Effects of ramipril in patients with type 2 diabetes mellitus and hypertension

Diabetes mellitus (DM) is one of the most common diseases in the modern world, its structure is dominated by type 2 diabetes mellitus, the number of patients is about 250 million people. Arterial hypertension (AH) occurs in approximately 80% of patients with type 2 diabetes mellitus. The comorbidity of these two interrelated diseases significantly increases the incidence of premature disability and the mortality of patients from cardiovascular complications. Consequently, correction of blood pressure (BP) is a priority task in the treatment of patients with diabetes mellitus. Among modern antihypertensive drugs, perhaps the most studied class of drugs are angiotensin-converting enzyme (ACE inhibitors).

Indeed, currently the leading role in the pathogenesis of arterial hypertension in patients with type 2 diabetes is associated with activation of sympathetic-adrenal and renin-angiotensin systems (RAS). The key effector hormone of RAS is angiotensin, which has a powerful vasoconstrictor effect, increases the reabsorption of sodium and water, sympathetic and adrenal activity and regulates not only functional but also structural changes in the myocardial and vascular tissues.

Pharmacological action and ACE is the ability to suppress the activity of angiotensin I-converting enzyme (or kininase II) and, thus, the effect on the functional activity of PAC and kallikrein-kinin systems. By inhibiting the activity of angiotensin I-converting enzyme, ACE inhibitors reduce the formation of angiotensin II and, as a result, weaken the main cardiovascular effects of PAC, including arterial vasoconstriction and aldosterone secretion.

One of the ACEIs is ramipril (polupril, Polpharma Pharmaceutical Works SA, Actavis hf, Actavis Ltd., Poland / Iceland / Malta), which unlike other drugs in this group significantly reduces the incidence of myocardial infarction, stroke and cardio - vascular death in patients with increased cardiovascular risk due to vascular disease (coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus, who have at least one additional risk factor (microalbuminuria, arterial hypotension ertensia, increased total cholesterol, low levels of high-density lipoproteins, smoking); reduces overall mortality and the need for revascularization procedures, slows the onset and progression of chronic heart failure. As in patients with diabetes mellitus, and without it, ramipril significantly reduces the existing microalbuminuria and the risk of developing nephropathy.

The aim of the study was to study the clinical, hemodynamic and biochemical effects of 12-week ramipril in patients with type 2 diabetes and arterial hypertension.

The study included 40 patients (25 women and 15 men) - the main group - over the age of 50 with arterial hypertension and type 2 diabetes mellitus. Exclusion criteria were severe uncontrolled arterial hypertension (AD> 200/110 mm Hg), severe liver disease, acute cerebrovascular accident or acute myocardial infarction during the last 6 months, unstable angina, congestive heart failure, terminal stages of microvascular complications of diabetes mellitus.

All patients with arterial hypertension and type 2 diabetes for therapy received ramipril. The therapy lasted for 12 weeks. The initial dose of ramipril was 2.5 mg. Titration of the dose of drugs occurred every 2 weeks according to the standard scheme. The control group consisted of 25 practically healthy persons. The diagnosis of AH and diabetes mellitus was verified in accordance with the current criteria.

The study of the indices was carried out before and after treatment.

The study of the structural and functional state of the myocardium by Echo-CG and Doppler echocardiography was performed using the Ultima pro 30 (Holland) device in M-modal and two-dimensional regimens, in standard echocardiographic positions. The thickness of the walls and the size of the cavity of the left ventricle (LV) were determined from the parasternal position of the LV axis in the M-mode with an ultrasonic beam parallel to the short axis of the LV. The following parameters were determined: ejection fraction (EF,%), end-diastolic and end-systolic dimensions (CDR and CSF) of LV in cm, end-diastolic and end-systolic volumes (BDW and CSR) of LV. The mass of the myocardium of LV was calculated by the formula:

MMLZH = 1.04 [(MZV + LZZHZH + KDR) 3 - (KDP) 3] - 13.6,

Where 1.04 is the density of the myocardium (in g / cm2) and 13.6 is the correction factor per gram.

All patients underwent 24-hour BP monitoring ("Meditech", "CardioTens"). Depending on the value of the daily index, the following groups of patients were distinguished: "dipper" - 10-22%, "non-dipper" - <10%, "over-dipper" -> 22%, "night-peaker" - negative value of daily index . The upper limits of the norm of variability of day and night systolic blood pressure were 15.7 and 15.0 mm Hg. Art. Respectively, diastolic - 13.1 and 12.7 mm Hg. Art.

Determination of the content of glycosylated hemoglobin (HbAlc) in whole blood was performed by photometric method by reaction with thiobarbituric acid using the commercial test system of Reagent (Ukraine) in accordance with the attached instruction.

The glucose level was determined by the glucose oxidative method in capillary blood taken on an empty stomach. Normal was considered to be a glucose level of 3.3-5.5 mmol / l.

The serum insulin level was established by an enzyme immunoassay using the ELISA kit (USA). The expected range of insulin values is normally 2.0-25.0 mC / ml.

Determination of the level of total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL cholesterol), low density lipoprotein cholesterol (LDL cholesterol), very low density lipoprotein cholesterol (VLDL) and atherogenic coefficient (CA) enzymatic photocolorimetric method by the sets of the firm "Human" (Germany).

The content of resistin and adiponectin in the serum of patients was determined by the enzyme immunoassay on the enzyme immunoassay analyzer "Labline-90" (Austria). The determination of the resistin level was carried out using a commercial test system manufactured by BioVendor (Germany); the level of adiponectin - using a commercial test system manufactured by ELISA (USA).

For statistical processing of the data obtained, the computer program "Statistics 8.0" (Stat Soft, USA), the method of variational statistics (Student's test) was used; The relationship between the signs was evaluated using correlation analysis.

In the preliminary analysis, the output anthropometric (body weight, BMI, waist and hip volume), hemodynamic (SBP and DBP, heart rate, pulse) and biochemical parameters of carbohydrate metabolism in the group before treatment and after treatment did not differ significantly (p> 0.05). On the basis of this, it can be stated that the effect of the investigated method of drug therapy was realized on an identical background.

The level of HDL cholesterol was significantly increased by 4.1% (p <0.05), which is probably associated with a decrease in the catabolism of these lipoproteins. A decrease in the TG content by 15.7% (p <0.05) and LDL by 17% (p <0.05) was noted, which may be associated with an increase in tissue sensitivity to insulin and a decrease in hyperinsulinemia, which largely determine the rate education and metabolism of these lipids in the body. Other parameters of lipid metabolism did not change significantly.

When studying the dynamics of adipocytocone metabolism against the background of ongoing therapy with ramipril, a significant decrease in the level of resistin was detected by 10% and an increase in the level of adiponectin by 15% (p <0.05). This can be explained by the fact that resistin is considered as a mediator of insulin resistance, and its decrease, possibly, is associated with an increase in the sensitivity of tissues to insulin.

Ramipril therapy contributed to a significant decrease in wall thickness, LV mass and size (p <0.05) and an increase in myocardial contractility by 2.3% (p <0.05).

According to SMAD, the initial mean level of blood pressure corresponded to the 2-nd degree of arterial hypertension. Increased pulsatile blood pressure and variability of systolic blood pressure during the day were noted, which are independent risk factors for cardiovascular complications. Among the patients examined, there were 16 dippers, 14 non-dippers, 6 over-dippers and 4 night-peakers. It should be noted that an insufficient reduction in blood pressure at night is a confirmed risk factor for cardiovascular and cerebrovascular complications.

In the course of SMAD, normalization of mean systolic and diastolic blood pressure was revealed. Target blood pressure levels were achieved in 24 (60%) patients. In addition, as a result of treatment, the degree of pressure loading was reduced and the variability of systolic blood pressure normalized during the day. The value of pulse BP during the day, reflecting the rigidity of the main arteries and being an independent cardiovascular risk factor, normalized after 12 weeks.

Therapy with ramipril favorably influenced the daily rhythm of BP. The number of patients with a normal diurnal index (dippers) increased to 23, and the number of patients with a predominantly nocturnal increase in blood pressure (night-peakers) decreased to 2. Cases of excessive blood pressure lowering at night (over-dipper) were not recorded.

The results confirm the effectiveness of ramipril at a dose of 10 mg / day in the treatment of mild and moderate arterial hypertension in patients with type 2 diabetes. The therapy was effective, target BP values were achieved in 24 (60%). In addition, ramipril had a beneficial effect on the indicators of SMAD, which are considered cardiovascular risk factors, in particular, caused a decrease in the pressure load index and normalization of the variability of systolic blood pressure during the day. The latter index increases the risk of damage to target organs and positively correlates with the mass of the myocardium and abnormal geometry of the LV, the level of resistin. The parameters of the circadian rhythm of blood pressure, the violation of which in patients with type 2 diabetes is associated with more than a 20-fold increase in the risk of cardiovascular death, significantly improved. Normalization against the background of pulse pressure therapy in the daytime testifies to the improvement of the elastic properties of the wall of large vessels and reflects the positive effect of the drug on the processes of vascular remodeling.

After 12 weeks, a significant improvement in carbohydrate and lipid metabolism was revealed, which certainly contributes to reducing cardiovascular risk.

Thus, ramipril meets all the requirements for antihypertensive drugs and provides not only adequate daily control of blood pressure, but also has a positive metabolic effect, which leads to a significant reduction in the risk of development and progression of cardiovascular complications.

Therefore, we can draw the following conclusions.

Against the background of ongoing therapy with the inclusion of ramipril, significant improvements in carbohydrate, lipid and adipocytokine metabolism were noted.
Therapy with ramipril in patients with arterial hypertension and type 2 diabetes mellitus led to a significant decrease in blood pressure during the day, normalization of the load index by day and night pressure and a disturbed two-phase profile of blood pressure and a significant decrease in the variability of systolic blood pressure during the day. The use of ramipril is accompanied by a low incidence of side effects, which increases adherence to treatment and its effectiveness.

Prof. PG Kravchun, OI Kadykova. Effects of ramipril in patients with type 2 diabetes mellitus and arterial hypertension // International Medical Journal - №3 - 2012

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