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

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

Indeed, at present, the leading role in the pathogenesis of arterial hypertension in patients with type 2 diabetes mellitus is attributed to the activation of the sympathetic-adrenal and renin-angiotensin systems (RAS). The key effector hormone of the 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 myocardial and vascular tissues.

The pharmacological action of ACE is the ability to suppress the activity of angiotensin I-converting enzyme (or kininase II) and, thus, influence the functional activity of the RAS 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 the RAS, including arterial vasoconstriction and aldosterone secretion.

One of the ACE inhibitors is ramipril (Polapril, 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 cardiovascular death in patients with increased cardiovascular risk due to vascular diseases (ischemic heart disease, previous stroke or peripheral vascular disease) or diabetes mellitus, who have at least one additional risk factor (microalbuminuria, arterial hypertension, increased total cholesterol, low high-density lipoprotein, smoking); reduces overall mortality and the need for revascularization procedures, slows the onset and progression of chronic heart failure. Both in patients with and without diabetes mellitus, ramipril significantly reduces existing microalbuminuria and the risk of developing nephropathy.

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

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

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

The study of indicators was carried out before and after treatment.

The study of the structural and functional state of the myocardium using echocardiography and Doppler echocardiography was performed using the Ultima pro 30 apparatus (Holland) in M-modal and two-dimensional modes, in standard echocardiographic positions. The wall thickness and dimensions of the left ventricle (LV) cavity were determined from the parasternal position of the LV axis in M-mode with an ultrasound beam parallel to the short axis of the LV. The following parameters were determined: ejection fraction (EF, %), end-diastolic and end-systolic sizes (EDS and EDS) of the LV in cm, end-diastolic and end-systolic volumes (EDV and ESV) of the LV. The mass of the LV myocardium was calculated using the formula:

LVMM = 1.04 [(LVS + LVSD + EDR)3 -- (EDR)3] - 13.6,

Where 1.04 is the myocardial density (in g/cm2) and 13.6 is the correction factor in grams.

All patients underwent 24-hour BP monitoring (ABPM) (Meditech, CardioTens). Depending on the value of the 24-hour index, the following groups of patients were distinguished: "dipper" - 10-22%, "non-dipper" - < 10%, "over-dipper" -> 22%, "night-peaker" - negative value of the 24-hour index. The upper limits of the norm for variability of daytime and nighttime systolic BP were considered to be 15.7 and 15.0 mm Hg, respectively, diastolic - 13.1 and 12.7 mm Hg.

Determination of the content of glycosylated hemoglobin (HbAlc) in whole blood was carried out by a photometric method using a reaction with thiobarbituric acid using a commercial test system from the Reagent company (Ukraine) in accordance with the attached instructions.

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

The level of insulin in the blood serum was determined by the enzyme immunoassay using the ELISA kit (USA). The expected range of insulin values is normally 2.0-25.0 μU/ml.

Determination of the level of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C) and the atherogenic index (AI) were performed in blood serum using the enzymatic photocolorimetric method using kits from the company "Human" (Germany).

The content of resistin and adiponectin in the blood serum of patients was determined by the enzyme immunoassay method on the enzyme immunoassay analyzer "Labline-90" (Austria). The level of resistin was determined 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 obtained data, the computer program “Statistics 8.0” (Stat Soft, USA) and the method of variation statistics (Student’s criterion) were used; the relationship between the features was assessed using correlation analysis.

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

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

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

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

According to ABPM data, the initial average blood pressure level corresponded to stage 2 hypertension. An increase in pulse blood pressure and systolic blood pressure variability during the daytime was noted, which are independent risk factors for cardiovascular complications. Among the examined patients, there were 16 dippers, 14 non-dippers, 6 over-dippers, and 4 night-peakers. It should be noted that insufficient blood pressure reduction during the night is a confirmed risk factor for the development of cardiovascular and cerebrovascular complications.

During ABPM, normalization of average daily 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 load decreased and the variability of systolic blood pressure during the daytime hours normalized. The value of pulse blood pressure during the daytime hours, reflecting the stiffness of the main arteries and being an independent cardiovascular risk factor, normalized after 12 weeks.

Ramipril therapy also had a favorable effect on the circadian rhythm of blood pressure. The number of patients with a normal circadian index (dippers) increased to 23, and the number of patients with predominantly nocturnal increases in blood pressure (night-peakers) decreased to 2. No cases of excessive decreases in blood pressure at night (over-dipper) were registered.

The obtained results confirm the efficacy 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, the target BP values were achieved in 24 (60%). In addition, ramipril had a favorable effect on the 24-hour BP parameters, which are considered cardiovascular risk factors, in particular, it caused a decrease in the pressure load index and normalization of systolic BP variability during the daytime. The latter parameter increases the risk of target organ damage and positively correlates with myocardial mass and abnormal LV geometry, and resistin levels. The parameters of the circadian BP rhythm, the disruption of which in patients with type 2 diabetes is associated with a more than 20-fold increase in the risk of cardiovascular death, significantly improved. Normalization of pulse pressure during daytime hours against the background of therapy indicates an improvement in the elastic properties of the walls of large vessels and reflects the positive effect of the drug on vascular remodeling processes.

After 12 weeks, a significant improvement in carbohydrate and lipid metabolism was revealed, which, of course, makes an additional contribution to reducing cardiovascular risk.

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

Therefore, the following conclusions can be drawn.

Against the background of the therapy with the inclusion of ramipril, reliable improvements in the parameters of carbohydrate, lipid and adipocytokine metabolism were noted.
Ramipril therapy in patients with arterial hypertension and type 2 diabetes mellitus led to a reliable decrease in blood pressure during the day, normalization of the pressure load index during the day and night and the disturbed two-phase blood pressure profile and a reliable 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 compliance with treatment and its effectiveness.

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

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