Metabolic and vascular effects of indapamide retard and hydrochlorothiazide in patients with arterial hypertension and metabolic syndrome

The dissertation is devoted to the comparative evaluation of the metabolic and vascular effects of two thiazide diuretics — indapamide retard and hydrochlorothiazide — in patients with essential arterial hypertension and metabolic syndrome. The study was designed as a prospective randomized clinical trial analyzing the dynamics of blood pressure, parameters of lipid and carbohydrate metabolism, total coronary risk, vascular endothelial function and the activity of the platelet-vascular component of hemostasis.

The author examines the concept of the metabolic syndrome as a unifying pathogenetic basis of atherosclerosis and arterial hypertension and analyzes the differences between the diuretics in their influence on intermediate end points of cardiovascular risk. The data obtained are intended to substantiate a differentiated approach to the choice of diuretic therapy in patients at high cardiovascular risk.

RELEVANCE OF THE PROBLEM. According to the data of the World Health Organization, cardiovascular diseases are the cause of one third of all deaths registered in the world, and, despite the expanding possibilities of therapy, morbidity is steadily increasing both in developed and in developing countries. Arterial hypertension is a well-studied risk factor for coronary heart disease and stroke, and its prevalence and contribution to mortality from cardiovascular diseases are extremely high (7.1 million premature deaths worldwide). [274] In Russia, the prevalence of AH among the adult population reaches more than 40% in men and 30% in women [289, 296, 297, 319, 329, 332, 333].

A close association between arterial hypertension and atherosclerosis of the vessels and its complications can be traced in many aspects. Thus, on the one hand, arterial hypertension is an independent risk factor for atherosclerosis, and on the other hand many risk factors for atherosclerosis, such as obesity, sedentary lifestyle, disorders of carbohydrate and lipid metabolism, and stress, are risk factors for arterial hypertension itself. In addition, despite the fact that in arterial hypertension the vessels are subjected to high pressure, its main complications (myocardial infarction, stroke) are not hemorrhagic but atherothrombotic [142]. At present, these interrelationships can to a large extent be explained by the concept of the metabolic syndrome, proposed in 1988 by Gerald Reaven [198], which on a pathogenetic basis unites a number of the most important risk factors for atherosclerosis (dyslipidemia, disorders of carbohydrate metabolism, obesity) and arterial hypertension, and also explains the mechanisms of damage to the vascular wall, accelerated atherosclerosis and activation of the hemostasis system in the presence of this complex of disorders. According to a review of 11 prospective studies, the prevalence of the metabolic syndrome in the adult European population amounts to 15%, while arterial hypertension among these patients is detected in 66.5% of men and 60.5% of women [104].

No less important is the issue of pharmacological therapy of arterial hypertension. At present, there are 5 classes of antihypertensive drugs with a proven influence on final cardiovascular end points (diuretics, beta-adrenoblockers, calcium antagonists, ACE inhibitors and angiotensin receptor blockers) [96], as well as 2 classes of drugs (imidazoline receptor antagonists and alpha-adrenoblockers) proposed as basic ones in the latest Russian Recommendations for the treatment of arterial hypertension [305].

Despite the fact that hypotensive drugs have obvious differences in their mechanism of action and in a number of pleiotropic effects, such as influence on neuro-humoral systems, blood lipids, carbohydrate metabolism, the vascular wall and the blood coagulation system, the majority of large prospective studies have not revealed differences in clinical efficacy among the five main classes of hypotensive drugs in patients with arterial hypertension. Nevertheless, discussions about the presence in certain drugs of advantages over others in terms of improvement of cardiovascular prognosis, especially in particular groups of patients, continue to the present day. One of the reasons for the persisting disagreements on this issue is the relatively short duration of controlled studies (4-5 years), whereas in reality the duration of hypotensive therapy in the majority of patients may amount to decades. As an alternative, for the determination of the efficacy of hypotensive therapy, in addition to the hypotensive effect, it is proposed to evaluate so-called "intermediate end points", such as changes in lipid and carbohydrate metabolism and the morphological and functional state of the vascular wall [96, 190].

Diuretics, in particular thiazide diuretics, are the oldest hypotensive drugs; however, in the latest recommendations on arterial hypertension they are advanced as drugs of "first choice" for the treatment of AH [240]. Hydrochlorothiazide is the most studied drug of this class. Along with positive clinical effects, its unfavorable metabolic effects are well known, such as changes in blood lipids and influence on carbohydrate metabolism [27, 83]. In the small number of available studies, hydrochlorothiazide did not demonstrate the ability to restore the function of the vascular endothelium [175, 182] and exerted an unfavorable influence on the progression of carotid atherosclerosis in the large clinical trial PHYLLIS [281].

At present, on the market of hypotensive drugs, another diuretic close in its mechanism of action to the thiazide diuretics, indapamide, is actively promoted. There is a number of studies demonstrating the metabolic neutrality of indapamide (especially of its retard form) even in subjects with AH and diabetes mellitus [126, 264]. There are experimental works demonstrating the presence in indapamide of positive endothelial [25, 62, 133, 209] and antiatherogenic effects [61, 130].

The presence of real differences between these drugs in metabolic and vascular effects and in the influence on cardiovascular prognosis may exert a substantial influence on the priorities in the prescription of diuretics in patients with arterial hypertension, especially in groups at high cardiovascular risk, and ultimately on the efficacy of hypotensive therapy.

Taking into account the above data and the absence of direct comparative clinical studies of the influence of hydrochlorothiazide and indapamide on the process of atherogenesis and cardiovascular risk, it appears relevant to carry out a comprehensive evaluation of the clinical efficacy of indapamide retard, its influence on the components of cardiovascular risk (lipid and carbohydrate metabolism) and on the risk of atherothrombotic complications (vascular wall and primary hemostasis) in patients with arterial hypertension and metabolic syndrome in comparison with the standard diuretic, hydrochlorothiazide, in a prospective randomized study.

AIM OF THE STUDY. In order to optimize the treatment of patients with AH and MS, to carry out a comparative evaluation of the influence of indapamide retard and hydrochlorothiazide on metabolic parameters, EF and the activity of the platelet component of hemostasis.

OBJECTIVES OF THE STUDY:

1. To compare the clinical efficacy and the influence on lipid and carbohydrate metabolism and on total coronary risk of therapy with indapamide retard and hydrochlorothiazide in patients with essential AH.

2. To evaluate the influence of therapy with indapamide retard and hydrochlorothiazide on the function of the vascular wall and on the activity of the platelet-vascular component of hemostasis in patients with essential AH.

3. To identify the leading factors influencing changes in total coronary risk, in indicators of the function of the vascular wall and in the activity of the platelet-vascular component of hemostasis during therapy with indapamide retard and hydrochlorothiazide in patients with essential AH.

4. To carry out a comparative evaluation of the metabolic and endothelial effects of indapamide retard and hydrochlorothiazide in patients with metabolic syndrome.

SCIENTIFIC NOVELTY. For the first time, a direct comparison has been carried out of the clinical efficacy, metabolic and vascular effects, and influence on the activity of the primary component of hemostasis of two thiazide diuretics — indapamide retard and hydrochlorothiazide — in essential AH and MS.

It has been proved that, with equal hypotensive efficacy, the two diuretics differ in their influence on metabolic parameters, CV risk and the function of the vascular wall, with a positive or neutral effect for indapamide retard and a negative effect for hydrochlorothiazide. The ability of indapamide retard to reduce the activity of the platelet-vascular component of hemostasis has been demonstrated. The main factors influencing changes in TCR and in the function of the vascular wall during diuretic therapy have been determined. The unfavorable influence of metabolic shifts developing during therapy with hydrochlorothiazide on the dynamics of TCR and of vasomotor EF has been shown. It has been revealed that, in MS, the negative metabolic and vascular effects of hydrochlorothiazide are expressed to a greater degree than in patients with essential AH overall, whereas in this group of patients as well, indapamide retard exerts no unfavorable influence on metabolic parameters and exerts a positive influence on EF.

PRACTICAL SIGNIFICANCE. The necessity has been substantiated of monitoring indicators of lipid and carbohydrate metabolism for the evaluation of the efficacy of therapy and of CV prognosis in the prescription of hydrochlorothiazide to patients with essential AH, whereas for the determination of the efficacy of therapy with indapamide retard, monitoring of the AH level is sufficient. The differences revealed between the two diuretics necessitate a differentiated approach to the prescription of pharmacological therapy in patients with AH, especially in the presence of MS. The importance has been substantiated of using indicators of vasomotor EF in the comprehensive evaluation of CV prognosis at the early stages of pharmacological therapy of AH.

MAIN STATEMENTS PRESENTED FOR DEFENSE:

1. With an equal hypotensive effect, therapy with hydrochlorothiazide for 3 months at a dose of 25 mg/day, in comparison with indapamide retard at a dose of 1.5 mg/day, leads to a significant increase in the level of triglycerides and blood glucose and does not reduce total coronary risk.

2. The two diuretics differ significantly in their influence on vasomotor EF and on the dilatory reserve of the arteries, with improvement during therapy with indapamide retard and worsening during therapy with hydrochlorothiazide. Indapamide retard, in contrast to hydrochlorothiazide, possesses an additional antiaggregant effect, reducing spontaneous platelet aggregation.

3. The reduction of TCR during treatment with indapamide retard occurs due to the hypotensive effect of the drug, while its endothelial and antiaggregant effects do not depend on the degree of reduction of AH and on changes in metabolic parameters. The negative metabolic changes induced by hydrochlorothiazide exert an unfavorable influence on the dynamics of TCR and of vasomotor EF. The reduction of AH during diuretic therapy diminishes the severity of damage to the vascular wall and increases the dilatory reserve of the arteries.

4. In MS, the negative metabolic and vascular effects of hydrochlorothiazide are expressed to a greater degree than in patients with essential AH overall, whereas indapamide retard, in this group of patients as well, exerts no unfavorable influence on metabolic parameters and exerts a positive influence on EF.

IMPLEMENTATION INTO PRACTICE. The propositions developed in the dissertation are used in the work of the hospital and polyclinic of Omsk City Clinical Hospital No. 1 named after A. N. Kabanov (an act of implementation is available).

APPROBATION OF THE WORK. The main propositions of the dissertation were reported at the 1st Joint Congress of the International and European Societies of Hypertension (Prague, Czech Republic, 2002), the 1st Interregional Scientific and Practical Conference "Actual Problems of Hemostasiology and Endotheliology" (Omsk, 2003), the XIV and XV European Congresses on Hypertension (Paris, France, 2004 and Milan, Italy, 2005), the II Interregional Scientific and Practical Conference "Vascular Pathology and Hemostasis" (Omsk, 2005), and the International Conference Artery 5 (Paris, France, 2005).

PUBLICATIONS. On the topic of the dissertation, 19 works have been published.

STRUCTURE AND VOLUME OF THE WORK. The dissertation is set out on 144 pages of typewritten text and consists of an introduction, 3 chapters, a conclusion, conclusions, practical recommendations, and a bibliography including 48 domestic and 286 foreign sources. The work is illustrated with 28 tables and 8 figures.