab and evolocumab (both are injections) are two commonly used PCSK9 inhibitors in clinical practice.

How does the body clear LDL-C?

LDL-C is transported from surrounding tissues to the liver by high-density lipoprotein cholesterol (HDL-C). After they reach the liver, they will bind to the LDL receptors on the liver cells and be transported into the liver cells. LDL-C is degraded and metabolized in liver cells.

What is PCSK9?

Proprotein Convertase Subtilisin/Kexin Type 9 is the full name of PCSK9. It degrades LDL receptors by binding to LDL receptors on the surface of liver cells. It reduces the number of LDL receptors on the surface of liver cells and prevents the removal of LDL-C from the blood.

How do PCSK9 inhibitors lower blood lipids?

PCSK9 is specifically bound by PCSK9 inhibitors so that it cannot bind to LDL receptors. Thus, the degradation of LDL receptor caused by PCSK9 is inhibited. This can increase the number of LDL receptors on the surface of liver cells and enhance the effect of clearing LDL-C in the blood.

What is the approximate strength of lipid-lowering effect of PCSK9 inhibitors?

PCSK9 inhibitors such as alirocumab and evolocumab have strong cholesterol-lowering effects. LDL-C can be lowered by about 50 to 70% by them. Several commonly used lipid-lowering regimens and their magnitude of lowering LDL-C:

• Ezetimibe: It lowers LDL-C by about 20% on average.
• Moderate-strength statins (such as simvastatin and pravastatin): They lower LDL-C by about 30% on average.
• High-intensity statins (such as atorvastatin and rosuvastatin): They lower LDL-C by about 50% on average.
• Monotherapy with PCSK9 inhibitors: They reduce LDL-C by about 60% on average.
• High-intensity statin + Ezetimibe: They reduce LDL-C by about 65% on average.
• High-intensity statin + PCSK9 inhibitor: They reduce LDL-C by about 75% on average.
• High-intensity statin + PCSK9 inhibitor + Ezetimibe: They reduce LDL-C by about 85% on average.

Usage and dosage of PCSK9 inhibitors.

Both alirocumab and evolocumab are given subcutaneously. Alirocumab is injected every 2 weeks and evolocumab is injected monthly. 

	Alirocumab	Evolocumab
Common dosage forms	Single-dose prefilled injection pen
	75mg/1ml/pen 150mg/1ml/pen	140mg/1ml/pen
Dosage	Subcutaneous injection: Upper arms, abdomen or thighs.
	1 time every 2 weeks, 75 to 150mg each time.	1 time per month, 420mg each time.
Storage	Store away from light at 2 to 8oC. They should not be refrigerated and shaken. Return to room temperature for at least 30 minutes before use. It can be stored at room temperature (25 oC) for up to 30 days when the patient travels.

What are their side effects?

1. Common adverse reactions of PCSK9 inhibitors include: 

Influenza, nasopharyngitis, upper respiratory infection, back pain. In addition, there may be pain, erythema and bruising at the injection site.

2. Specific adverse reactions of PCSK9 inhibitors are:

PCSK9 inhibitors, like other therapeutic protein drugs, may cause immune reactions. Clinical studies have pointed out that in patients with neutralizing antibodies, the long-term lipid-lowering effect of the drug will not be affected. However, they have an increased incidence of local injection reactions.

What is the difference between the adverse effects of PCSK9 inhibitors and statins?

Muscle toxicity: PCSK9 inhibitors did not increase the incidence of muscle-related adverse reactions in the current clinical research performance. They have the opportunity to become a new option for lipid-lowering therapy in patients with muscle-related adverse events on statins.

Hepatotoxicity: PCSK9 inhibitors did not significantly increase liver function damage compared with placebo in the current clinical research performance. Therefore, no dosage adjustment is required for their use in patients with mild or moderate hepatic impairment.

Blood glucose changes in patients: PCSK9 inhibitors did not accelerate the transformation of prediabetic patients to diabetes in current clinical studies. They also did not affect fasting blood glucose and glycated hemoglobin levels in non-diabetic patients. The incidence of dysglycemic events was not increased by the use of PCSK9 inhibitors.

What are the clinical applications of PCSK9 inhibitors?

For patients who are intolerant to statins or have contraindications, PCSK9 inhibitors can be used alone or in combination with other lipid-lowering drugs.

PCSK9 inhibitors combined with maximally tolerated doses of statins can further reduce the risk of cardiovascular events in patients with atherosclerotic cardiovascular disease.

If after four to six weeks of treatment with statins combined with ezetimibe in patients with ultra-high-risk atherosclerotic cardiovascular disease, the patient's LDL-C does not reach the treatment target (LDL-C<1.4mmol/L), it is recommended to add PCSK9 Inhibitors.

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Learning about ezetimibe.📜📜📜

Ezetimibe was the first drug to inhibit cholesterol absorption in the gut. It can be combined with statins to enhance the ability to lower cholesterol levels. It is widely used clinically. The following will introduce the relevant knowledge about ezetimibe.

1. The mechanism of ezetimibe.

Ezetimibe is converted to ezetimibe-glucuronide in the intestinal tract. Ezetimibe-glucuronide acts at the brush border of intestinal epithelial cells. It inhibits the activity of the sterol carrier transporter NPC1L1, thereby reducing intestinal absorption of cholesterol.

Dosage: Once a day, 10mg ezetimibe each time. Ezetimibe can be taken any time of the day. It can also be taken on an empty stomach or with food.

2. The enterohepatic circulation of ezetimibe.

First, ezetimibe is converted to ezetimibe-glucuronide in the intestine. It then travels from the portal vein to the liver and from the liver to the bile. Finally it goes back into the intestines. Enterohepatic circulation maintains ezetimibe-glucuronide in the brush border of intestinal epithelial cells. It can inhibit the intestinal absorption of cholesterol. In addition, enterohepatic circulation can also slow the elimination of ezetimibe-glucuronide. Its half-life is 22 hours.

3. The lipid-lowering intensity of ezetimibe.

Cholesterol in the human body can be divided into endogenous synthesis by the body and exogenous absorption in the diet. About 2/3 of cholesterol is synthesized endogenously and 1/3 of cholesterol is absorbed exogenously. 

Ezetimibe alone can reduce low-density lipoprotein cholesterol (LDL-C) by about 20%. 

	Total cholesterol (TC)	Low-density lipoprotein cholesterol (LDL-C)	High-density lipoprotein cholesterol (HDL-C)	Triglycerides (TG)
Ezetimibe	13%↓	18%↓	8%↓	1%↑
Pravastatin	17%↓	25%↓	8%↓	7%↑
Simvastatin	26%↓	36%↓	17%↓	7%↑
Atorvastatin	32%↓	44%↓	25%↓	4%↑

From the above table, it can be seen that statins have stronger lipid-lowering intensity than ezetimibe. Therefore, ezetimibe is often used in combination with statins to further reduce LDL-C.

	Lipid-lowering treatment plan	Reduced levels of LDL-C
Monotherapy	Ezetimibe	20%
	Moderate-intensity statins (eg, simvastatin, pravastatin)	30%
	High-intensity statins (eg, atorvastatin, rosuvastatin)	50%
	PCSK9 inhibitors (eg, evolocumab, alirocumab)	60%
Combination therapy	High-intensity statin + Ezetimibe	65%
	High-intensity statin + PCSK9 inhibitor	75%
	High-intensity statin + PCSK9 inhibitors + Ezetimibe	85%

4. Adverse reactions.

Because ezetimibe is not metabolized by CYP450 enzymes, it is less likely to have drug interactions. Ezetimibe was well tolerated and safe. Its adverse effects are mild and mostly transient. Its main adverse reactions are gastrointestinal discomfort and headache. In addition, side effects such as muscle pain and increased transaminases can occur when it is used in combination with statins.

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