The place of angiotensin receptor blockers in the treatment of arterial hypertension. Answers on questions.

- Dear Colleagues! Today we started with cardiology, and we are again moving into this very interesting area. Our program will be continued by Professor Maksim Leonidovich Maksimov, “The place of angiotensin II receptor blockers in the treatment of arterial hypertension.” Please, Maxim Leonidovich.

Maxim Leonidovich Maksimov , professor:

– Good evening, dear colleagues! I think that today my topic “The place of angiotensin II receptor blockers in the treatment of arterial hypertension” should not begin in such a high society with the relevance of the treatment of arterial hypertension, in general. We are all well aware of the relevance of the problem of treating arterial hypertension, and we know the dangers of this disease and the risks. Therefore, I would like to focus on those drugs that are most modern and most relevant to use in this category of patients today.

Angiotensin II receptor blockers belong to the main group of antihypertensive drugs along with angiotensin-converting enzyme inhibitors, along with thiazide and thiazide-like diuretics, and calcium antagonists. But I would like to note that the most important thing is that angiotensin receptor blockers are among the three most relevant drugs that can not only attract the patient to good treatment results, but prolong the patient’s life, improve the prognosis of the patient with arterial hypertension, and not only with arterial hypertension.

ACE inhibitors, angiotensin receptor blockers and β-blockers are used today for almost any cardiovascular disease.

If we pay attention to the recommendations (Russian and European) for the diagnosis and treatment of arterial hypertension, we will see that the primary indications for prescribing angiotensin receptor blockers are almost in a leading position along with the often used angiotensin-converting enzyme inhibitors. The indications are much superior to those of β-blockers and calcium antagonists.

Of course, we began our acquaintance with angiotensin receptor blockers with a single indication - cough when taking ACE inhibitors. Today, sartans have their own advantages, their own evidentiary values, their own data from clinical studies showing that this group of drugs has its own irreplaceable emphasis on each of the pathologies. Take, for example, metabolic syndrome (diabetes mellitus), pay attention to diabetic and non-diabetic nephropathy and other diseases.

Recommendations for the selection of medications for the treatment of patients with arterial hypertension. When we look at this table, we can pay attention to the fact that angiotensin receptor blockers - in almost the majority of clinical cases of diseases associated with arterial hypertension, we can start therapy with this group of drugs along with ACE inhibitors, along with β-blockers and to some extent with thiazide diuretics.

Angiotensin II receptor antagonists are today the world leaders among antihypertensive drugs. For many years, drugs such as calcium antagonists and ACE inhibitors were in the leading position. But today, the safest and most effective drugs for the treatment of arterial hypertension, which are famous not only for their main hypotensive effect, but also for their so-called side effects, are becoming the leaders on the world market. These are cardioprotective, vasoprotective, cerebroprotective, nephroprotective effects that can be useful in a fairly wide group of different patients.

The mechanism of action of sartans is fundamentally different from ACE inhibitors, although, at first glance, we can say that these drugs are quite similar to each other. What is the difference between sartans and ACE inhibitors? The fact is that ACE inhibitors affect the transition of angiotensin I to angiotensin II through the angiotensin-converting enzyme. This reduces the content of angiotensin II in the blood plasma and tissues. But sartans block angiotensin type I receptors, thereby, without reducing the level of angiotensin II, they block its entry into this type of receptor.

Please note that along with ACE inhibitors, which may not be entirely competent in reducing the concentration of angiotensin II, which appears through alternative tissue pathways. This is the first difference. On the other hand, sartans do not reduce the amount of angiotensin II, which reaches other types of angiotensin receptors, in particular, angiotensin receptors of the second, third and other types.

If you look at the effects of blockade of AT 1 receptors, which precisely reduce, level out, blockade of angiotensin receptors, this is a decrease in the manifestations of myocardial hypertrophy, a decrease in the risk of developing arrhythmias. This is a vasoprotective effect, in particular, a decrease in the manifestation of vasoconstriction, a decrease in the activation of lipid peroxidation, and a decrease in the stimulation of atherogenesis. It is necessary to pay attention to a decrease in general neurohumoral regulation. And of course, a nephroprotective effect, such as: a decrease in fluid and sodium retention, an increase in renal blood flow, and a decrease in the phenomenon of nephroangiosclerosis.

On the other hand, β-blockers open the way to excite angiotensin type II receptors, where angiotensin II is fully revealed in effects such as preventing activation of the sympathoadrenal system, reducing insulin resistance, blocking aldosterone synthesis, preventing hypertrophy and fibrosis. In the vascular bed, vasodilation and improvement of endothelial function are noted, and the development of atherogenesis is prevented. It is important in the nephroprotective function - we see a decrease in albuminuria, a decrease in pressure in the renal glomerulus, an increase in natriuresis and also a decrease in new cases of type 2 diabetes mellitus.

Valsartan is one of the leading drugs in the group of angiotensin receptor blockers. Today it is the world leader among sartans. “Valsartan” is a drug that has a fairly serious history, both in terms of the time of its discovery and synthesis, and in the studies that have been and are being carried out on this drug all over the world. Today, Valsartan is the most studied angiotensin receptor blocker, ahead of Telmisartan and far ahead of other groups of sartans, such as Lazortan, Candesartan and other sartans.

Today, Valsartan has noted its positive presence in more than 150 clinical studies, almost 100 thousand patients are participants in international clinical randomized studies. Therefore, we can say with absolute certainty that Valsartan is of significant interest for modern cardiology and therapy. Unlike other sartans and, in particular, ACE inhibitors, Valsartan blocks the effects of AT1 receptors most pronouncedly, 20 thousand times more than it blocks AT2 receptors. That is, it is a highly selective blocker of type 1 angiotensin receptors. This is a non-competitive drug, therefore, it does not change its action depending on the level of angiotensin II. And also its action determines the two-hour presence of the effects of blockade of angiotensin receptors, in contrast to ACE inhibitors, which cannot block all pathways of AT2 formation. This effect is also called the “ACE inhibitor escape effect.” We can clearly note that sartans are their class, their effect, but “Valsartan” here, today, has the largest evidence base and the largest points for monitoring effectiveness.

Valsartan clearly reduces the risk of cardiovascular complications such as stroke, such as new cases of diabetes. Please note - these are very interesting numbers. Valsartan seriously and significantly reduces the risk of developing the first and subsequent heart attacks and strokes. Valsartan reduces the frequency of hospitalizations due to angina pectoris. The pharmacodynamics and pharmacokinetics of Valsartan also have their own specific characteristics. When taking sartans, there is no effect of hypotension of the first dose; accordingly, it is quite safe at the start of therapy. It is quite safe for long-term therapy, especially in elderly patients. Sudden o is not accompanied by the development of rebound hypertension. Valsartan has two routes of elimination: 70% through the liver and 30% through the kidneys. Accordingly, this will also be a positive feature of this drug for the treatment of high-risk patients. Metabolism of one of the well-known generics “Valsartan” is not carried out through the cytochrome P450 system. This ensures there are no interactions.

Thus, I would like to emphasize that today Valsartan and angiotensin receptor blockers are not only effective and safe drugs in monotherapy, but, of course, these drugs are important and must be taken in combination with other hypertensive drugs, such as thiazide diuretics . And we know not only the combination, but also fixed combinations of such drugs - these are drugs combined with dihydropyridine calcium antagonists, in particular, with Amlodipine. We are well aware of the fixed combination drugs “Valsartan” plus “Amlodipine”, “Valsartan” plus non-dihydropyridine calcium antagonists. Green arrows in this diagram indicate rational, complete combinations that not only have the ability to significantly reduce arterial hypertension. Also, these combinations are characterized by a small number of side effects and, most importantly, can significantly reduce the risk of cardiovascular events and protect target organs from quite serious damage, which is dangerous for the development of arterial hypertension.

The blood pressure of a healthy person has daily peaks and valleys, and, interestingly, all sartans, and Valsartan, in particular, have the ability to normalize the daily rhythm of blood pressure. This slide presents our own studies of one of Valsartan’s generic drugs, Valsacor, which shows that the number of normal blood pressure profiles based on 24-hour monitoring looks quite significant compared to the number of pathological profiles. This shows not so much the effectiveness as the safety of this drug in treating patients every day for many months and years. Blood pressure variability also affects the prognosis of patient treatment, accordingly, we can understand that Valsartan is able to positively adjust and reduce the number of unregulated increases in blood pressure. It has been proven that blood pressure variability is a factor that determines myocardial mass, creatinine level and changes in the fundus over 7 years, that is, the higher the variability, the higher the damage to target organs. If a drug is able to reduce this variability, reduce these peaks of decrease and increase in blood pressure, there is a clear effect on the prognosis and condition of target organs.

What is positive and why did I choose for today’s presentation one of the main generic drugs of Valsartan - Valsacor? The fact is that, along with the data of Valsartan itself, Valsacor has its own data from clinical studies, such as the use of Valsartan in weightlifters, showing, first of all, the safety of the drug and the normalization of blood pressure variability. Not a single patient noted poor tolerability, which, of course, is characteristic not only of the entire class of sartans, but also of Valsartan, first of all.

As a final slide... I'll skim a little bit. I would like to emphasize the need to combine even such an effective class of drugs as sartans with other antihypertensive drugs. For example, hydrochlorothiazide. It has been clearly proven that, firstly, the combinations are most acceptable in patients with a high risk of second and third degree arterial hypertension. On the other hand, the presence of the most combinable class of drugs, which are thiazide diuretics, we can say that the fixed combination of Valsartan plus hydrochlorothiazide, the fixed combination of sartans, in principle, with thiazide diuretics today has shown the ease of use for both the patient, which determines compliance And, of course, the convenience of dose titration, which determines the convenience for the doctor, as well.

- Look what they write. “It’s a terrible combination, the combination of an ACE inhibitor and sartan is terrible.” We're not saying it's good.

Maksimov M.L.:

– We didn’t even talk. I’m ready to show a slide, there was a combination with thiazide diuretics, with calcium antagonists and with non-dihydropyridine calcium antagonists. It is not rational to combine sartans with ACE inhibitors. There have been articles on the combination of ACE inhibitors with sartans in the treatment of chronic heart failure. This combination, of course, is not indicated either in the treatment of coronary artery disease or in the treatment of arterial hypertension. I absolutely agree with you.

– I want to say, I’ll also add, we’ll talk a little about this topic. Indeed, hypotheses were tested, for example, in the ONTARGET study, which is better? It would seem that if we block the renin-angiotensin-aldosterone system at all levels, wherever possible, then we will get many benefits, no. We do not receive any special benefits, although the combination of aldosterone blockers, such as speronolactone and ACE inhibitors or sartans, is important, especially in patients with heart failure. Look how interesting some sensational phenomena really are. Here are the questions again. Tell me, what do you think about the increased cancer risk of sartans?

Maksimov M.L.:

– The increased cancer risk of sartans is more likely some kind of remnant of marketing wars than scientific data. To date, sartans have not been proven to have cancer risks or have been confirmed by any research.

– Again, different listeners and viewers write. What is your attitude to the simultaneous administration of ACE inhibitors and sartan?

Maksimov M.L.:

– It is not advisable to prescribe ACE inhibitors and sartans at the same time for arterial hypertension.

– We received a message from Ismail-ala from Bishkek. Thank you very much, wonderful program, especially sartans and the modern view of nephroprotection.

Angiotensin receptor antagonists

Most doctors will recommend trying an ACE inhibitor first to treat hypertension; if that doesn't work, then they may recommend angiotensin receptor blockers (ARBs).

This group of drugs is better tolerated, they do not cause coughing - which is the most important condition for increasing a person’s adherence to therapy.

Recent discoveries have expanded the use of angiotensin receptor antagonists; they are now not only recommended as initial or adjunctive antihypertensive therapy, but they also show benefits in the treatment of heart failure (HF), diabetic kidney disease, especially among patients with ACE inhibitor intolerance and diabetes.

New indications have emerged, such as chronic heart failure after myocardial infarction, atrial fibrillation and metabolic syndrome. They can be used both in monotherapy and in combination with other antihypertensive drugs.

To date, 9 groups are known. They all have names that end in "sartan". They differ in their ability to reduce blood pressure, duration of action and the presence of additional indications.

The benefits of ARBs do not end there; titrating the dose is easy and simple; you do not have to select as carefully from the group as, for example, calcium antagonists or beta blockers .

Keep in mind that sartans will not have an immediate, sustained hypotensive effect. They work gently, the effect increases gradually, appears at 2–4 weeks and intensifies by the 6–8th week of therapy.

How do angiotensin receptor antagonists work?

The renin-angiotensin-aldosterone system (RAAS) is a coordinated hormonal cascade that controls cardiovascular, renal, and adrenal function by regulating body fluid and electrolyte balance and blood pressure. It is the main active element in the RAAS.

The renin-angiotensin-aldosterone system can be controlled by 4 groups: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), aldosterone antagonists and direct renin inhibitors. Each group only partially suppresses the work of the RAAS. They all act approximately the same way, suppressing the release of the hormone, but they do it in different ways.

ACE inhibitors block the enzyme that promotes its formation, ARBs block receptors , through which its action is realized.

What it does in the body:

leads to generalized vasoconstriction;
which increases peripheral resistance;
increase the load on the heart;
increases aldosterone, sodium in the blood, resulting in cell growth in the arteries and heart (hypertrophy);
promotes the release of catecholamines from the adrenal glands, causing hyperactivity of the sympathetic nervous system.

Its inactivation , with the help of ARBs, promotes regression (elimination and reversal) of pathological processes. People with a high renin-sodium profile have a greater risk of myocardial infarction than people with a normal or low profile.

Adverse events from this group include headache, dizziness, hyperkalemia, respiratory infections, angioedema and fatigue. ARBs should not be combined with ACE inhibitors because such combinations increase the risk of hypotension, hyperkalemia, and renal failure.

Losartan

The medicine undergoes transformation in the liver, so the activity of Losartan depends on its condition. The initial dose is 50 mg, the maximum is 150 mg, taken 1-2 times a day.

The effect of Losartan is volume dependent. The maximum reduction in blood pressure should be expected at 4-6 weeks. The medicine has the widest indications: hypertension, heart failure, stroke prevention in cardiac hypertrophy and kidney protection in diabetes (DM).

Pros:

Treats hypertension, but has a weaker effect on blood pressure than other representatives
Protects kidneys from diabetes damage
Reduces the risk of stroke in hypertension better than atenolol
Eliminates cardiac hypertrophy
Affects uric acid levels, which other ARBs do not, recommended for gout and hypertension
Dilates blood vessels
Excreted approximately 40% in urine and 60% in feces
Combines well with diuretics
Has an antiplatelet effect by blocking thromboxane A2 receptors
Inexpensive

Minuses:

Cannot be combined with rifampicin, fluconazole
Increases potassium in the blood
Has a short period of action, so you need to drink several times a day
To increase efficiency, you need to constantly increase the amount
May cause dizziness.

Analogues:

Losaran (Vertex, Russia) 1000 mg No. 90 – 400 rub.
Bloktran (Pharm standard, Russia) 50 mg No. 30 - 320 rub.
Cozaar (Merck) 100 mg No. 28 - 160 rub.
Lozap (Sanofi) 100 mg No. 90 – 531 rub.
Losartan (Teva) 50 mg No. 30- 150 rub.
Lorista (KRKA) 100 mg No. 90- 404 rub.

Losartan has been shown to be highly effective in studies in reducing the risk of death from heart attack or stroke by approximately 13% compared with atenolol, especially in patients with diabetes.

Candesartan cilexetil

Candesartan is a prodrug and therefore requires activation in the liver.

Initial dose - 4-8 mg, average 24 mg, maximum - 32 mg, taken 1-2 times a day. An excellent drug, practically devoid of drawbacks, deserves the attention of hypertensive patients, and is suitable for long-term lifelong use.

Pros:

Dilates blood vessels
Protects kidney tissue from damage from high blood pressure and diabetes
Indicated for the treatment of heart failure
Significantly reduces the risk of stroke, better than other ARBs
Well tolerated
It does not interact with other medications, so it does not interfere with their work.

Minuses:

May cause dizziness

Analogues:

Atakand (Astra Zeneca) England - 977 rub.
Hyposard Polfa 16 mg No. 28- 301 rub.
Cantab Nobel Türkiye 8 mg No. 28- 250 rub.
Kandesar Sunn India 8 mg No. 10- 42 rub.
Kasark (candesartan + hydrochlorothiazide) Evertogen India – 250 rub.

Olmesartan medoxomil

Also a prodrug, it needs to be converted by the liver. Initial amount 20 mg, maximum 40 mg, dose 1 time.

It is in second place in Europe in popularity, sold under the name “Benicar”. Shows the greatest effectiveness among sartans in controlling high blood pressure.

Pros:

Treats hypertension, for best effect a dose of 40 mg is needed
Starts working quickly in 1-2 hours
Good when combined with diuretics
Recommended for children from 6 years old
Excreted in feces (60%) and urine (40%)
Duration of action up to 24 hours
The maximum antihypertensive effect occurs at week 8, blood pressure results begin at week 2
Food does not affect absorption
Well tolerated, the number of side effects was comparable to placebo.

Minuses:

Hard
Has a number of heart restrictions
Recommended only for the treatment of hypertension
Not possible for congestive heart failure

Analogues:

Cardosal Berlin Chemie (Germany) 10 mg No. 28 - 468 rub.

Azilsartan medoxomil

After activation in the liver, azilsartan is converted into the active form. The initial dose is 40-80 mg, maximum 80 mg. Reception 1 time.

pros:

Binds more strongly to receptors than other ARBs
Has a powerful and long-lasting antihypertensive effect
Increases tissue sensitivity to insulin and affects the mass of adipose tissue, promising for patients with hypertension with metabolic disorders
Combines well with diuretics
2 weeks are enough for stable stabilization of blood pressure
Reduces anxiety levels
Lowers sugar levels
Has nephroprotective properties.

Minuses:

May cause dizziness, diarrhea
Recommended from 18 years of age
Not suitable for severe liver dysfunction
There are no analogues, dear.

Analogues:

Edarbi Takeda (Japan) 20 mg No. 28 - 377 rub., 80 mg No. 28 - 830 rub.
Edarby Clo Takeda (Japan) - Azilsartan 40 mg + chlorthalidone 25 mg No. 98 pcs - 1840 rub.

According to clinical studies, azilsartan in a minimum dose (40 mg) reduces blood pressure better than taking the maximum dose of valsartan and olmesartan.

Eprosartan

They are not a prodrug, so they can be used for liver pathologies. Initial dose - 600 mg, maximum - 800 mg, taken 1 - 2 times a day.

Tops the popularity rating in Europe, recommended only for the treatment of hypertension. Excellent protection against primary and recurrent stroke.

Pros:

Treats hypertension
Dilates blood vessels
Has a mild diuretic effect
Open 24 hours
Maximum effect after 2 weeks
Does not affect heart rate
Mainly excreted through the intestines (90%)

Minuses:

Sometimes causes headaches and indigestion
There are no analogues, only the brand is on sale, expensive

Analogues:

Teveten (Abbot, Netherlands) 600 mg No. 14– 1299 rub.

Patients who took telmisartan, eprosartan, and irbesartan were less likely to refuse to continue treatment than patients who were on losartan.

Irbesartan

It is not a prodrug, it works immediately, without the help of the liver. Irbesartan has one of the highest bioavailability. The initial dose is 150 mg, the maximum is 300, taken 1 time. It differs from analogues in its powerful nephroprotective effect.

Pros:

Ideal for hypertension and kidney damage due to diabetes
Shows antiplatelet effect
Valid for 24 hours
Exceeds the effectiveness of valsartan
In lowering diastolic blood pressure it was inferior to olmesartan
Reduces the incidence of congestive heart failure
Combines well with diuretics
Recommended for hypertension and obesity
Protects kidneys from damage
Well tolerated

Minuses:

Possible dizziness
Increases potassium levels in the blood.

Analogues:

Aprovel (Sanofi Aventis, France) 150 mg No. 14 - 200 rubles, 300 mg No. 28 - 706 rubles.
Irbesartan Atoll, Russia 300 mg No. 28 - 559 rub.
Irbesartan (Canon, Russia) 150 mg No. 28- 391 rub.

Telmisartan

Telmisartan is record to date for an ARB. Provides a hypotensive effect for up to 48 hours.

Sartan of the second generation, is one of the active metabolites of losartan, superior to it in all respects.

The initial dose is 40 mg, the maximum is 80 mg. Reception 1 time. Telmisartan is the drug of choice in patients with obesity and hypertension, especially resistant to therapy.

Pros:

Not a prodrug, acts immediately
Duration 48 hours
Has a rapid onset of action within 30 minutes
Increases tissue sensitivity to insulin and enhances glucose utilization in muscles and tissues
In therapeutic dosages it acts as a hypoglycemic agent
Has a beneficial effect on carbohydrate and fat metabolism
Suitable for elderly patients
Has antiplatelet activity.
Reduces the risk of heart attack and stroke in diabetics.

Minuses:

Coadministration of telmisartan with digoxin increases plasma digoxin levels, which may lead to toxicity.

Analogues:

Mikardis (Boehringer Ingelheim) Germany 40 mg No. 14 – 335 rub.
Telzap Sanofi, France 40 mg No. 90- 703 rub.
Telmista (KRKA, Slovenia) 40 mg No. 84 – 724 rub.
Elmisartan SZ (Northern Star, Russia) 40 mg No. 30 - 216 rub.
Telsartan (Doctor Reddis, India) 40 mg No. 30 - 230 rub.
Tanidol (Gedeon Richter, Hungary) 40 mg No. 30 – 196 rub..

Valsartan

Valsartan and losartan were first on the market. It is not a prodrug.

The initial dose is 20-40 mg or 160 mg, the average is 254 mg, the maximum is 160 mg. Once a day.

In Europe it is in third place in popularity.

Pros:

Treats hypertension
Starts working in 2 hours
Indicated for chronic heart failure and after a heart attack
Mortality from cardiovascular diseases decreases with cardiac weakness or after myocardial infarction
Reduces the risk of blood clots
Has a vasodilating effect
Has many analogues on the market
Does not affect glycemic levels, does not change lipid profile and triglyceride levels.

Minuses:

Not recommended for severe liver and kidney damage

Analogues:

Valz (Balkanfarma Bulgaria) 40 mg No. 30 - 124 rub.
Valsacor (KRKA, Slovenia) 80 mg No. 90 — 682 rub.
Diovan (Novartis, Switzerland) 80 mg No. 28 – RUB 1,570.
Valsartan (Atoll, Russia) 80 mg No. 30- 183 rub.
Exforge Novartis, Switzerland - this is (valsartan / amlodipine) combined - 1228 rubles.

A number of studies have shown that valsartan for hypertension is comparable to amlodipine in the long term.

News: A new effective combination drug for the treatment of heart failure has recently been tested. It contains sartan (valsartan) and a new class of drugs - neprilysin inhibitors (sacubitril).

It's called "Uperio" (sacubitril + valsartan). Uperio showed good results in chronic HF with hypertension.

Fimasartan

Another new ARB inhibitor developed by a Korean company. Obtained by converting the losartan molecule, it is 10 times superior to it and valsartan.

Used only as an antihypertensive agent. The initial dose is 60 mg, the maximum is 120 mg. Take once a day.

Pros:

Treats hypertension
Can be used for heart failure
Acts quickly and for a long time
Shows antihypertensive effect within 24 hours
Dilates blood vessels
It is excreted only in feces.

Minuses:

The market is represented by one representative, dear.

Analogues:

Kanarb (Boryung, Korea) 6 mg No. 30 - 907 rub., 120 mg No. 30 - 1348 rub.

Key points

Sartans (BRA) are a unique group. If a sick person tolerates it well, his blood pressure has stabilized and remains stable for 24 hours, and he has diabetes and increased weight, then there is no need to look for the best remedy among other groups of drugs. You can stay on it for life, if necessary, just increase the dose and add a diuretic.

After a few years of taking it, we will see positive changes: the size of the heart and the thickness of blood vessels will return to normal, kidney function will be restored, sugar and cholesterol levels will stabilize. In the long term, they will reduce the risk of heart attack and stroke.

They will also prevent a recurrent heart attack, slow the progression of renal failure, and reduce the risk of diabetes in patients at risk.

In addition, angiotensin receptor antagonists are well tolerated and should be considered as first-line agents for the prevention and management of risk factors for CVD and other diseases.

The addition of sartans to ACE inhibitors or aldosterone antagonists is unlikely to be advisable and should be avoided due to the risk of hyperkalemia.

If a person taking an ACE inhibitor or sartan still has symptoms, perhaps adding a calcium antagonist (amlodipine) or a beta blocker (nebivolol) or trying angiotensin/neprilysin (Uperio).

In the Russian ranking according to doctors' recommendations, losartan is in the lead, with valsartan in second place. This is explained by its affordable price and good knowledge. Despite the fact that other representatives of the group are more powerful, have a longer effect, and are used less frequently.

The choice of ARB can be considered ideal if it is recommended taking into account the individual characteristics of the body, tolerance and existing pathology.

How to choose a worthy drug so that it brings maximum benefit for various conditions:

Hypertension - any sartan can be used. Olmesartan, eprosartan and telmisartan have proven themselves well.
Prevention of cardiac pathology - telmisartan is better, losartan is also possible
Heart failure (shortness of breath) - losartan, valsartan, candesartan
Immediately after a heart attack - valsartan is better, telmisartan is allowed
Stroke - losartan or telmisartan, candisartan, eprosartan.
Atrial fibrillation - telmisartan, in second place is candesartan, valsartan and losartan
Diabetes – telmisartan, valsartan. In second place are losartan, irbisartan and candisartan. Undesirable – olmesartan
Metabolic syndrome (obesity) – telmisartan, in the background – valsartan
Gout – losartan, undesirable – candesartan
For sexual weakness , give preference to valsartan, losartan, irbesartan.
Cognitive impairment – Candesartan, Irbesartan, Losartan, Valsartan, Eprosartan, Telmisartan.

Only the right approach to choosing a medicine will improve the quality of life, prolong it and reduce the risk of fatal cases.

Rating

The latest 2013 European recommendations for the treatment of arterial hypertension (ESH/ESC Guidelines for the management of arterial hypertension) declare that “... since metabolic syndrome is often regarded as a “prediabetic” condition, preference is given to blockers of the renin-angiotensin system and calcium antagonists, t . To.

they have the potential to improve, or at least not worsen, insulin sensitivity, while beta blockers (except beta blockers with vasodilating properties) and diuretics should be considered as adjunctive agents, preferably used in low doses." The recommendations in the section “Drugs of choice in certain situations” also indicate that angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium antagonists are the drugs of choice for metabolic syndrome [1].

It is known that ARBs (sartans) suppress the activity of the renin-angiotensin-aldosterone system more completely than ACEIs and do not affect the bradykinin system. In terms of antihypertensive effectiveness, ACEIs and ARBs are equivalent, but the latter have a better tolerability profile, since they do not cause cough or angioedema. ARBs provide higher adherence to therapy among patients with hypertension due to a better tolerability profile and the absence of “escape” of the hypotensive effect.

ARBs have pronounced cardio- and nephroprotective effects: they prevent left ventricular hypertrophy, increase the duration of sinus rhythm retention in paroxysmal atrial fibrillation, reduce the degree of microalbuminuria and proteinuria, and slow the progression of heart and renal failure. With long-term use, ARBs reduce carotid intima-media thickness and the volume of large atherosclerotic plaques (MORE study with telmisartan).

A significant reduction in the risk of developing diabetes mellitus during ARB therapy was also found in the LIVE, VALUE, CHARM, and ALPIN studies.

In the LIFE study, the reduction in the relative risk of developing new cases of diabetes mellitus while taking losartan was 25%, in SCOPE with eprosartan therapy - 20%, and in CHARM with candesartan therapy - 22%. A meta-analysis also showed that ARB therapy is associated with a reduction in the development of new cases of diabetes mellitus [2].

At the same time, a significant reduction in the incidence of cardiovascular complications was noted in the treatment of ARBs in hypertensive patients with diabetes mellitus (LIFE, IDNT, RENAAL).

An important advantage of ARB therapy in light of the metabolic syndrome epidemic is that the number of AT1 receptors and their sensitivity to angiotensin II increases dramatically in obesity, hyperinsulinemia, and dyslipidemia.

An important mechanism of action of ARBs is the modulation of the activity of PPARγ receptors responsible for glucose homeostasis, lipid metabolism and blood pressure regulation. This effect not only reduces blood pressure, but also normalizes levels of glucose, insulin and triglycerides. Moreover, the results of a number of studies indicate a decrease in tissue insulin resistance due to stimulation of nuclear PPARγ receptors in cells of adipose, muscle tissue, and hepatocytes, and this effect is comparable to the effect of oral hypoglycemic drugs.

Thus, there is a compelling case for widespread use of the ARB class in metabolic syndrome. At the same time, the practicing physician faces the problem of differentiated selection of a specific drug for a specific patient. In this regard, it is advisable to consider the clinical and pharmacological characteristics of ARB representatives. Moreover, significant intraclass differences between them find new confirmation [3]. Thus, in a clinical study, two drugs of the ARB group (telmisartan and losartan) were compared, during which it was found that telmisartan, unlike losartan, reduces the concentration of free blood glucose, unbound insulin and HbA1c, thereby identifying the main intraclass differences between the drugs in potential improvement metabolic disorders in patients with metabolic syndrome [4].

Losartan

The prevalence of hyperuricemia with a combination of arterial hypertension and metabolic syndrome is 37.8%, and in its absence – 22% [6]. However, the duration of the disease does not affect the frequency of hyperuricemia. The study authors showed that patients with uric acid levels above 300 μmol/L have more pronounced metabolic risk factors, which are directly dependent on the degree of increase in uric acid. Losartan blocks the two main transport systems of distal tubular epithelial cells involved in the reabsorption of urates (urate/lactate and urate/chloride) and protects the structures of the renal tubulointerstitium from the damaging effects of urates. When using losartan, the excretory pool of uric acid increases only due to inhibition of urate reabsorption without increasing filtration, which fundamentally distinguishes it from classical uricosuric drugs, the use of which increases urate filtration and increases the risk of developing nephrolithiasis. It has been shown that losartan itself, and not its active metabolite E-3174, has uricosuric activity [7]. Consequently, this activity is due to the characteristics of the molecule, and not to blockade of the AT1 receptor, which is fundamentally important when analyzing the class-specific effects of this group of antihypertensive drugs. The LIFE trial, which assessed the effect of losartan and atenolol on cardiovascular events and mortality among high-risk hypertensive patients with left ventricular hypertrophy, also examined the association of baseline uric acid levels with other risk factors and disease prognosis, and was the first large-scale study to demonstrate that a decrease in uric acid levels during losartan therapy is associated with a positive effect on the incidence of complications in the treatment of arterial hypertension.

Valsartan

The NAVIGATOR study showed that in patients with impaired glucose tolerance and risk factors, treatment with valsartan leads to a relative reduction of 14% and an absolute reduction of 3.8% in the incidence of new cases of diabetes mellitus [8].

A distinctive feature of valsartan is its positive effect on sexual function in men and women [9, 10]. This is due to its ability to have a direct vasodilating effect, improve endothelial function and microcirculation, reduce the volume of connective tissue in the corpora cavernosa, increase testosterone levels in men and indirectly, through metabolites of angiotensin II (angiotensin IV), influence the dopaminergic system involved in the regulation of sexual behavior.

Candesartan

The metabolic effects of long-term antihypertensive therapy with candesartan were studied in the ALPINE study [11]. When compared with hydrochlorothiazide, the candesartan group showed a decrease in insulin levels, blood glucose, triglycerides and an increase in HDL. In the hydrochlorothiazide group, compared with the candesartan group, there was also an increase in the ratios of high- and low-density lipoprotein cholesterol and apolipoprotein B/apolipoprotein AI, which indicates a deterioration in the lipid profile. Against the background of these changes, diabetes mellitus was diagnosed in 4.1% of patients in the hydrochlorothiazide group and only in 0.5% of patients in the candesartan group, and metabolic syndrome was diagnosed in 18 patients in the hydrochlorothiazide group and only in 5 patients in the candesartan group. A distinctive feature of the drug is the presence of an evidence base for effective use in chronic heart failure, including in the subgroup of patients with impaired carbohydrate metabolism.

Irbesartan

The nephroprotective effect and the ability of the drug to reduce albuminuria have been proven in large studies (IRMA, IDNT). But an important feature of irbesartan is its ability to ensure that 70% of patients achieve target blood pressure in metabolic syndrome. At the same time, all of them showed a decrease in waist circumference and a decrease in the initially elevated levels of insulin, glucose and blood lipids. Moreover, it should be noted that it is most pronounced when arterial hypertension and metabolic syndrome are combined [12]. Similar results were obtained in another study [13]. In addition, recent studies have shown that irbesartan and telmisartan act as partial agonists of peroxisome proliferator-activated receptor γ (PPARγ) at concentrations achieved by oral administration and doses recommended as a treatment for hypertension, making their use possible for sensitization. to insulin [14].

Telmisartan

Telmisartan exhibits maximum activity against PPARs compared to other ARBs and has maximum lipophilicity. PPARγ play a key role in the metabolism and energy metabolism of adipose tissue - creating lipid reserves in white adipose tissue and increasing energy expenditure in brown fat. PPARγ is also involved in adipocyte differentiation and regulation of glucose metabolism by improving insulin sensitivity, being a link between lipid and carbohydrate metabolism. The use of telmisartan may prevent the development of atherosclerosis by reducing visceral fat, suppressing vascular inflammation and increasing adiponectin levels, especially in patients with metabolic syndrome.

A recently published meta-analysis of 10 randomized trials involving 546 patients with metabolic syndrome showed that telmisartan significantly reduced fasting glucose, hyperinsulinemia, glycated hemoglobin, increased insulin sensitivity and adiponectin levels [15].

It is important to note that telmisartan also has the same positive effect on all of these indicators, as well as lipids and resistin, during therapy with rosiglitazone [16]. In addition, only telmisartan in combination with rosuvastatin reduces insulin resistance and C-reactive protein levels, in contrast to the combination of this statin with irbesartan and olmesartan [17].

Thus, analysis of the evidence base for the use of ARBs in metabolic syndrome, the features of their clinical pharmacology and experience in practical use make it possible to offer the practitioner a simple algorithm for their differentiated use in this condition (see figure).

Algorithm for choosing antihypertensive therapy for metabolic syndrome and arterial hypertension

S.V.
Nedogoda, T.A. Chalyabi, A.S. Salasyuk, I.N. Barykina. D.A. Pocheptsov, A.A. Ledyaeva, V.V. Tsoma, E.V. Chumachek, Volgograd State Medical University ACE inhibitors and angiotensin II receptor blockers belong to the main classes of antihypertensive drugs used in the treatment of arterial hypertension in patients with metabolic syndrome.
Each of the representatives of this group has clinical-pharmacological characteristics and nuances of clinical use. Based on their analysis, an algorithm for differentiated selection of a specific drug is proposed. It is known that in arterial hypertension against the background of metabolic syndrome, pronounced dysfunction of the vascular endothelium (excess of vasoconstrictors and deficiency of vasodilators, primarily nitric oxide), increased activity of the renin-angiotensin-aldosterone and sympatho-adrenal systems (high levels of leptin), vasospasm against the background of increased cardiac output, increased sodium reabsorption in the nephron tubules (due to hyperinsulinemia and compression of the kidneys by adipose tissue), fluid retention and hypervolemia, increased sodium and calcium content in the vascular wall, obstructive sleep apnea. The vast majority of patients have insulin resistance. They experience early target organ damage (left ventricular hypertrophy, quickly leading to diastolic myocardial dysfunction, increased stiffness of large arteries, hypofiltration in the kidneys and microalbuminuria). Typical metabolic disorders in arterial hypertension are impaired glucose tolerance, increased levels of triglycerides, cholesterol and uric acid. All these features significantly influence the choice of antihypertensive drug for the correction of blood pressure (BP) in patients with metabolic syndrome.

For patients with arterial hypertension and metabolic syndrome, it seems fundamentally important to ensure the positive effect of antihypertensive drugs on adipokines produced by adipose tissue, which today is no longer considered as an energy depot, but as an endocrine and paracrine organ that has a humoral, prothrombogenic and pro-inflammatory effect on other organs and body systems. Among more than 50 adipokines in obesity, the greatest role in the pathogenesis of both obesity itself and associated diseases and conditions is played by resistin, ghrelin, visfatin, apelin, adiponectin, TNF-alpha and interleukin 6. However, by far the most studied and important adipokine in obesity leptin is a hormone produced by fat cells and circulating in the blood in free and bound forms. Through its influence on specific receptors of the hypothalamus, leptin changes the expression of neuropeptides that regulate energy intake and expenditure in the body. In obesity, compensatory resistance of the hypothalamus to the central action of leptin develops with the development of leptin resistance (hyperleptinemia) through a feedback mechanism. Leptin has a number of effects that can aggravate existing disorders in arterial hypertension and obesity (stimulation of the sympatho-adrenal system, increased rate of fibrosis of the heart muscle, increased platelet aggregation, sodium retention, increased insulin resistance).

It seems clinically important to find a “leader” drug, since a patient with a combination of arterial hypertension and metabolic syndrome requires not only normalization of blood pressure, but also the maximum possible correction of all other modifiable risk factors (Fig. 1 and 2). The latest 2013 European recommendations for the treatment of arterial hypertension (ESH/ESC Guidelines for the management of arterial hypertension) declare that since metabolic syndrome is often regarded as a “prediabetic” condition, preference is given to blockers of the renin-angiotensin system and calcium antagonists, so as they have the potential to improve, or at least not worsen, insulin sensitivity, whereas beta blockers (except beta blockers with vasodilating properties) and diuretics should be considered as adjunctive agents, preferably used in low doses. The recommendations in the section “Drugs of choice in certain situations” also indicate that ACE inhibitors, angiotensin II receptor blockers (ARBs) and calcium antagonists are the drugs of choice for metabolic syndrome [1].

Thus, while there is some certainty with the classes of antihypertensive drugs that have benefits in patients with arterial hypertension and metabolic syndrome, there is no certainty regarding their specific representatives. At the same time, it is quite clear that the so-called “class-specific effects” are increasingly being called into question. That is why it seems advisable to clarify the capabilities of specific drugs for this pathology and offer the doctor an algorithm for their differentiated use.

ACE inhibitors

It is no coincidence that ACE inhibitors play an important role in the treatment of arterial hypertension in patients with metabolic disorders. This is due to their positive influence on the key links in the pathogenesis of the disease. Representatives of this group of drugs reduce the activity of the RAAS both in plasma and in tissues, slow down the inactivation of bradykinin and reduce the activity of the sympathetic nervous system (primarily by reducing insulin resistance and the level of postprandial glycemia).

The undoubted advantage of drugs in this group is the absence of a negative effect on carbohydrate, lipid and purine metabolism. Large multicenter studies SOLVD, ASCOT, HOPE revealed a significant reduction in the number of new cases of diabetes among patients receiving long-term ACE inhibitors.

These drugs have an organoprotective effect: they reduce left ventricular myocardial hypertrophy, slow down myocardial remodeling and fibrosis, reduce MAU, proteinuria, and prevent nephroangiosclerosis and chronic renal failure. The high effectiveness of ACEIs in slowing the progression of kidney disease and reducing the risk of cardiovascular complications was shown in the AIRE, REIN, PROGRESS, ADVANCE studies. The vasoprotective effect of ACE inhibitors is to improve the function of the endothelium of the vascular wall, antiproliferative and antiatherogenic effects. Large clinical studies (PHYLLIS, SECURE) have found that ACE inhibitor therapy can reduce the thickness of the carotid artery intima-media complex in patients with asymptomatic or manifest atherosclerosis.

An important advantage of ACE inhibitors is the ability to prevent the development of cardiovascular complications in high- and very high-risk patients, including hypertensive patients with MS and diabetes. The studies SOLVD, EUROPA, PROGRESS, FACET, ADVANCE showed that treatment with ACE inhibitors reduces the risk of recurrent stroke, ischemic events, hospitalizations due to decompensation of CHF and other cardiovascular complications and death from them.

There are 3 groups of ACE inhibitors depending on the chemical structure: those containing an SH group (captopril, zofenopril), a carboxyl group (enalapril, quinapril, ramipril, perindopril (Prestarium A®), trandolapril, spirapril, cilazapril, lisinopril), a phosphinyl group (fosinopril) . Since in arterial hypertension with metabolic disorders there is often an increase in the volume of adipose tissue, the choice of a specific ACEI should take into account its lipophilicity, since a higher level of lipophilicity determines a greater tissue affinity of the drug (i.e., the ability to influence ACE activity not only in circulation , but also directly in tissues). Most ACEIs are eliminated by the kidneys; only 4 drugs (zofenopril, fosinopril, trandolapril, spirapril) have a dual elimination route - through the liver and kidneys.

The active metabolites of fosinopril, quinapril, trandolapril, ramipril and perindopril (Prestarium A®) are highly lipophilic; moderate - enalapril, moexipril and captopril; Lisinopril is a hydrophilic compound. It is the high lipophilicity that determines the preferred choice of drug when a patient has a combination of arterial hypertension and metabolic syndrome, since only in this case is it possible to block the release of vasoactive humoral substances (primarily angiotensin II and proinflammatory cytokines) from the adipocyte. Currently, in the absence of a large evidence base on the differentiated use of antihypertensive drugs, there are two polar points of view on the choice of the optimal drug depending on lipo- and hydrophilicity. Proponents of the predominant use of hydrophilic ACEIs in the treatment of patients with obesity and arterial hypertension believe that lipophilic ACEIs are distributed in adipose tissue, and therefore it is necessary to increase their dosage to achieve the desired therapeutic effect. They believe that lisinopril, which is the only hydrophilic ACEI and is not “absorbed” by adipose tissue, appears to be more effective in this clinical situation. In addition, the following argument is put forward in favor of lisinopril: obese patients often have concomitant liver diseases (steatosis and steatohepatitis), and therefore preference should be given to ACEIs that are not metabolized in the liver, namely lisinopril, which is the only ACEI with no hepatic metabolism. However, it should be noted that there is also a fairly strong argument in favor of the use of lipophilic ACE inhibitors. First, today adipose tissue is considered as an endocrine-active tissue, in which the secretion of adipokines is closely related to the activity of RASS (primarily angiotensin). Therefore, it is the action of ACEIs at the level of the adipocyte itself that can positively influence the production of adipokines, which hydrophilic ACEIs, by definition, cannot do.

Among ACE inhibitors with high lipophilicity, the most studied in the treatment of arterial hypertension and metabolic syndrome are perindopril (Prestarium A®) and ramipril.

Perindopril (Prestarium A®) has clearly demonstrated its advantages over enalapril and losartan in several studies [3, 4, 5]. It has been shown that therapy with perindopril (Prestarium A®) in patients with arterial hypertension and metabolic syndrome can achieve better blood pressure control than with enalapril and losartan, more pronounced cardio-, angio- and nephroprotection, improvement in lipid and carbohydrate metabolism, reduction insulin resistance and inflammation, as well as a positive effect on one of the key adipokines in obesity - leptin.

Ramipril demonstrated its benefits in patients with arterial hypertension and metabolic syndrome in the international MICRO-HOPE study and the Russian CHARISM study.

Angiotensin II receptor blockers

It is known that ARBs (sartans) suppress the activity of the renin-angiotensin-aldosterone system more completely than ACEIs and do not affect the bradykinin system. In terms of antihypertensive effectiveness, ACEIs and ARBs are equivalent, but the latter have a better tolerability profile, because do not cause cough, angioedema. ARBs provide higher adherence to therapy among patients with hypertension due to a better tolerability profile and the absence of “escape” of the hypotensive effect.

ARBs have a pronounced cardio- and nephroprotective effect: they prevent left ventricular hypertrophy, increase the duration of sinus rhythm retention in paroxysmal atrial fibrillation, reduce the degree of microalbuminuria and proteinuria, and slow the progression of heart and renal failure. With long-term use, ARBs reduce carotid intima-media thickness and the volume of large atherosclerotic plaques (MORE study with telmisartan).

A significant reduction in the risk of developing diabetes during ARB therapy was also found in the LIVE, VALUE, CHARM, and ALPIN studies. In the LIFE study, the reduction in the relative risk of developing new cases of diabetes while taking losartan was 25%, in SCOPE with eprosatartan therapy - 20%, and in CHARM with candesartan therapy - 22%. Meta-analysis data also showed that ARB therapy is associated with a reduction in the development of new cases of diabetes [2].

At the same time, a significant reduction in the incidence of cardiovascular complications was noted in the treatment of ARBs in hypertensive patients with diabetes (LIFE, IDNT, RENAAL).

An important advantage of ARB therapy in light of the metabolic syndrome epidemic is that the number of AT1 receptors and their sensitivity to angiotensin II increases sharply with obesity, hyperinsulinemia and dyslipidemia.

An important mechanism of action of ARBs is the modulation of the activity of PPARγ receptors responsible for glucose homeostasis, lipid metabolism and blood pressure regulation. This effect not only reduces blood pressure, but also normalizes levels of glucose, insulin and triglycerides. Moreover, the results of a number of studies indicate a decrease in tissue insulin resistance due to stimulation of nuclear PPARγ receptors in the cells of adipose, muscle tissue and hepatocytes, and this effect is comparable to the effect of oral hypoglycemic drugs.

Thus, there is a compelling case for widespread use of the ARB class in metabolic syndrome. At the same time, the practicing physician faces the problem of differentiated selection of a specific drug for a specific patient. In this regard, it is advisable to consider the clinical and pharmacological characteristics of ARB representatives. Moreover, significant intraclass differences between them find new confirmation [5]. Thus, in a clinical study, two drugs from the ARB group (telmisartan and losartan) were compared. The study found that telmisartan, unlike losartan, reduces the concentration of free blood glucose, unbound insulin and HbA1c, thereby identifying the main intraclass differences between drugs in the potential improvement of metabolic disorders in patients with MS [6]. Losartan

Over the past decade, numerous and convincing data have emerged on the close relationship between increased uric acid levels and an increased risk of cardiovascular complications in hypertension, metabolic syndrome, and type 2 diabetes. At the same time, a connection has been proven between impaired uric acid metabolism and endothelial dysfunction [7]. According to the PIUMA Study, the presence of hyperurecemia increases the risk of cardiovascular complications by 1.73 times, and the risk of mortality by 1.96 times. The prevalence of HU with a combination of arterial hypertension and metabolic syndrome is 37.8%, and in its absence - 22% [8]. At the same time, the duration of the disease does not affect the frequency of GU. Patients with uric acid levels above 300 µmol/l have more pronounced metabolic risk factors, which are directly dependent on the degree of increase in uric acid. Losartan blocks the two main transport systems of distal tubular epithelial cells involved in the reabsorption of urates (urate/lactate and urate/chloride) and protects the structures of the renal tubulointerstitium from the damaging effects of urates. When using losartan, the excretory pool of uric acid increases only due to inhibition of urate reabsorption without increasing filtration, which fundamentally distinguishes it from classical uricosuric drugs, the use of which increases urate filtration and increases the risk of developing nephrolithiasis. It has been shown that losartan itself, and not its active metabolite E-3174, has uricosuric activity [9]. Consequently, it is due to the characteristics of the molecule, and not to blockade of the AT1 receptor, which is fundamentally important when analyzing the class-specific effects of this group of antihypertensive drugs. The LIFE trial, which assessed the effects of losartan and atenolol on cardiovascular events and mortality in high-risk hypertensive patients with left ventricular hypertrophy, also examined the association of baseline uric acid levels with other risk factors and disease prognosis and was the first large-scale study to do so. demonstrated that a decrease in uric acid levels during losartan therapy is associated with a positive effect on the incidence of complications in the treatment of arterial hypertension.

Valsartan

A distinctive feature of valsartan is its positive effect on sexual function in men and women [11,12]. This is due to its ability to exhibit a direct vasodilating effect, improve endothelial function and microcirculation, reduce the volume of connective tissue in the corpora cavernosa, increase testosterone levels in men and indirectly, through metabolites of angiotensin II (angiotensin IV), influence the dopaminergic system involved in the regulation of sexual behavior.

Candesartan

The metabolic effects of long-term antihypertensive therapy with candesartan were studied in the ALPINE study [13]. When compared with hydrochlorothiazide, the candesartan group showed a decrease in insulin levels, blood glucose, triglycerides and an increase in HDL. In the hydrochlorothiazide group, compared with the candesartan group, there was also an increase in the ratios of LDL cholesterol/HDL cholesterol and apolipoprotein B/apolipoprotein A-I, indicating a deterioration in the lipid profile. Against the background of these changes, diabetes mellitus was diagnosed in 4.1% of patients in the hydrochlorothiazide group and only 0.5% of patients in the candesartan group, and metabolic syndrome was diagnosed in 18 patients in the hydrochlorothiazide group and only 5 patients in the candesartan group. A distinctive feature of the drug is the presence of an evidence base for effective use in chronic heart failure, including in the subgroup of patients with impaired carbohydrate metabolism.

Irbesartan

The nephroprotective effect and ability of the drug to reduce albuminuria has been proven in large studies (IRMA, IDNT). But an important feature of irbesartan is its ability to achieve target blood pressure in metabolic syndrome in 70% of patients. At the same time, all of them showed a decrease in waist circumference and a decrease in the initially elevated levels of insulin, glucose and blood lipids. Moreover, it should be noted that these changes are most pronounced when the patient has a combination of arterial hypertension and metabolic syndrome [14]. Similar results were obtained in another study [15]. In addition, recent studies have shown that irbesartan and telmisartan act as partial agonists of peroxisome proliferator-activated receptor γ (PPARγ) at oral concentrations and doses recommended for the treatment of hypertension, making their use possible for improving insulin sensitivity [16]. Telmisartan

Telmisartan exhibits maximum activity against PPARs compared to other ARBs and has maximum lipophilicity. PPARγ play a key role in the metabolism and energy metabolism of adipose tissue - creating lipid reserves in white adipose tissue and increasing energy expenditure in brown fat. PPARγ is also involved in adipocyte differentiation and in the regulation of glucose metabolism by improving insulin sensitivity, being a link in the metabolism of lipids and carbohydrates. The use of telmisartan may prevent the development of atherosclerosis by reducing visceral fat, suppressing vascular inflammation and increasing adiponectin levels, especially in patients with metabolic syndrome.

A recently published meta-analysis of 10 randomized trials involving 546 patients with metabolic syndrome showed that telmisartan significantly reduced fasting glucose, hyperinsulinemia, glycated hemoglobin and increased insulin sensitivity and adiponectin levels [17].

It is important to note that telmisartan also has the same positive effect on all of these indicators, as well as on lipids and resistin, during therapy with rosiglitazone [18]. In addition, only telmisartan in combination with rosuvastatin reduces insulin resistance and C-reactive protein levels, in contrast to the combination of this statin with irbesartan and olmesartan [19].

Thus, analysis of the evidence base for the use of ARBs in metabolic syndrome, the features of their clinical pharmacology and experience in practical use allows us to offer the practitioner a simple algorithm for their differentiated use in this condition (Fig. 3). Calcium antagonists

As is known, this group includes dihydropyridine (nifedipidine, amlodipine, felodipine, lacidipine) and non-dihydropyridine (verapamil and diltiazem) calcium antagonists. Representatives of the first subgroup, against the background of a decrease in blood pressure, which develops due to peripheral vasodilation, can increase the heart rate (HR) and contribute to the activation of the SAS. Representatives of the second group, while maintaining pronounced antihypertensive activity, have a significantly less pronounced peripheral vasodilating effect than dihydropyridine calcium antagonists. Moreover, they are able to reduce heart rate (by suppressing the activity of sinus node automaticity) and reduce the activity of the SAS (data from the VAMPHYR study), which is important for obese patients. It should be noted that, according to many large studies, calcium antagonists significantly reduce the number of new cases of diabetes mellitus (INVEST, INSIGHT, ALLHAT), are able to reduce left ventricular hypertrophy and have an anti-sclerotic effect (VHAS).

Diuretics

One of the main mechanisms of increased blood pressure in arterial hypertension against the background of metabolic syndrome is hypervolemia, which occurs as a result of increased reabsorption of sodium and water in the proximal renal tubules against the background of hyperinsulinemia and increased vascular resistance. Therefore, diuretics could become one of the main classes of antihypertensive drugs used for this pathology. However, the undoubted advantages of classical thiazide diuretics are clearly insufficient to compensate for their negative effects (primarily metabolic effects - hypokalemia, deterioration of carbohydrate, lipid and purine metabolism).

According to the results of clinical observations, all thiazide diuretics worsen carbohydrate metabolism, even at a daily dose of 12.5 mg. Moreover, the higher the initial level of glycemia, the more it increases with their use. In young people, impaired glucose tolerance develops on average after 5 years of continuous use of thiazide diuretics, and in older people - 1 to 2 years after the start of their use. In the case of concomitant diabetes mellitus, glycemic control worsens within the first few days of starting thiazide diuretics. In addition to the adverse effect on carbohydrate metabolism, thiazide diuretics can have a negative effect on lipid and purine metabolism.

Indapamide retard (Arifon retard) stands apart among diuretics, which, unlike classical thiazide diuretics, does not have a negative effect on the metabolism of glucose, lipids and uric acid. Thus, according to the Russian multicenter study MINOTAVR (619 patients with metabolic syndrome and arterial hypertension), it proved to be a drug that can effectively reduce blood pressure and have a positive effect on carbohydrate, lipid and purine metabolism. It must be borne in mind that indapamide retard (Arifon retard) has a proven and pronounced cardio-, angio- and nephroprotective effect, which makes it in the group of diuretics the drug of choice for the treatment of patients with obesity and disorders of carbohydrate, lipid and purine metabolism, both mono- and combination therapy.

Beta blockers

Increased activity of the SAS in obese patients dictates the need for the use of β-blockers. However, non-selective β-blockers (atenolol, propranolol) negatively affect carbohydrate and lipid metabolism. In addition, β-blockers (including selective β1-blockers in high doses), by blocking β-adrenergic receptors of the pancreas, inhibit the release of insulin. Since β-blockers cause the development of IGT and weight gain, their use in uncomplicated hypertension and obesity is not recommended as first-line therapy. However, this group of drugs can be used for obesity and arterial hypertension in cases where it is not possible to achieve the target blood pressure level due to pronounced activation of the SAS and tachycardia.

“New” highly selective β1-blockers (bisoprolol, carvedilol, nebivolol) are practically free of those adverse side effects that limited their widespread use in patients with impaired carbohydrate and lipid metabolism. In addition, nebivolol has the unique property of increasing NO production and reducing the manifestations of endothelial dysfunction, which is typical for obese patients. In addition, the drug has a beneficial effect on carbohydrate metabolism (decrease in triglyceride levels) and cerebral hemodynamics, which can significantly expand the possibilities of its use in arterial hypertension against the background of metabolic syndrome. Nebivolol does not have an “antilipase” effect and it reduces total and peripheral vascular resistance, improves regional blood flow, renal perfusion, glomerular filtration rate, and increases the sensitivity of peripheral tissues to insulin. Therefore, among beta-blockers, the drug of choice for a combination of arterial hypertension and metabolic syndrome is nebivolol.

Imidazoline receptor agonists

A prerequisite for prescribing I2-imidazoline receptor agonists to patients with obesity and arterial hypertension is their ability to increase tissue sensitivity to insulin and improve carbohydrate metabolism. At the same time, according to the Russian multicenter study ALMAZ, in patients with metabolic syndrome, moxonidine therapy significantly improved lipid and carbohydrate metabolism, tissue sensitivity to insulin, contributed to a decrease in body weight and leptin levels in the blood and improved vascular endothelial function. Moreover, these positive changes were comparable in severity to metformin therapy.

Alpha - adrenergic blockers

Alpha-blockers (despite the results of the ALLHAT study) retain their therapeutic potential in the treatment of arterial hypertension in obese patients, due to their ability to reduce insulin resistance, improve carbohydrate and lipid metabolism and have a positive effect on renal hemodynamics. However, use should be limited to use only in combination with other antihypertensive agents.

As a result of the analysis of clinical trial data, the evidence base and the clinical pharmacology of antihypertensive drugs, it is possible to offer the practitioner an algorithm for their differentiated use in arterial hypertension and metabolic syndrome (Fig. 4).

Literature

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