Antihypertensive therapy for a comorbid patient: what to look for when choosing a drug?

Hypotensive effect - what is it? This question is asked by women and men who are faced with the problem of high blood pressure or hypertension for the first time and who have no idea what the hypotensive effect of the drugs prescribed to them by their attending physician means. An antihypertensive effect is a decrease in blood pressure under the influence of a particular drug.

Experienced professional therapists of the highest category at the Yusupov Hospital Therapy Clinic, who are proficient in advanced treatment and diagnostic methods, will provide qualified assistance to patients with arterial hypertension and select an effective treatment regimen that eliminates the development of negative consequences.

Antihypertensive therapy: general rules

Both symptomatic hypertension and hypertension require correction with drugs that have a hypotensive effect. Antihypertensive therapy can be carried out with drugs that differ in their mechanism of action: antiadrenergic agents, vasodilators, calcium antagonists, angiotensin antagonists, and diuretics.

You can obtain information about the hypotensive effect of the drug and what medications to take for high blood pressure not only from your doctor, but also from your pharmacist.

Arterial hypertension is a chronic disease that requires constant drug support, daily monitoring and regular use of prescribed medications. Not only the state of health, but also the life of a person depends on compliance with these rules.

Despite the general availability of treatment rules for reducing blood pressure, many patients have to be reminded what a treatment regimen for hypertension should look like:

• Antihypertensive medications should be taken regularly, regardless of the patient’s well-being and blood pressure level. This allows you to increase the effectiveness of blood pressure control, as well as prevent cardiovascular complications and target organ damage;
• It is necessary to strictly adhere to the dosage and use the form of the drug prescribed by the attending physician. Independently changing the recommended dose or replacing the drug may distort the hypotensive effect;
• even if you are constantly taking antihypertensive drugs, it is necessary to systematically measure blood pressure, which will allow you to evaluate the effectiveness of therapy, timely identify certain changes and adjust treatment;
• in the case of an increase in blood pressure against the background of constant antihypertensive treatment - the development of an uncomplicated hypertensive crisis, an additional dose of a previously taken long-acting drug is not recommended. Blood pressure can be quickly reduced using short-acting antihypertensive drugs.

Antihypertensive therapy: drugs to lower blood pressure

During antihypertensive therapy, several main groups of drugs that help lower blood pressure are currently used:

• beta blockers;
• ACE inhibitors;
• calcium antagonists;
• diuretics;
• angiotensin II receptor blockers.

All of the above groups have comparable effectiveness and their own characteristics that determine their use in a given situation.

Beta blockers

Drugs in this group reduce the likelihood of developing coronary complications in patients suffering from angina pectoris, prevent cardiovascular accidents in patients with myocardial infarction, tachyarrhythmia, and are used in patients with chronic heart failure. Beta-blockers are not recommended for patients with diabetes mellitus, lipid metabolism disorders and metabolic syndrome.

ACE inhibitors

Angiotensin-converting enzyme inhibitors have pronounced hypotensive properties, they have organoprotective effects: their use reduces the risk of complications of atherosclerosis, reduces left ventricular hypertrophy, and slows the decline in renal function. ACE inhibitors are well tolerated and have no negative effects on lipid metabolism and glucose levels.

Calcium antagonists

In addition to antihypertensive properties, drugs in this group have antianginal and organoprotective effects, help reduce the risk of strokes, atherosclerotic lesions of the carotid arteries and left ventricular hypertrophy. Calcium antagonists may be used alone or in combination with other drugs that have antihypertensive properties.

Diuretics

Diuretic drugs are usually used in combination with other antihypertensive drugs in order to enhance the therapeutic effect.

Diuretics are also prescribed to persons suffering from pathologies such as refractory hypertension and chronic heart failure. To avoid the development of side effects, when taking these drugs continuously, minimal dosages are prescribed.

Angiotensin II receptor blockers

Drugs in this group, which have neuro- and cardioprotective effects, are used to improve control of blood glucose levels. They can increase the life expectancy of patients suffering from chronic heart failure. Antihypertensive therapy using angiotensin II receptor blockers can be prescribed to patients who have had a myocardial infarction, suffer from renal failure, gout, metabolic syndrome and diabetes mellitus.

The results of clinical studies that assessed the incidence of certain clinical outcomes indicate that a sustained reduction in blood pressure (BP) leads to a statistically significant reduction in the risk of coronary heart disease (CHD) and stroke [1, 2]. It is an adequate reduction in blood pressure that is considered one of the necessary conditions for effective prevention of complications of cardiovascular diseases (CVD). The results of a meta-analysis of observational studies that included about 1 million people showed that a decrease in systolic blood pressure of only 2 mm Hg. Art. leads to a reduction in the risk of death from coronary artery disease and stroke by 7 and 10%, respectively [3].

Until recently, it was believed that any antihypertensive drugs recommended as first-line drugs were equally effective in reducing the risk of CVD complications [4, 5]. The first doubts about the effectiveness and safety of representatives of certain classes of antihypertensive drugs arose after receiving data from the ALLHAT (Antihypertensive and Lipid–Lowering Treatment to Prevent Heart Attack Trial) study [6] about a 25% increase in the combined risk of nonfatal myocardial infarction (MI) and cardiac death , as well as a twofold increase in the risk of developing heart failure when using the alpha-blocker doxazosin compared with placebo. Although results from the ALLHAT trial indicated similar effects of the thiazide diuretic chlorthalidone, the calcium antagonist (CA) amlodipine, and an angiotensin-converting enzyme (ACE) inhibitor on the primary composite rate of CAD events, evidence has emerged that thiazide diuretics and ACE inhibitors have different effects on the progression of asymptomatic carotid atherosclerosis. Thus, the use of monotherapy with hydrochlorothiazide (HCTZ) is supported by the recently published results of the PHYLLIS (Plaque HYpertension Lipid Lowering Italian Study) study [7], which show that with the use of HCTZ there is a statistically significant progression of atherosclerosis of the carotid arteries, while taking an ACE inhibitor does not accompanied by such changes.

In the ALLHAT trial [6], antihypertensive therapy with an ACE inhibitor resulted in a statistically significant reduction in the incidence of new cases of diabetes mellitus (DM) compared with a thiazide diuretic (odds ratio [HR] at 95% confidence interval [CI] 0.56 to 0.86).

The data presented showed that monotherapy with a thiazide diuretic cannot in all cases be considered the optimal tactics of antihypertensive treatment. It is not surprising that in real clinical practice, thiazide diuretics are used as first-line drugs in no more than 9% of patients [8].

In addition, in the ALLHAT study, during treatment with a thiazide antibiotic, a high incidence of hypokalemia was noted, which required the use of potassium supplements. In the chlorthalidone group, hypokalemia (plasma potassium concentration less than 3.5 mEq/L) after 2 years was observed in approximately 13% of patients, and by the 5th year of therapy, 8% of patients were forced to take potassium supplements. Thus, doubts arise about the validity of the use of diuretics as first-line drugs, at least in some patients with arterial hypertension (AH).

A recent meta-analysis published in the Lancet suggests that beta-blockers have a significantly lower effect on stroke compared with other antihypertensive agents, but no benefit in preventing MI or death [9]. The authors of the meta-analysis, based on the data obtained, express doubts about the validity of the use of beta-blockers as first-line antihypertensive drugs.

Another recent meta-analysis was performed to compare the effectiveness of ACE inhibitors and angiotensin II receptor blockers in reducing the risk of stroke, heart failure and MI [10]. The analysis technique made it possible to compare the effectiveness of drugs of these classes, regardless of their hypotensive effect. It was shown that ACE inhibitors and angiotensin receptor blockers do not differ statistically significantly in their effect on the incidence of stroke and heart failure, but when taking ACE inhibitors, a significant reduction in the risk of MI by 9% was noted. Taking angiotensin II receptor blockers was accompanied by a tendency to increase the risk of developing MI (by 7%). And although a retrospective analysis of data from the CHARM study [11] indicates a reduction in the risk of MI due to the use of candesartan in patients with heart failure, doubts remain about the equal effectiveness of ACE inhibitors and angiotensin receptor blockers in the prevention of MI.

Thus, the presented data from evidence-based medicine suggest that the most acceptable first-line antihypertensive drugs, which effectively reduce the risk of developing most CVD complications and have a positive effect on the course of atherosclerosis, can be considered dihydropyridine AKs and ACE inhibitors.

In the 1990s the results of individual observational studies [5] raised doubts about the safety of the use of dihydropyridine AA. It should be noted that, despite the widespread use of drugs in this class, until 1997 there were no large controlled studies assessing their effectiveness and safety [13]. It is now generally accepted that the best way to assess the effect of treatment on the incidence of adverse clinical outcomes is through randomized clinical trials that prospectively compare the effectiveness of drugs with each other, and in some cases with placebo or no therapy.

Evidence-based basis for the use of amlodipine in the treatment of hypertension

The possibility of preventing stroke using antihypertensive therapy was proven in the earliest randomized clinical trials of antihypertensive drugs, which are either not used today or are considered “old” [14]. The results of a recent meta-analysis [11], which compared the effectiveness of antihypertensive drugs belonging to different classes with placebo or no treatment, indicate the high effectiveness of AC use in the prevention of stroke. The risk of stroke when using beta-blockers, ACE inhibitors, diuretics and AKs was reduced by 29, 31, 34 and 40%, respectively.

The higher effectiveness of AKs compared to ACE inhibitors was confirmed in another meta-analysis performed on the basis of data from 28 clinical studies, including 179,122 patients [16]. It was shown that, in general, the use of AC or ACE inhibitors leads to a reduction in the risk of stroke by 11% compared with the use of beta-blockers and/or diuretics or placebo (p = 0.005). Taking ACE inhibitors compared with placebo was associated with a 16% reduction in the risk of stroke (p = 0.02). At the same time, the use of AC compared to placebo reduced the risk of stroke by 35% (p = 0.001).

The effectiveness of amlodipine and other dihydropyridine AKs is largely determined by their hypotensive effect. It should be noted that differences in BP levels between treatment groups may account for differences in efficacy between groups in several clinical trials [17–19], even in cases where the benefit of one treatment strategy over another was initially explained by a specific drug effect independent of the drug. blood pressure level [18, 19].

However, the effectiveness of amlodipine as a means of preventing CVD appears to be determined not only by its ability to lower blood pressure, but also by the presence of additional properties. The largest comparative clinical trial of antihypertensive drugs, ALLHAT [6], compared amlodipine with the best-studied diuretic, chlorthalidone. Despite the slightly more pronounced hypotensive effect of chlorthalidone compared to amlodipine (the difference in systolic blood pressure is 0.8 mm Hg), the use of AC was accompanied by a tendency to reduce the risk of stroke (by 8%). These data may indicate greater effectiveness of ACs compared to thiazide diuretics in reducing the risk of stroke in patients with hypertension.

The results obtained are very important, since currently reducing the risk of stroke is becoming one of the main goals of antihypertensive therapy. In the United States, stroke has become the third leading cause of death and one of the leading causes of permanent disability. In Russia, by the end of the 1990s. Mortality from stroke was in second place in the structure of overall mortality, second only to ischemic heart disease [20].

In recent years, the idea of ​​the goals of treatment for hypertension has changed somewhat. This concerns, first of all, the need for more careful monitoring of blood pressure levels and its normalization in most patients, and in many cases, the achievement of an optimal level, which may be lower than the values ​​currently recognized as “normal”. It is believed that the goals of effective antihypertensive therapy may be:

• reduction in the relative risk of developing CVD by at least 50% (corresponds to a decrease in systolic blood pressure by approximately 20 mm Hg);
• achieving generally accepted target blood pressure levels (140/90 mm Hg in most patients, 130/80 in diabetes and kidney disease) [21].

In fact, the optimal blood pressure value has not been established, although it is believed that this is the lowest blood pressure level that ensures the normal functioning of the organs and systems of a given body. To achieve this level, the use of more than one antihypertensive drug is usually necessary. Typically, taking one drug reduces systolic blood pressure by approximately 10 mmHg. Art., so it is obvious that to reduce it by 20 mm Hg. Art. combination use of drugs is required. That is why today it is more correct to talk not about the advantages of one class of antihypertensive drugs over another, but about the advantages of certain types of combination antihypertensive therapy.

In light of these ideas, one should refer to the recently published results of the ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm) study [22], which compared the effectiveness of preventing CVD complications in antihypertensive therapy based on the use of amlodipine in combination with perindopril and atenolol in combination with bendroflumethiazide (BFT). The effect of these combinations on the incidence of non-fatal myocardial infarction and mortality from coronary artery disease was assessed. It included 19,257 patients aged 40 to 79 years with untreated hypertension (systolic blood pressure ≥ 160 mm Hg and/or diastolic blood pressure ≥ 100 mm Hg) or treated hypertension (systolic blood pressure ≥ 140 mm Hg Art. and/or diastolic blood pressure ≥ 90 mm Hg) in the presence of at least 3 additional risk factors such as:

• left ventricular hypertrophy according to echocardiography or ECG,
• DM type 2;
• peripheral arterial disease;
• previous stroke or transient cerebrovascular accident;
• male gender;
• age ≥ 55 years;
• microalbuminuria or proteinuria;
• smoking;
• ratio of total cholesterol to high-density lipoprotein cholesterol in the blood ≥ 6;
• presence in the family history of indications of cases of premature development of coronary artery disease.

Patients were randomized to treatment groups based on the use of amlodipine with the addition of perindopril if necessary to enhance the hypotensive effect (amlodipine group; n = 9639) or atenolol with the addition of the thiazide diuretic BFT and potassium (atenolol group; n = 9618). The initial dose of amlodipine was 5 mg/day, if necessary it was increased to 10 mg/day.

The initial dose of atenolol was 50 mg/day, if necessary it was increased to 100 mg/day. If the use of amlodipine and atenolol in such doses was not effective enough, perindopril (4–8 mg/day) was added to amlodipine, and BFT (1.25–2.5 mg/day) was added to atenolol. If the desired effect was not achieved, then in both groups doxazosin was added to therapy (4–8 mg/day in the form of a gastrointestinal transport system).

The study was stopped early when the difference between groups in the primary composite endpoint (nonfatal MI or coronary death) had not yet reached statistical significance. The difficult decision to end the study early was due to the fact that there was a statistically significant difference between the groups in almost all additional indicators, including the risk of stroke. In the amlodipine group, its incidence was 23% lower than in the atenolol group (RR 0.77, 95% CI 0.66 to 0.89; p = 0.0003). Thus, the results of the ASCOT-BPLA study finally confirmed previously obtained data on the higher effectiveness of preventive therapy for stroke based on the use of AKs compared to treatment based on the use of beta-blockers and diuretics.

Some opponents of the ASCOT-BPLA study note that the difference in the effectiveness of the two antihypertensive therapy tactics could be largely due to the achievement of lower blood pressure levels in the group of combined use of amlodipine and perindopril compared with the use of atenolol and BFT. S. Yusuf noted the early appearance of differences in blood pressure levels between the amlodipine and atenolol groups [23]. However, this expert agrees with the study authors that differences in blood pressure levels can only partially explain the differences in the incidence of the clinical outcomes studied. Data from many clinical studies show that the difference between the amlodipine and atenolol groups in the level of systolic blood pressure, reaching 2.7 mm Hg. Art., could cause a difference in the incidence of complications of coronary artery disease, equal to 4–8%, and in the incidence of stroke, equal to 11–14%, and according to observational studies, 8 and 11%, respectively [24, 25]. FH Messerli notes that for him as a doctor it does not matter whether the greater effectiveness of one treatment tactic compared to another depends on the severity of the hypotensive effect or on the presence of additional properties of the drugs used [26]. In his opinion, the answer to this question is of interest primarily to researchers and scientists, but not to practicing doctors.

There is another important result of the ASCOT study regarding stroke prevention. It turned out that the most effective prevention of this complication is achieved with the combined use of AK, an ACE inhibitor and a statin. Compared with the use of a beta-blocker and a diuretic, the combined use of amlodipine, perindopril and atorvastatin led to a reduction in the relative risk of fatal and non-fatal stroke by 44% [26].

There is evidence that amlodipine may be superior in tolerability to other known AKs. In a comparative study of compliance with therapy with amlodipine and felodipine in elderly patients with hypertension, it was shown that after a year of treatment in the amlodipine group, the likelihood of discontinuing therapy was 21% lower than in the felodipine group [27].

Possible mechanisms for the high effectiveness of amlodipine in the treatment of hypertension

Since there is a relationship between elevated blood pressure levels and the risk of stroke, one of the mechanisms determining the high effectiveness of ACs in the prevention of this complication may be their rather pronounced hypotensive effect. A greater reduction in blood pressure with AA compared to other drugs was observed in several randomized clinical trials, for example, VALUE (Valsartan Antihypertensive Lon gamma-term Use Evaluation) [28] and ASCOT-BPLA [19]. This more pronounced hypotensive effect was accompanied in the VALUE study by a clear trend towards a 15% reduction in the incidence of stroke in the amlodipine group compared with the valsartan group (p = 0.08). In the ASCOT-BPLA [19] and FEVER (Felodipine EVent Reduction) studies [29, 30], even a small difference in blood pressure between the AC group and the control group was accompanied by a statistically significant reduction in the risk of stroke.

And yet, why is there such a small difference in systolic blood pressure in the ASCOT-BPLA study - 2.7 mm Hg? Art. – was there such a significant difference in the incidence of stroke between the amlodipine and atenolol groups? Part of the answer to this question was obtained in the CAFE (Conduit Artery Function Evaluation) study [31], which was planned as part of the main ASCOT study. CAFE, which included more than 2000 participants in the pivotal ASCOT trial, assessed the effect of 2 antihypertensive treatment strategies on central aortic pressure measured using a noninvasive technique using the US FDA-approved Sphygmocor system (AtCor Medical).

After measuring the pressure in the radial artery, the computer system generated a pulse wave, the evaluation of which allowed the pressure in the large arteries to be measured. It turned out that with almost the same level of blood pressure measured in the brachial artery, the central systolic blood pressure was 4.3 mm Hg. Art., and the central pulse pressure in the aorta is 3.0 mm Hg. Art. lower with treatment tactics based on amlodipine compared with tactics based on the use of atenolol.

The results of the CAFE study suggest that for the same blood pressure measurements on the arm, the pressure in the central arteries can differ significantly when using antihypertensive drugs, which have different effects on the so-called reflected waves. In particular, amlodipine, due to its active vasodilating effect, more effectively reduces the severity of reflected waves compared to beta-blockers and diuretics. When using a drug with a vasodilating effect, the power of reflected waves weakens, which is accompanied by a decrease in central blood pressure. The CAFE study authors suggest that the statistically significant difference in clinical efficacy between amlodipine and atenolol observed in the ASCOT study can largely be explained by their different effects on central arterial pressure.

The positive effect of long-acting OCs on the risk of stroke may be partly due to their effect in preventing increases in blood pressure in the morning. There is convincing evidence of a connection between morning increases in blood pressure and the risk of stroke [32]. With an increase in blood pressure in the morning and without it, the incidence of stroke over 3.5 years was 19.0 and 7.3%, respectively (p = 0.004). Morning increase in systolic blood pressure by 10 mm Hg. Art. is accompanied by an increase in the risk of stroke by 22–25% [32, 33]. In a comparative study of amlodipine and valsartan, it was shown that the use of AK allows a statistically significant reduction in the level of systolic blood pressure in the morning compared with an angiotensin II receptor blocker (p < 0.02) [34].

The results of a clinical study that included 106 patients with mild and moderate hypertension indicate that the combined use of a small dose of amlodipine (5 mg/day) and an average therapeutic dose of an ACE inhibitor leads to a more pronounced increase in arterial distensibility compared to the use of maximum therapeutic doses of drugs [35]. When using combined therapy, maximum doses of amlodipine and ACE inhibitor, distensibility increased by 0.71 ± 0.51, 0.28 ± 0.69 and 0.39 ± 0.62% ml/mmHg. Art. The use of combination therapy also led to a statistically more pronounced regression of left ventricular myocardial hypertrophy compared to monotherapy with each drug (p < 0.02). These data may be the basis for wider use of combination drugs containing amlodipine and an ACE inhibitor.

Efficacy and safety of dihydropridine ACs for the prevention of stroke in patients with diabetes

In 1999, a review was published in the New England Journal Medicine, which noted that “the use of AA in diabetes may lead to an increased risk of developing CVD” [36]. This opinion was based on an analysis of limited data obtained from clinical trials [37, 38]. The results of a meta-analysis of randomized clinical trials, which were published in 2004, completely refuted the above statement [39]. It was shown that the use of AC in patients with diabetes led to a statistically significant reduction in overall mortality and the incidence of all adverse clinical outcomes associated with heart disease, as well as stroke, compared with placebo.

In patients with diabetes, the use of AC had a similar effect on the risk of developing coronary artery disease and overall mortality as standard therapy, while causing a slight reduction in the risk of stroke (HR = 0.87; p = 0.08) [39]. Thus, the use of AC in patients with diabetes turned out to be an effective and safe method for preventing most CVD complications and death from them. However, the use of ACs did not reduce the risk of heart failure, especially compared with drugs that suppress the activity of the renin-angiotensin system, although drugs of these classes had a similar effect on overall mortality and the incidence of stroke or coronary artery disease. It should, however, be taken into account that the diagnosis of “heart failure” during the use of AC may be established erroneously and be a consequence of slight fluid retention.

It is also known that in patients with diabetes, monotherapy with non-dihydropyridine AA is more effective in reducing the severity of proteinuria than monotherapy with dihydropyridine drugs of this class. However, with the combined use of AKs and ACE inhibitors, such a difference, according to FH Messerli [26], may become clinically insignificant.

Thus, the results of recently completed clinical studies indicate that amlodipine, both due to its fairly powerful hypotensive effect and due to the likely presence of additional properties, is becoming one of the main drugs for the treatment of CVD, since its use not only reduces the symptoms of the disease , but also reduce in many cases the risk of developing such severe complications of CVD as MI, stroke and premature death.

Evidence-based basis for the selection of drugs for combination antihypertensive therapy

The theoretical basis for the combined use of dihydropyridine AA and ACE inhibitors can be data from randomized clinical trials, the results of which indicate a higher effectiveness of initial therapy with drugs of these two classes compared with monotherapy of each of them [40].

The justification for the use of ACE inhibitors as part of combined antihypertensive drugs is determined by the fact that their use not only leads to a decrease in blood pressure, but also allows one to achieve other goals of therapy, including regression of left ventricular hypertrophy [41]. Being an important indicator of target organ damage, left ventricular myocardial mass is considered the most informative prognostic factor for the development of adverse clinical outcomes in patients with hypertension. According to a comparative analysis of the effectiveness of diuretics, AC, beta-blockers and ACE inhibitors, the latter cause the greatest regression of hypertrophy [42, 43]. ACE inhibitors also have a nephroprotective effect [44]. Some ACE inhibitors, in particular lisinopril, have been shown to reduce not only the severity of left ventricular hypertrophy, but also myocardial fibrosis, which is accompanied by an improvement in diastolic heart function [45].

The combined use of a dihydropyridine AK and an ACE inhibitor can be considered an effective treatment tactic for patients with isolated systolic hypertension, since in this case a more pronounced reduction in systolic blood pressure is provided than with monotherapy with these drugs [46]. To make a final judgment about the prospects of the combined use of amlodipine and an ACE inhibitor for the treatment of isolated systolic hypertension, a large clinical trial, Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) [47], which is planned to include more than 6000 patients with hypertension, is currently being conducted. .

The occurrence of peripheral edema is considered a common complication of dihydropyridine ACs [48] and often becomes the reason for refusal to continue therapy. The occurrence of such edema is due to a pronounced expansion of the lumen of the arterioles while maintaining the same diameter of the lumen of the venules. In this case, insufficient blood outflow from peripheral tissues causes the formation of edema. Additional use of diuretics for these edemas may be ineffective. The combined use of amlodipine and an ACE inhibitor, compared with therapy with AA alone, can almost halve the incidence of edema due to the venodilating effect of ACE inhibitors [48].

Evidence-based basis for the use of lisinopril as part of combination therapy

The choice of any drug for the treatment and prevention of CVD largely depends on the availability of evidence of the effectiveness of its use in at least one of these diseases. Data on the effectiveness of using even small doses of lisinopril in the treatment of heart failure were obtained in the large clinical trial ATLAS (Assessment of Treatment with Lisinopril And Survival) [49]. At the same time, the safety of using high doses of lisinopril was noted [50], which is especially important for patients with hypertension, in whom an increase in the dose of the ACE inhibitor may be required to achieve the necessary hypotensive effect. The results of a secondary analysis of data from 3164 participants in the ATLAS study who had a high risk of developing CVD complications (including patients with diabetes) confirmed the safety of high-dose lisinopril [51].

Further justification for the widespread use of lisinopril in the treatment of hypertension, especially in patients with metabolic syndrome, is data from the ALLHAT trial, indicating that the use of this drug led to a 32% reduction in the risk of developing new cases of diabetes compared with the use of chlorthalidone (RR 0 .68 with 95% CI from 0.50 to 0.80; p = 0.01). At the same time, lisinopril in preventing the development of diabetes was more effective than amlodipine, treatment of which led to a reduction in the risk of developing diabetes by only 21% [6].

The effectiveness of lisinopril in hypertension has been proven in several randomized clinical trials. According to the multicenter placebo-controlled TROPHY (Treatment in Obese Patients With Hypertension) study, lisinopril monotherapy was not inferior to HCTZ monotherapy in terms of the effectiveness of lowering blood pressure in hypertensive patients with obesity [52]. However, it should be noted that in 57% of patients in the lisinopril group, the initial dose of the drug (10 mg/day) was effective, while in the HCTZ group, half of the patients needed to increase the dose of the drug to the maximum (50 mg/day).

The high effectiveness of the combined use of lisinopril and amlodipine was confirmed in a small prospective study that included 98 patients with hypertension [53]. The combined use of these drugs led to a significant decrease in systolic (from 197.7 ± 18.1 to 139.9 ± 10.5 mm Hg) and diastolic blood pressure (from 107.1 ± 13.1 to 82.6 ± 5 .5 mmHg). Treatment was well tolerated - therapy was discontinued in only 3 patients due to the development of swelling of the legs and dry cough.

Recently, when assessing the effectiveness of antihypertensive drugs, they are increasingly focusing on the so-called surrogate evaluation criteria. The results of a small study indicate that the use of lisinopril in elderly patients with systolic hypertension led to a pronounced hypotensive effect, increased blood flow through the cerebral vessels and increased distensibility of the carotid arteries, but did not cause cerebral hypoperfusion [54]. At the same time, there was a decrease in vascular resistance without disruption of autoregulation of cerebral circulation.

The results of the ELVERA study (Effects of amlodipine and lisinopril on Left Ventricular mass) [55], which included patients aged 60–75 years with newly diagnosed hypertension, indicate a statistically significant decrease in the total thickness of the intima and media of the carotid arteries while taking lisinopril (by 0.065 mm) and amlodipine (by 0.089 mm). These data indicate the antiatherosclerotic effect of the drugs.

Microalbuminuria is considered one of the main risk factors for the development of CVD complications, and its reduction is accompanied by a decrease in the incidence of adverse clinical outcomes. Data obtained in the EUCLID (EURODIAB Controlled Trial of Lisinopril in Insulin–Dependent Diabetes Mellitus) study [56] indicate the effectiveness of lisinopril in slowing the progression of renal dysfunction in patients with type 1 diabetes in the presence of microalbuminuria. However, therapy with lisinopril did not lead to an increase in the risk of hypoglycemia.

Thus, according to modern concepts, the optimal tactics of combination antihypertensive therapy in many patients includes the combined use of a long-acting dihydropyridine AA, for example amlodipine, and one of the ACE inhibitors with proven effectiveness, which includes lisinopril.