Statins (HMG-CoA reductase inhibitors). Drug lipid-lowering therapy Functions of HDL in the blood

28. Describe the mechanism of action of HMGCoA reductase inhibitors (for example, simvastatin, atorvastatin).

These substances dose-dependently inhibit HMG-CoA reductase, which is necessary for the conversion of 3-HMG-CoA to the cholesterol precursor mevalonate (see.

Figure 37). This reduces the production of LDL and the formation of atherosclerotic plaques.

29. Discuss the effect of statins (eg, pravastatin, lovaspmin) on the thickness of the inner and middle tunica of the coronary arteries

It has been shown that substances of this group, with long-term use, significantly reduce the thickness of the inner and middle lining of the arteries. Accordingly, the frequency of strokes and heart attacks and mortality from them are reduced.

30. Discuss the side effects of HMG CoA reductase inhibitors.

Side effects include dyspepsia, constipation and flatulence. More serious complications have also been described - blockage of the renal tubules, rhabdomyolysis and myopia. Most often this is observed with the simultaneous use of drugs, brake *"

Megabolism of HMG-CoA reductase inhibitors (for example, systemic anti- ® 0A - drugs or macroscopic antibiotics), as well as during consumption

ev. There may also be an increase in liver enzyme levels (eg

mer, transaminases).

31. Discuss the interaction of calcium channel blockers with HMG-CoA reductase inhibitors.

Verapamil and diltiazem, acting on cytochrome SURZA4, inhibit the metabolism of HMG-CoA reductase inhibitors during their first passage through the liver.

32. Why are grapefruit contraindicated when using statins?

33. Describe the effect of pravastatin on HDL levels.

Pravastatin has been shown to increase HDL levels in patients with heterozygous familial and non-familial hypercholesterolemia and mixed dyslipidemia, as well as dyslipoproteinemia types 2a and 26 (Frederickson classification)

More on the topic HMG-CoA REDUCTASE INHIBITORS:

1. C10. HYPOLYPIDEMIC CONDITIONS.S10A. DRUGS THAT REDUCE THE CONCENTRATION OF CHOLESTEROL AND TRIGLYCERIDES IN BLOOD SERUM. C10AA. Inhibitors of HMG CoA reductase
2. Disorders of mitochondrial beta-oxidation of fatty acids Medium-chain acyl-CoA dehydrogenase deficiency

HMG-CoA reductase:

1) increase a) insulin

2) decrease b) glucagon

c) glucocorticoids

d) mevalonate

d) cholesterol

CHOOSE THE CORRECT ANSWER.

The mechanism of regulation of HMG CoA reductase by cholesterol:

a) allosteric activation

b) covalent modification

c) induction of synthesis

d) repression of synthesis

e) activation by protector

Test 18.

CHOOSE THE CORRECT ANSWER.

Coenzyme HMG CoA reductase(cholesterol synthesis) is:

b) NADPH +H +

c) NADH +H +

e) biotin

Test 19.

CHOOSE THE CORRECT ANSWER.

The mechanism of regulation of the synthesis of B 100, E-receptors for LDL cholesterol:

a) allosteric activation of a regulatory enzyme

b) covalent modification

c) induction of synthesis

d) repression of synthesis

e) inhibition of the regulatory enzyme by an allosteric mechanism

Test 20.

CHOOSE THE CORRECT ANSWER.

Synthesis intermediate Cholesterol is used by the body to synthesize:

a) purines

b) pyrimidines

c) coenzyme Q

d) ornithine

e) thiamine

Test 21.

ADD ANSWER.

Regulatory enzyme for cholesterol conversion in bile acids is ________________.

Test 22.

Cholesterol synthesis in the liver increases with a diet rich in:

a) proteins

b) carbohydrates

c) animal fats

d) vegetable oils

d) vitamins

ESTABLISH STRICT COMPLIANCE.

Enzyme: Process:

1) 7a cholesterol hydroxylase a) synthesis of cholesterol esters in the cell

2) ACHAT b) synthesis of cholesterol esters in the blood

on the surface of HDL

3) 1acholesterol hydroxylase c) synthesis of bile acids in the liver

4) LCAT d) synthesis of steroid hormones

e) formation of the active form

vitamin D 3 in the kidneys

CHOOSE THE CORRECT ANSWER.

Triglycerides of chylomicrons and VLDL are hydrolyzed:

a) pancreatic lipase

b) triacylglyceride lipase

c) lipoprotein lipase

ADD ANSWER.

ADD ANSWER.

Statins reduce the activity of HMG-CoA reductase by the mechanism of ______________ ____________ inhibition.

MATCH

(for each question there are several correct answers, each answer can be used once)

ESTABLISH THE CORRECT SEQUENCE.

The release of cholesterol from the liver into peripheral tissues:

a) formation of LDL

b) attachment of Apo C to VLDL in the blood

c) formation of VLDL

d) action of lipase lipase

e) capture of lipoproteins by specific tissue receptors

CHOOSE ALL CORRECT ANSWERS.

Functions of HDL in the blood:

a) transport of cholesterol from extrahepatic tissues to the liver

b) supply of apoproteins to other drugs in the blood

c) antioxidant functions in relation to modified LDL

d) take up free cholesterol and transfer cholesterol esters

LP in the blood

e) transport of cholesterol from the liver to peripheral tissues

CHOOSE ALL CORRECT ANSWERS.

Risk factors for the development of atherosclerosis are:

a) hypercholesterolemia

b) smoking

c) high blood pressure

d) weight loss

e) physical inactivity

Answers on the topic: “CHOLESTEROL METABOLISM. Lipoproteins”

1. d 2 . b 3 . A 4. A

5. b 6. V 7. G 8 . d

9. b 10 .G 11 . b,c,d 12 . a,b,d,e

13. a,b,d,e 14 . 1c,2a,3d,4b

15. mevalonate, HMGCoA reductase

16. 1a 2bvgd

21. 7α-cholesterol hydroxylase

22. b,c

23. 1c, 2a, 3d, 4b

25. increases

26 . competitive reversible

27. 1ad 2bvg

28. vbgad

29. a B C D

30. a,b,c,d

1. Topic 20. Lipid disorders

Independent work of students during class time

Venue: Department of Biochemistry

Lesson duration – 180 min.

2. Purpose of the lesson: teach students to independently work with special and reference literature on the proposed topic by solving situational problems, speak reasonedly on specific issues, discuss among their colleagues and answer their questions; consolidate knowledge on the topic “Chemistry and lipid metabolism.”

3. Specific tasks:

3.1. The student must know:

3.1.1. Structure and properties of lipids.

3.1.2. Digestion of lipids in the gastrointestinal tract.

3.1.3. Tissue metabolism of fatty acids (oxidation and synthesis).

3.1.4. Metabolism of ketone bodies.

3.1.5. Synthesis of triglycerides and phospholipids.

3.1.6. Interconversion of nitrogenous alcohols.

3.1.7. Cholesterol exchange. Cholesteryl ester exchange.

3.1.8. The TCA cycle is a single pathway for the metabolism of lipids, carbohydrates and proteins.

3.2. The student must be able to:

3.2.1. Analyze, summarize and present literature materials.

4. Motivation: the ability to correctly adapt materials from reference books and journal articles is necessary for the work of a future specialist; knowledge of lipid metabolism, metabolism of ketone bodies, cholesterol in normal conditions and in pathology is mandatory for the practical work of a doctor.

5. Self-preparation task: Students should study the recommended literature using self-study questions.

Main:

5.1.1. Lecture material and materials of practical work on the topic "Lipids".

5.1.2. Berezov T.T., Korovkin B.F. "Biological chemistry". – M., Medicine. – 1998. - P.194-203, 283-287, 363-406.

5.1.3. Biochemistry: Textbook / Ed. E.S. Severina. – M.: GEOTAR-Med., 2003. – P.405-409, 417-431, 437-439, 491.

Additional:

5.1.4. Klimov A.N., Nikulcheva N.G. Metabolism of lipids and lipoproteins and its disorders. Guide for doctors, St. Petersburg. – 1999. – Peter. - 505 s.

5.2. Prepare for test control.

6. Questions for self-preparation:

6.1. The synthesis of ketone bodies and their use by the body is normal.

6.2. The concept of ketoacidosis. Reasons for the formation of ketosis, protective

mechanisms that prevent fatal consequences for the body.

6.3. What is b-oxidation of fatty acids. Necessary conditions for

process.

6.4. Phospholipid synthesis. Possibilities of synthesis in the body.

6.5. Interconversion of nitrogenous alcohols.

6.6. Sphingolipidoses, gangliosidoses. The reasons leading to them

occurrence.

6.7. Digestion of lipids in the gastrointestinal tract.

6.8. Bile acids. Structure and functions in the body.

6.9. Cholesterol. Causes of increased blood cholesterol levels. Synthesis, breakdown and transport of cholesterol.

6.10. The concept of lipoproteins.

6.11. Reasons for the development of atherosclerosis

6.12. Lipid peroxidation and bioantioxidants.

6.13. Transformations of arachidonic acid in the body.

The results of controlled clinical studies using statins indicate that these drugs have a lipid-lowering effect, reduce cardiovascular and overall mortality, improve the quality of life and prognosis of patients with coronary heart disease (CHD) and atherosclerosis.

In modern conditions, with the use of atorvastatin and rosuvastatin, the possibility of stabilization and reverse development of atroscalerotic plaques in the coronary arteries has been demonstrated. The results of clinical studies of statins in recent years have demonstrated their effectiveness and safety in patients with arterial hypertension, type 2 diabetes mellitus, and acute coronary syndrome.

The classification of HMG-CoA reductase inhibitors is based both on differences in statins in the chemical structure (Medicines obtained by fermentation of mushrooms and synthetic statins) and on the time of start of use in clinical practice (statins I-IV generations).

All statins are produced and used in tablet form. As a rule, statins are prescribed once, usually before bedtime, due to the fact that cholesterol synthesis occurs most intensively at night.

Atorvastatin and rosuvastatin can be used at any time of the day.

• Lovastatin (Mevacor, Medostatin, Holetar) - initial dose 20 mg once a day immediately after dinner; In most cases, the target LDL cholesterol level can be achieved with a dose of 40 mg/day. Currently, lovastatin is practically not used due to the emergence of more modern statins.
• Simvastatin (Zocor, Actolipid, Atherostat, Vasilip, Vero-simvastatin, Zovatin, Zorstat, Levomir, Simvahexal, Simvacard, Simvacol, Simvastatin-Verte, Simvalimit, Simvastol, Simvor, Simgal, Simlo) - in terms of equivalence, it is twice as strong as lovastatin, that is, taking 10 mg/day. Simvastatin produces the same reduction in LDL cholesterol as lovastatin 20 mg/day. The initial dose is 10-20 mg 1 time per day; the target content is usually achieved at 40 mg; the maximum dose is 80 mg (in practice it is rarely used due to the high risk of complications - increased liver enzymes, myopathy and rhabdomyolysis).
• Pravastatin (Lipostat) is prescribed in a dose of 20-40 mg/day. Any time of the day. The 80 mg dose has not been studied and is not commonly used.
• Fluvastatin (Leskol, Leskol XL - prescribed at a dose of 20-40 mg/day, but more often in the form of a slow release of 80 mg once a day. Taking into account the characteristics of pharmacokinetics (high selectivity of action in the liver and metabolism through the 2C9 isoform of cytochrome P-450), Fluvastatin is prescribed to patients after organ transplantation who are receiving cytostatics.
• Atorvastatin (Liprimar, Atoris, Liptonorm, Torvacard, Tulip) is a third-generation synthetic statin. It is twice as effective as simvastatin and fluvastatin. Therapy begins with a dose of 10-20 mg/day; if there is no effect, the dose can be increased to 40 mg to achieve the target level. For patients with acute coronary syndrome or those classified as very high risk, based on the results of studies on “aggressive” lipid-lowering therapy (IDEAL, REVERSAL, MIRACLE, PROVE-IT TIM122), atorvastatin is recommended to be prescribed at a dose of 80 mg/day.
• Rosuvastatin (Crestor) is equivalent in effectiveness to atorvastatin. This is the newest of the drugs presented, and many large-scale studies on its use have not yet been completed (GALAXY, JUPITER, CORONA, AURORA). However, already completed studies (STELLAR, MERCURY I,II, ASTEROID, METEOR, EXPLORER) have demonstrated the maximum effectiveness of the drug. Prescribed at a dose of 5-10 mg/day; the maximum dose used primarily in patients with severe familial hypercholesterolemia is 40 mg/day.

Currently, generic statins are widely used. More than 30 generic statins (reproduced copies of original drugs) are registered in Russia. All generics have been tested for bioequivalence to original drugs, however, post-registration, trial, and clinical studies have not been carried out for all generics, which, according to experts of the All-Russian Scientific Society of Cardiologists, is incorrect, since practice shows that in some cases there is no complete equivalence of generics to original drugs by the degree of change in lipid spectrum indicators.

Generic statins are used in the same doses as brand-name statins. As a rule, their lipid-lowering activity is not inferior to the original drugs, but they are less expensive, which to some extent helps to solve the problem of their accessibility to a wider range of patients.

Statins are well tolerated - according to clinical studies, they are one of the safest classes of drugs.

Occasionally, taking statins may be accompanied by abdominal pain, flatulence, and constipation.

An increase in the activity of the liver enzymes ALT, AST, is observed in 1-5% of patients taking statins. In the usual practice of using each statin in monotherapy, the first monitoring of enzyme activity is prescribed 1 month from the start of treatment, and then every 3-6 months.

If the activity of at least one of the listed enzymes on two consecutive measurements exceeds 3 times the upper limits of normal values, the statin should be discontinued. In cases of a more moderate increase in enzyme levels, it is sufficient to limit the dose to a reduction in the drug.

Enzyme levels usually return to normal within a short time, and treatment can be restarted with either the same drug at a lower dose or a different statin.

According to modern concepts, statin therapy can be recommended for patients with chronic liver diseases, non-alcoholic steatohepatitis, fatty infiltration of the liver, subject to careful monitoring of the activity of liver enzymes.

It is extremely rare that when taking statins, fatigue, sleep disturbances, taste disturbances, itchy skin, headaches, and dizziness may occur; possible teratogenic effect.

Rarely (0.1-3%) when taking statins, myopathy and myalgia are observed, which are manifested by pain and weakness in the muscles, are accompanied by an increase in CPK activity by more than 5 times and require discontinuation of the drug.

The most dangerous complication of statin therapy—rhabdomyolysis, or the breakdown of muscle tissue with possible damage to the renal tubules—occurs in cases where the presence of myopathy is not diagnosed in time and statin treatment is continued if it is present.

Rhabdomyolysis is a severe, life-threatening complication, accompanied by myalgia, myopathy, muscle weakness, an increase in CPK levels by more than 10 times, an increase in creatinine and darkening of the color of urine due to myoglobinuria.

If rhabdomyolysis occurs, statins should be stopped immediately. Urgent hospitalization of the patient is required. In particularly severe cases of rhabdomyolysis (renal failure), extracorporeal blood purification methods are used for its treatment - plasmapheresis and hemodialysis.

Rhabdomyolysis is more often observed with the simultaneous administration of statins with fibrates, cytostatics, and macrolide antibiotics; in these cases, patients should be under careful, intensive medical supervision with monitoring of all listed enzymes at least once a month.

The reason for the more frequent occurrence of complications with this combination is due to the fact that the metabolism of lovastatin, simvastatin, and atorvastatin occurs through the cytochrome-450 system and its isoform 3A4. Competitive binding of the enzyme leads to an increase in the concentration of statins in the blood plasma and, consequently, to an increase in their myotoxic properties.

The table shows through which enzyme isoforms of cytochrome P-450 the metabolism of various statins occurs, as well as a list of the main drugs of other classes, the metabolism of which is carried out through the same isoforms.

Cytochrome P 3A4	Cytochrome P 2C9
Cyclosporine	Atenolol
Erythromycin	Diclofenac
Felodipin	Hexobarbital
Lidocaine	N-desmethyldiazepam
Mibefradil	Tolbutamide
Midazolam	Warfarin
Nifedipine
Quinidine
Terbinafine
Triazolam
Verapamil
Warfarin

If it is necessary to combine these drugs with statins, especially potent ones, a minimum dose of statins should be prescribed and the levels of liver enzymes and creatine phosphokinase (CPK) should be carefully monitored at least once a month.

Particular caution must be observed if the patient experiences a severe injury during treatment with statins, undergoes major abdominal surgery, or has endocrine or electrolyte disturbances.

• Statins interact with the following drugs: antacids, antipyrine, colestipol, digoxin, erythromycin, clarithromycin, azithromycin, hormonal contraceptives, amlodipine, proteinase inhibitors.

  Drug interactions of statins.

  Interacting drugs	Statins	Result of interaction
  Antifungal drugs - azole derivatives (ketoconazole, itraconazole)	Lovastatin, simvastatin, atorvastatin, rosuvastatin
  Immunosuppressants (cyclosporine)	Simvastatin, fluvastatin, pravastatin, rosuvastatin	Increased risk of developing myopathy and rhabdomyolysis
  Fibrates	Lovastatin, fluvastatin, atorvastatin, rosuvastatin	Increased risk of developing myopathy
  A nicotinic acid

Dyslipoproteinemia- a very important avoidable risk factor for atherosclerosis. The level of total cholesterol and LDL cholesterol is directly proportional to the risk of coronary artery disease. It is an independent and powerful risk factor, the significance of which has been clearly demonstrated for men and women of all ages. More than half of American adults (102 million) have total cholesterol levels greater than 200 mg% (5.2 mmol/L), of which 40% (41 million) have levels greater than 240 mg% (6.2 mmol/L) . On average, a 1% increase in LDL cholesterol leads to a 2-3% increase in the risk of coronary artery disease.

Lipoproteins are macromolecular complexes involved in the transport of cholesterol and triglycerides. They consist of a lipid core formed by triglycerides and cholesteryl esters, and a hydrophilic shell of phospholipids and special proteins - apoproteins. Lipoproteins are represented by five main groups: chylomicrons, VLDL (very low density lipoproteins), ILDL (intermediate density lipoproteins), LDL (low density lipoproteins) and HDL (high density lipoproteins).

Apoproteins play a structural role and are involved in lipid metabolism. Apoprotein AI is an important component of HDL, and apoprotein B is the main apoprotein of the remaining lipoproteins (non-HDL).

Despite the abundance of data on the benefits of lipid-lowering therapy, many patients with dyslipoproteinemia do not receive treatment. The Third National Educational Program on Hypercholesterolemia recommends choosing treatment tactics depending on the risk of cardiovascular complications.

Primary prevention of coronary artery disease: recommendations of the Third National Educational Program on Hypercholesterolemia

Cholesterol level measurement

Measurement of the levels of total cholesterol, LDL cholesterol and HDL cholesterol in persons over 20 years of age without coronary artery disease and other manifestations of atherosclerosis is carried out every 5 years. If, in a non-fasting test, the total cholesterol level exceeds 200 mg% (5.2 mmol/l) or the HDL cholesterol level does not exceed 40 mg% (1.0 mmol/l), test
repeat on an empty stomach.

Plasma lipoprotein levels are normal in hyperlipoproteinemia (in accordance with the recommendations of the Third National Educational Program on Hypercholesterolemia)

Risk assessment

The risk of cardiovascular complications depends on the presence of coronary artery disease and other manifestations of atherosclerosis, diabetes mellitus (which is considered equivalent to coronary artery disease) and other risk factors, which include age (over 45 years for men and 55 years for women), smoking, arterial hypertension (BP). more than 140/90 mm Hg or reception
antihypertensive drugs), family history (coronary artery disease in first-degree relatives under the age of 55 years in men or under 65 years in women) and cholesterol levels
HDL less than 40 mg% (1.0 mmol/l). An HDL cholesterol level of 60 mg% (1.6 mmol/L) or more is called a negative risk factor because it balances one risk factor.

Taking into account risk factors, patients are divided into three groups.
The highest risk group includes patients with coronary artery disease, non-coronary atherosclerosis, diabetes mellitus, or multiple risk factors and a 10-year risk of cardiovascular events greater than 20%. Manifestations of non-coronary atherosclerosis include: abdominal aortic aneurysm, peripheral artery disease and carotid artery stenosis with clinical manifestations. The ten-year risk of cardiovascular complications is calculated using the Framingham scale. The target LDL cholesterol level for these patients is less than 100 mg% (2.6 mmol/L).

The average risk group includes people with multiple risk factors and a ten-year risk of cardiovascular complications of no more than 20%. The target LDL cholesterol level for these patients is less than 130 mg% (3.3 mmol/L).

The low-risk group includes individuals with no more than one risk factor and a ten-year risk of less than 10%. The target LDL cholesterol level for these patients is less than 160 mg% (4.1 mmol/L).

Treatment of dyslipoproteinemia depending on the risk group

Treatment consists of lifestyle changes and lipid-lowering medications. In most cases, achieving LDL cholesterol goals requires both.

High risk group

In patients with coronary artery disease or its equivalent, the risk of complications is the highest, which means that the benefit of lipid-lowering therapy is greatest for them. If the LDL cholesterol level is 130 mg% (3.3 mmol/l) or more, taking an HMG-CoA reductase inhibitor and changing lifestyle are indicated. If your LDL cholesterol level is 100-130 mg% (2.6-3.3 mmol/L), there are three options:

• lifestyle changes and taking an HMG-CoA reductase inhibitor

• Lifestyle changes focusing on weight loss and vigorous exercise to improve HDL cholesterol levels

• taking other lipid-lowering agents, such as fibric acid derivatives and niacin (this is advisable if HDL cholesterol is low or triglyceride levels are high).

If the LDL cholesterol level does not exceed 100 mg% (2.6 mmol/l), only lifestyle changes are indicated. Following publication of these recommendations, the HPS study was completed and showed that simvastatin 40 mg/day improved survival regardless of baseline LDL cholesterol. Therefore, it is believed that all patients with coronary artery disease or its equivalent, regardless of LDL cholesterol levels, are advised to take an HMG-CoA reductase inhibitor and lifestyle changes.

Intermediate risk group (10-year risk of cardiovascular complications 10-20%)

The target LDL cholesterol level in this group is below 130 mg% (3.3 mmol/L). They start with lifestyle changes. If the LDL cholesterol level exceeds 160 mg% (4.1 mmol/L), drug treatment is immediately indicated.

Low-risk group (ten-year risk of cardiovascular complications less than 10%, no more than one risk factor for atherosclerosis)

A change in lifestyle is indicated. The target LDL cholesterol level is below 160 mg% (4.1 mmol/L). Drug treatment is indicated if after 3 months the LDL cholesterol level exceeds 160 mg% (4.1 mmol/L) despite lifestyle changes. In addition, it is indicated when the initial LDL cholesterol level is more than 190 mg% (4.9 mmol/l). Drug treatment is advisable if the ten-year risk of cardiovascular complications is close to 10%, with early coronary artery disease in the family history, with very low HDL cholesterol levels, with arterial hypertension that is difficult to treat, and also if the patient smokes a lot.

Lifestyle change

Lifestyle changes include increasing physical activity, maintaining an ideal weight, and following a diet limiting saturated fatty acids (less than 7% of total calories) and cholesterol (less than 200 mg/day). These and other measures to reduce cholesterol levels are listed in the table.

Consumption of trans fatty acids should be kept to a minimum. Reducing the proportion of saturated fatty acids in your total fat intake is more important than reducing your fat intake altogether. With the syndrome of multiple metabolic disorders, the proportion of fats in the diet should be 30-35%, this helps to normalize lipid metabolism and eliminate other metabolic disorders. Excess carbohydrates in the diet may worsen the lipid profile of these patients. Carbohydrates should come primarily in the form of polysaccharides, which are found in whole grains, fruits and vegetables. Consumption of soluble fiber (5-10 g/day) reduces LDL cholesterol by about 5%, and plant sterols and stanols by another 6-15%. Lifestyle changes can reduce LDL cholesterol by up to 30%, but it requires a lot of willpower. Lifestyle changes should be the basis of any prevention. LDL cholesterol levels are determined after following the diet for 6 weeks. If the desired result is not achieved, they switch to an even more strict diet and add plant sterols and stanols. A nutritionist can provide valuable assistance at this stage. If results cannot be achieved within 3 months, drug treatment is started.

HMG-CoA reductase inhibitors (statins)

HMG-CoA reductase inhibitors reduce LDL cholesterol and reduce mortality, which is why they are used first.
In the Third National Educational Program on Hypercholesterolemia, these drugs are considered as the drugs of choice. These include drugs such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin.

Efficiency

If diet alone is not enough, HMG-CoA reductase inhibitors can significantly reduce the level of total cholesterol and LDL cholesterol in mixed hyperlipoproteinemia (that is, with increased levels of cholesterol and triglycerides). The most effective inhibitors of HMG-CoA reductase for hypercholesterol-
mii. They reduce total cholesterol by 15-60% and LDL cholesterol by 20-60%, while increasing HDL cholesterol by 5-15%. Apoprotein B levels decrease to approximately the same extent as LDL cholesterol.

Triglyceride levels are reduced by 10-25%. Apparently, HMG-CoA reductase inhibitors have almost no effect on the level of apoproteins AI, AN and lipoprotein(a). Lovastatin, simvastatin, pravastatin, and fluvastatin are well tolerated and appear to be approximately equally safe.

Side effects

HMG-CoA reductase inhibitors are generally very safe, and adverse reactions are very rare. However, they are contraindicated during pregnancy.

Mild adverse reactions

Mild gastrointestinal disturbances most often occur; nausea, abdominal pain, diarrhea, constipation and flatulence. In addition, headache, fatigue, itching and myalgia are possible, but these side effects usually do not require discontinuation of the drug.

Liver dysfunction

A slight transient increase in the activity of liver enzymes is possible when prescribing any HMG-CoA reductase inhibitor. Significant increases in liver enzyme activity are rare; in the HPS study, it was necessary to stop taking the drug due to increased ALT activity in only 0.5% of cases. On average, when the dose of an HMG-CoA reductase inhibitor is doubled, the risk of increased aminotransferase activity increases by 0.6%. The drug is discontinued if aminotransferase activity is three times higher than normal. After discontinuation of the drug, liver enzyme activity usually normalizes within 2 weeks. After this, you can resume taking the same drug, but at a lower dose, or switch to another HMG-CoA reductase inhibitor. All patients taking HMG-CoA reductase inhibitors should periodically measure the activity of liver enzymes. This is done 6 weeks and 3 months after the start of treatment, then every 6 months. Pravastatin and simvastatin are considered the safest, so the FDA allows you to stop monitoring liver enzyme activity after 3 months of taking pravastatin and after 6 months of taking simvastatin at a constant dose.

Myopathy

Myopathy- a rare but dangerous complication of therapy with HMG-CoA reductase inhibitors. It is characterized by muscle weakness, muscle pain, and an increase in serum CPK activity more than 10 times the upper limit of normal. Measurement of CPK activity is indicated only when complaints occur. Complaints of myalgia and muscle weakness are also very common in those who do not take HMG-CoA reductase inhibitors. In the HPS study, a third of patients had similar complaints at least once. Moreover, in both groups (placebo and simvastatin), myalgia and increased CPK activity occurred equally often; Due to muscle pain, the drug had to be discontinued in 0.5% of patients, in both groups. The risk of myopathy appears to be increased in elderly and thin patients, with severe comorbidities (eg, chronic renal failure), in the perioperative period, and when taking a large number of other medications.

Drug interactions

The risk of increased CPK activity and rhabdomyolysis increases when HMG-CoA reductase inhibitors are combined with other drugs, in particular erythromycin, gemfibrozil, ketoconazole and other azoles, cimetidine, methotrexate and cyclosporine. These drugs should be combined with HMG-CoA reductase inhibitors only when absolutely necessary, while regularly measuring the activity of CPK and liver enzymes. Pravastatin and fluvastatin are less likely to interact with other drugs because they are metabolized without the participation of cytochrome P450 isoenzyme IIIA4. Among the cardiovascular drugs that inhibit this cytochrome, verapamil and amiodarone are most often used; their combination with simvastatin, atorvastatin or lovastatin may predispose to myopathy and rhabdomyolysis.

Anion exchange resins

Anion exchange resins (bile acid sequestrants) are safe agents that do not have systemic side effects. However, patients often stop taking them due to gastrointestinal disorders. Anion exchange resins reduce LDL cholesterol by 15-30%, increase HDL cholesterol by 3-5%, and do not change or slightly increase triglyceride levels. These drugs are usually used for mildly elevated LDL cholesterol levels, in young patients and women planning pregnancy, and in combination with HMG-CoA reductase inhibitors for very high LDL cholesterol levels.

During pregnancy, iron supplements and folic acid may be required simultaneously with anion exchange resins, since anion exchange resins interfere with their absorption.

A nicotinic acid

Nicotinic acid has a beneficial effect on all lipid fractions: the level of LDL cholesterol decreases by 5-25%, triglycerides by 20-25%, and HDL cholesterol increases by 15-30%. This is one of the few remedies that significantly (up to 30%) reduces the level of lipoprotein(a). Nicotinic acid, however, often causes hot flashes, itching, abdominal discomfort, impaired glucose tolerance, and hyperuricemia.

Liver damage is rare, more common when taking long-acting drugs. It is often preceded by a sharp decrease in lipid levels. Long-term use of niacin has been poorly studied. It may be useful if LDL cholesterol levels are only slightly elevated; in addition, it can be used in low doses for diabetic dyslipoproteinemia. Nicotinic acid in high doses should not be prescribed for diabetes mellitus, as well as for gout, peptic ulcers and liver diseases.

Fibric acid derivatives

Fibric acid derivatives reduce triglyceride levels by 20-50% and increase HDL cholesterol levels by 10-35%. The reduction in LDL cholesterol varies by drug and is 5-20% in the absence of hypertriglyceridemia. In a WHO study, clofibrate increased mortality compared with placebo. No such data were obtained in studies of gemfibrozil and bezafibrate. These drugs reduce the risk of complications of coronary artery disease, they are used for low HDL cholesterol. For mixed hyperlipoproteinemia, they are often combined with other lipid-lowering drugs. Fibric acid derivatives are often combined with HMG-CoA reductase inhibitors, although there is no data confirming the effectiveness of this combination, and the risk of myopathy increases. severe hypertriglyceridemia, fibric acid derivatives reduce the risk of pancreatitis.

Ezetimibe

Ezetimibe is a relatively new drug that interferes with the absorption of cholesterol by enterocytes. Ezetimibe reduces cholesterol absorption by 23-50%. When added to an HMG-CoA reductase inhibitor, ezetimibe reduces LDL cholesterol by an additional 14-20%. Although there are no large, long-term studies yet, this combination is well tolerated and promises to be effective.

Choice of lipid-lowering therapy

When choosing an HMG-CoA reductase inhibitor, you should consider how much it reduces LDL cholesterol.

Effect of HMG-CoA reductase inhibitors on LDL cholesterol levels

The dose-response relationship for most HMG-CoA reductase inhibitors is power-law: with each doubling of the dose, LDL cholesterol levels decrease by approximately 6%. Side effects of these drugs are also dose-dependent, their frequency is higher when taking high doses.

Combination of HMG-CoA reductase inhibitors with anion exchange resins

For isolated increases in LDL cholesterol, these drugs complement each other very well. This combination is also good because it does not increase the risk of side effects. Anion exchange resins rarely have systemic side effects, especially since low doses can often be used to lower LDL cholesterol. However, patients often stop taking anion exchange resins due to gastrointestinal problems. When HMG-CoA reductase inhibitors are combined with anion exchange resins, LDL cholesterol levels can be reduced by 70%, but the effect of this combination quickly reaches its limit, after which increasing the dose of either drug does not lead to a further reduction in LDL cholesterol.

Combination of HMG-CoA reductase inhibitors with nicotinic acid

The combination of HMG-CoA reductase inhibitors with nicotinic acid is good because it affects all lipid fractions. Side effects when combining these drugs occur more often, but do not enhance each other. The risk of myopathy appears to be lower than previously thought. The most serious side effect is hepatotoxicity, but its risk can be reduced by using short-acting niacin preparations. A persistent increase in aminotransferase activity by more than 3 times compared to the norm was observed when taking HMG-CoA reductase inhibitors with nicotinic acid at a dose of 2 g/day in 1% of patients.

Combination of HMG-CoA reductase inhibitors with fibric acid derivatives

The combination of HMG-CoA reductase inhibitors with fibric acid derivatives is very effective in mixed hyperlipoproteinemia. Although this combination is theoretically very attractive, its clinical effectiveness has not been proven. The risk of myopathy with this combination increases. In the first studies on this issue, the incidence of myopathy was quite high, but with modern drugs the risk of myopathy is 1%.

Combination of HMG-CoA reductase inhibitors with ezetimibe

The combination of HMG-CoA reductase inhibitors with ezetimibe has been studied in small studies. It appears to greatly reduce LDL cholesterol and is quite safe. For very high LDL cholesterol levels, this combination may become the standard of care, but so far it has been studied in a small number of patients and without assessing long-term results, so ezetimibe should be prescribed only in cases where HMG-CoA reductase inhibitors are in high doses or in combination with anion exchange resins does not help.

Literature:

B. Griffin, E. Topol “Cardiology” M. 2008