What Is the Connection Between Statins and Fibrates?

Lipid-lowering drugs are drugs that lower blood lipid levels. Blood lipids are a collective term for neutral fats (triglycerides and cholesterol) and lipids (phospholipids, lipids, sterols, steroids) in plasma, and are widely present in the human body. They are essential metabolites for life cells. Generally speaking, the main components of blood lipids are triglycerides and cholesterol.

Lipid-lowering drugs

Lipid-lowering drugs are drugs that lower blood lipid levels. Blood lipids are a collective term for neutral fats (triglycerides and cholesterol) and lipids (phospholipids, lipids, sterols, steroids) in plasma, and are widely present in the human body. They are essential metabolites for life cells. Generally speaking, the main components of blood lipids are triglycerides and cholesterol.

Chinese name

Lipid-lowering drugs

Basic explanation

Drugs that lower blood lipid levels

Lipid-lowering western medicine classification

Statins, fibrates, niacin, etc.

Blood lipid is an important substance in the human body and has many very important functions, but it cannot exceed a certain range. If there is too much blood lipid, it is easy to cause "blood thickness", which deposits on the blood vessel wall, and gradually forms small plaques (also known as "atherosclerotic plaques"). These "plaques" increase, increase, and gradually Blocking blood vessels slows blood flow, which is interrupted in severe cases. If this happens in the heart, it will cause coronary heart disease; if it happens in the brain, there will be a stroke; if it blocks the blood vessels in the fundus, it will cause vision loss and blindness; if it happens in the kidney, it will cause renal arteriosclerosis and renal failure ; Occurred in the lower limbs, limb necrosis, ulceration and so on. In addition, hyperlipidemia can induce gallstones, pancreatitis, aggravate hepatitis, cause male sexual dysfunction, and dementia and other diseases. ^[1]

The same is hyperlipidemia, which occurs in different people. Due to the differences between individuals, even if the same drug is applied, a comprehensive trade-off must be made. A treatment plan cannot be applicable to all people. Generally, clinical treatment is carried out. Instead of overemphasizing the etiology and category of hyperlipidemia, drugs are selected according to the different types of hyperlipidemia simple classification. So, how should patients with hyperlipidemia choose targeted lipid-lowering drugs?

First, medication for patients with high cholesterol

For patients with hypercholesterolemia, different cholesterol-lowering drugs can be selected according to their serum cholesterol levels. For mild to moderate hypercholesterolemia, cholesterol levels of 5.7-9.1 mmol / L, low doses are available

There are many lipid-lowering drugs commonly used in the clinic, which can be roughly divided into five categories.

1 statins

These drugs are inhibitors of intracellular cholesterol synthesis rate-limiting enzyme, namely trihydroxytrimethylglutaryl coenzyme A (HMG-CoA) reductase, and are currently the most widely used class of lipid-lowering drugs in clinical practice. Because the English names of these drugs contain "statin", they are often referred to simply as statins. Since the first statin drug, lovastatin, was approved for the treatment of hyperlipidemia in 1987, there are currently 6 statins available for clinical use in China. Statins inhibit the rate-limiting enzymes in the early stages of intracellular cholesterol synthesis, resulting in a decrease in free cholesterol in the cell and a feedback up-regulation of the expression of LDL receptors on the cell surface, thereby increasing the number and activity of LDL receptors in the cell and accelerating the circulation Clearance of Very Low Density Lipoprotein (VLDL) Residual Medium Density Lipoprotein or (IDL) and Low Density Lipoprotein (LDL). Clinical studies in the past 20 years have shown that statins are currently very important drugs for the prevention and treatment of hypercholesterolemia and atherosclerotic diseases.

At present, statins available for clinical use in China are: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and ruvastatin. Rosuvastatin. Statins reduced LDL-C by 18% to 55%; HDL-C increased by 5% to 15%; and TG decreased by 7% to 30%. Table 2 compares the effect of different doses of the first 5 statins on reducing TG and increasing TG and increasing HDL-C. Although the effects of statins on reducing TC and LDL-C were related to drug dose, they were not linearly related. When the dose of statins was doubled, the decrease in TC increased by only 5%, and the decrease in LDL-C increased by 7%. It is currently believed that the use of statins should reduce at least 30% to 40%. In addition, the domestic traditional Chinese medicine Xuezhikang capsules contain a variety of natural statins, mainly lovastatin. According to the patient's cardiovascular disease and other critical illnesses, cardiovascular risk factors, and blood lipid levels, determine whether to use lipid-lowering treatment. If medication is needed, first determine the target value of treatment. According to the difference between the level of LDL-C or TC in the patient's blood and the target value, consider whether the standard dose of one statin alone can achieve the treatment requirements. If possible, according to the characteristics of different statins (strength of action, safety, drug interactions) Role), the specific conditions of patients choose appropriate statins. If the blood LDL-C or TC level is very high, it is estimated that the standard dose of one statin alone is not enough to meet the treatment requirements, and statins can be selected in combination with other lipid-lowering drugs. The guideline emphasizes the principle of reducing and achieving treatment, and does not make recommendations for the specific dosage of various statins. In some special cases, the maximum allowable dosage of various statins, such as atorvastatin 80mg / d It can be used, but the adverse reactions of the drug need to be carefully monitored. When statins are enabled, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine creatase (CK) should be detected, and regularly monitored and reviewed during treatment. Mild transaminase elevation (less than 3 times the normal upper limit) is not considered a contraindication for treatment. Asymptomatic mild CK elevations are common. It is recommended that patients report muscle discomfort or weakness during taking statins and report brown urine in a timely manner, and further detect CK. If myositis occurs or is highly suspected, statin treatment should be stopped immediately.

2 Bate

Also known as phenoxy aromatic drugs. These drugs stimulate the expression of lipoprotein lipase (LPL), apolipoprotein A (apoA) and apolipoprotein A (apoA) genes by activating peroxidase proliferator activated receptor (PPAR), and inhibiting The expression of lipoprotein C (apoC) gene enhances the lipolytic activity of LPL, which is beneficial to remove TG-rich lipoproteins in the blood circulation, reduce plasma TG and increase HDL-C levels, promote the reverse transport of cholesterol, and make LDL The subtype changed from small and dense particles to large and loose particles.

Clinically available fibrate drugs are: fenofibrate (tablet 0.1g, tid; micronized capsules 0.2g, qd), benzabate (0.2g, tid), gefibrate (0.6 g, tid). Fibrates can reduce TC by 6% to 15%, LDL-C by 5% -20%, TG by 20% -50%, and HDL-C by 10% -20%. Its indications are hypertriglyceridemia or mixed hyperlipidemia and hypoHDL-Cemia with elevated TG. Clinical trials including HHS, VA-HIT, BIP, DAIS, FIELD, etc. have confirmed that fibrates may delay the progression of coronary atherosclerosis and reduce major coronary events.

Common adverse reactions of these drugs are indigestion, gallstones, etc., which can also cause liver enzymes and myopathy. Absolute contraindications are severe kidney disease and severe liver disease. Although gefitirozil has obvious lipid-lowering effects, it is not as safe as other fibrates. Myopathy can also occur when fibrates are used alone or in combination with statins, and liver enzymes and muscle enzymes need to be monitored when fibrates are used for safety.

3 Niacin

Niacin belongs to the B vitamins. When the dosage exceeds the dose that acts as a vitamin, it can have a significant lipid-lowering effect. The mechanism of niacin's lipid-lowering effect is not very clear, which may be related to inhibiting lipolysis in adipose tissue and reducing the synthesis and secretion of very low density lipoprotein in the liver. In addition, nicotinic acid also has the ability to promote lipoprotein lipase activity and accelerate the hydrolysis of TG in lipoproteins, so its effect of reducing TG is obvious. It is clinically observed that niacin not only lowers cholesterol and TG, but also has the effect of increasing HDL-C. At conventional doses, niacin can reduce TC by 10% to 15%, LDL-C by 15% to 20%, TG by 20% to 40%, and make HDL-C mildly to moderately increase. Therefore, this kind of drug has a wide range of applications and can be used for any type of hyperlipidemia except homozygous familial hypercholesterolemia and type I hyperlipoproteinemia. Niacin comes in two forms: immediate release and slow release. Immediate release agents have obvious adverse reactions and are generally difficult to tolerate. Sustained-release nicotinic acid tablets have significantly reduced adverse reactions and are easier to tolerate. Patients with mild to moderate diabetes continued to take it, and there were no obvious adverse reactions. Niacin can reduce TC by 5% -20%, LDL- C by 5% -25%, TG by 20% -50%, and HDL-C by 15% -35%. It is suitable for hypertriglyceridemia, low HDL-Cemia or mixed hyperlipidemia mainly with elevated TG. Clinical trials including CDP, CLAS, FATS, HATS, ARBITER2, etc. have confirmed that niacin can reduce major coronary events and possibly reduce total mortality.

The common adverse reactions of niacin include facial flushing, high blood sugar, high uric acid (or gout), and upper gastrointestinal discomfort. The absolute contraindications for this class of drugs are chronic liver disease and severe gout; the relative contraindications are ulcers, liver toxicity, and hyperuricemia. The side effects of the sustained-release preparations are light and easy to tolerate.

4Bile acid chelator

Mainly an alkaline anion exchange resin, it can bind irreversibly with bile acid in the intestine, thus blocking the enterohepatic circulation of bile acid, promoting the excretion of bile acid with the stool, and blocking the reabsorption of cholesterol in bile acid. LDL receptors on the surface of liver cell membranes are stimulated through a feedback mechanism to accelerate LDL clearance in LDL blood, resulting in a decrease in serum LDL-C levels.

Bile acid sequestrants can reduce TC by 15% to 20%, LDL-C by 15% to 30%, HDL-C increase by 3% to 5%, and have no or even a slight increase in TG. Clinical trials have confirmed that these drugs can reduce major coronary events and coronary heart disease deaths.

Common adverse reactions of bile acid chelators include gastrointestinal upset, constipation, and affect the absorption of certain drugs. The absolute contraindications of such drugs are abnormal lipoproteinemia and TG> 4.52mmol / L (400mg / dL); the relative contraindications are TG> 2.26mmol (200mg / dL).

5 Inhibition of cholesterol absorption

Such drugs mainly reduce blood lipids by inhibiting the intestinal diet and the absorption of cholesterol in bile. Currently, such drugs are rarely marketed.

Ezetimibe

Ezetimibe is a cholesterol absorption inhibitor. Fang Muchao and other male SD rats were used to study the blood lipid-lowering effect and mechanism. Total fecal cholesterol increased, indicating that ezetimibe can effectively reduce serum and liver cholesterol and promote cholesterol excretion from the intestine. Experiments have shown that ezetimibe exerts lipid-regulating effects by inhibiting the expression of CYP7A1 in the liver and NPC1L1 in the small intestine. The target of ezetimibe is NPC1L1 on the brush border of the small intestine. NPC1L1 is a transmembrane protein that is responsible for transporting cholesterol in the intestine into cells. There are at least two ways to convert cholesterol to bile acids: one is the neutral pathway, and its key enzyme is cholesterol 7 _alpha hydroxylase (CYP7A1); the second is An alternative pathway, the key enzyme of which is cholesterol hydroxylase (CYP7A1). Ezetimibe inhibits CYP7A1, that is, it inhibits the conversion of cholesterol to bile acids, thereby inhibiting the excretion of cholesterol. Therefore, it should not be used for non-dietary hypercholesterolemia patients, or it will not only fail to lower blood lipids, but also may increase blood cholesterol due to bile acid synthesis disorders.

6. Other

Antioxidant probucol: it can reduce serum TC by 20-2%, LDL-C by 5-15%, and HDL-C significantly increased (up to 25%); common adverse reactions include nausea, diarrhea, indigestion, etc. Can cause eosinophilia, elevated blood uric acid, prolonged QT interval; ventricular arrhythmia or prolonged QT interval is contraindicated. Antioxidants used in the clinic are mainly natural antioxidants and synthetic antioxidants. Natural antioxidants mainly include vitamin C, vitamin E, -carotene, etc. Compared with synthetic antioxidants, the antioxidant effect of natural antioxidants has greater limitations. For example, vitamin C is a water-soluble antioxidant, which is not easy. Combines with lipids and exerts anti-lipid oxidation effects. Vitamin E and -carotene are fat-soluble antioxidants, but are reversibly combined with oxygen free radicals. Their antioxidant capacity is weak, while probucol has a strong antioxidant capacity. It is irreversible and is 6 times more vitamin E. Therefore, studies on natural antioxidants and atherosclerosis are mostly negative, while studies on synthetic antioxidants are mostly positive.

The clinical incidence of probucol is not yet clear, but it has been reported to cause ventricular arrhythmias including apical torsional ventricular tachycardia. A recent study suggested that probucol can cause long QT syndrome, which may lead to the occurrence of malignant ventricular arrhythmias, but the incidence is very low.

Lipid-lowering drug treatment requires individualization, and safety must be monitored during treatment. Drugs and starting doses are selected based on the patient's cardiovascular condition and blood lipid levels. During drug treatment, adverse reactions must be monitored, mainly by regular monitoring of liver function and blood CK. If liver enzymes (AST / ALT) exceed 3 times the normal upper limit, dosing should be suspended. Liver function needs to be reviewed weekly after stopping the drug until it returns to normal. Patients should be asked during the medication for symptoms such as myalgia, myalgia, muscle weakness, fatigue, and fever. If the blood CK rises more than five times the normal upper limit, the drug should be discontinued. If you have any other acute or severe conditions that may cause muscle lysis during medication, such as sepsis, trauma, major surgery, hypotension, and convulsions, the medication should be suspended.