CC BY
9UDC 615.1/.4
ARTERIAL HYPERTENSION IN DIABETES MELLITUS TYPE 2 AND THE EXPERIENCE OF USING «ROTAZAR "
R. B. Sultanalieva1, V. G. Knyazeva1, K. B. Jooshbaev, D. M. Satarova, N. N. Usubaliev.
'international Higher School of Medicine, Bishkek, Kyrgyzstan
department of Endocrinology Centre at the Ministry of health Kyrgyz Republic, Bishkek, Kyrgyzstan
Abstract
Angiotensin-converting enzyme (ACE) inhibitors and type 1 angiotensin receptor blockers (ARBS) can slow the progression of nephropathy and provide regression of albuminuria and proteinuria in diabetes mellitus (DM). Effective reduction of blood pressure in patients with DM is no less significant for reducing the risk of complications than careful control of glycemia. Achieving the target blood pressure (BP) is one of the strategies for preventing cardiovascular complications in patients with diabetes.
This study aimed to evaluate the effectiveness and safety of Rotazar in patients with type 2 diabetes mellitus with uncontrolled arterial hypertension. Twenty patients (16 women and 4 men) were treated with Rotazar for 12 weeks with a diagnosis of diabetes and hypertension with no achievement of target blood pressure values. The drug was recommended to be taken 1 time a day in the morning at a dose of 150 mg. If the target blood pressure was not reached in one patient at the visit after 4 weeks, the dose was increased to 300 mg, 3 people were transferred to Rotazar plus (irbesartan 150 mg, hydrochlorothiazide 12.5 mg). It was found that all patients with grade 1 hypertension achieved the target blood pressure values (100%) during Rotazar monotherapy, while patients with grade 2-3 hypertension who received combined therapy with Rotazar achieved the target blood pressure level in 78.6%. In total, the positive dynamics of blood pressure was detected in 85% of the patients we observed. No patient's blood pressure decreased to less than 120/80 mmHg. It was concluded that the therapeutic regimen with the use of Rotazar as a monotherapy and in combination with other drugs in patients with type 2 diabetes with uncontrolled hypertension 1 -2-3rd degree shows a high antihypertensive efficacy, allowing you to reach target values of BP in 85% of patients after 12-week treatment with the satisfactory safety profile and metabolic neutrality.
Keywords: diabetes mellitus and hypertension, the selective receptor antagonists of angiotensin-II (type ATII), Rotazar.
2-ТИПТЕГИ КАНТ ДИАБЕТИНДЕГИ АРТЕРИАЛДЫК ГИПЕРТЕНЗИЯ ЖАНА «РОТАЗАРДЫ» КОЛДОНУУ
ТАЖРЫЙБАСЫ
Р.Б. Султаналиева1'2, В.Г. Князева2, Д.М. Сатарова3, H.H. Усубалиев2
'Б.Н. Ельцин атындагы КРСУ, Бишкек, Кыргызстан 2Эларалык Жогорку Медициналык Мектеп, Бишкек, Кыргызстан
3Саламаттык сактоо министрлигинин Эндокринологиялык борбор, Бишкек, Кыргызстан
Address for Correspondence: Usubaliev Nazarali Nuralievich., Ph.D., Associate Professor, Head of the department of therapy IHSM. Email:usubaliev25@list.ru Tel.: 0700115453 36
Аннотация
Ангиотензинди езгертуучу ферменттин (АСЕ) ингибиторлору жана 1-типтеги ангиотензин рецепторлорунун блокаторлору (ARBS) нефропатиянын енугушун басацдатып, кант диабетинде альбуминурия менен протеинуриянын регрессиясын камсыздай алат. ДМ менен ооруган адамдардын кан басымын эффективдуу темендетуу, гликемияны кылдат кеземелдееге Караганда, татаалдашуу коркунучун азайтуу учун кем эмес маанилуу. Максапуу артериалдык кан басымына (BP) жетишуу диабет менен ооруган бейтаптардын журек-кан-тамыр ооруларынын алдын алуу стратегиясынын бири болуп саналат.
Бул изилдее кезомелге алынбаган артериалдык гипертензия менен 2-типтеги кант диабети менен ооругандарда Ротазардын натыйжалуулугун жана коопсуздугун баалоо максатында багытталган. Диабет жана гипертензия диагнозу менен жыйырма бейтапка (16 аял жана 4 эркек киши) Ротазар менен дарылоо жургузул уп, 12 жумада кан басымынын максаттуу керсоткучтеруне жетише алган жок. Препаратты кунуне 1 маал, эртец менен 150 мг дозада ичуу сунушталды. Эгерде 4 жумадан кийин бир бейтапты Караганда максаттуу артериалдык кан басымы жетпесе, анда дозасы 300 мг чейин кобейтулсе, 3 адам Ротазар плюска (ирбесартан 150 мг, гидрохлоротиазид 12,5 мг) которулган. Ротазар монотерапиясы учурунда 1 -даражадагы гипертония менен ооругандар артериалдык кан басымынын максаттуу керсоткучтеруне (100%) жетишсе, Ротазар менен айкалыштырылган терапия алган 2-3-даражадагы гипертензия менен ооругандар 78,6% га жетишкен. Жалпысынан биз байкаган бейтаптардын 85% кан басымынын оц динамикасы аныкталды. Эч бир бейтаптын артериалдык кан басымы 120/80 мм рт.ст. темендеген эмес. Ротазарды монотерапия жана башка дары-дармектер менен айкалыштырып дарьшоонун терапиялык режими кеземелге алынбаган артериалдык гипертензиясы бар 1-2-3 типтеги диабет менен ооруган бейтаптарда гипертензияга каршы эффективдуулуктун жогорку децгээлин керсетет, деген тыянакка келишкен. Бейтаптардын 85% 12 жума дарылоодон кийин канааттандырарлык коопсуздук профилинде жана зат алмашуу нейтралитетинде болушкан.
Ачкыч сездер: кант диабети жана артериалдык гипертензия, ангиотензин- II нин (ATII туру) рецептордукселективдик антагонисттери, Ротазар.
АРТЕРИАЛЬНАЯ ГИПЕРТЕНЗИЯ ПРИ САХАРНОМ ДИАБЕТЕ 2 ТИПА И ОПЫТ ПРИМЕНЕНИЯ РОТАЗАР
Р.Б. Султаналиева1'2, В.Г. Князева2, Д.М. Сатарова3, H.H. Усубалиев2
'КРСУ им. Б.Н. Ельцина, Бишкек, Кыргызстан Международная Высшая Школа Медицины, Бишкек, Кыргызстан
'Эндокринологический центра Министерства Здравоохранения Кыргызской Республики, Бишкек, Кыргызстан
Аннотация
Ингибиторы ангиотензинпревращающего фермента (АПФ) и блокаторы рецепторов ангиотензина 1 типа (ARBS) могут замедлить прогрессирование нефропатии и обеспечить регресс альбуминурии и протеинурии при сахарном диабете (СД). Эффективное снижение артериального давления у пациентов с СД не менее важно для снижения риска осложнений, чем тщательный контроль гликемии. Достижение целевого артериального давления (АД) - одна из стратегий предотвращения сердечно-сосудистых осложнений у пациентов с диабетом.
Это исследование было направлено на оценку эффективности и безопасности Rotazar у пациентов с сахарным диабетом 2 типа с неконтролируемой артериальной гипертензией. Двадцать пациентов (16 женщин и 4 мужчин) получали лечение Ротазаром в течение 12 недель с диагнозом диабет и гипертензия без достижения целевых значений артериального давления. Препарат рекомендовано принимать 1 раз в сутки утром в дозе 150 мг. Если целевое артериальное давление не
было достигнуто у одного пациента при посещении через 4 недели, дозу увеличивали до 300 мг, 3 человека переводили на Ротазар плюс (ирбесартан 150 мг, гидрохлоротиазид 12,5 (мг). Установлено, что все пациенты с АГ 1 степени достигли целевых значений артериального давления (100%) на фоне монотерапии Ротазаром, тогда как пациенты с АГ 2-3 степени, получавшие комбинированную терапию с Ротазаром, достигли целевого уровня АД в 78,6%. В целом положительная динамика артериального давления выявлена у 85% обследованных нами пациентов. Ни у одного из пациентов артериальное давление не снизилось ниже 120/80 мм рт. Сделан вывод, что схема лечения с применением Ротазара в качестве монотерапии и в комбинации с другими препаратами у пациентов с сахарным диабетом 2 типа с неконтролируемой артериальной гипертензией 1-2-3 степени показывает высокую гипотензивную эффективность, позволяя достичь целевых значений АД. у 85% пациентов после 12 недель лечения с удовлетворительным профилем безопасности и метаболической нейтральностью.
Ключевые слова: сахарный диабет и артериальная гипертензия, селективные антагонисты рецепторов ангиотензина-П (тип ATII), Ротазар.
Introduction
Currently, there is evidence that the presence of hypertension is a predictor of diabetes. Patients with hypertension, left ventricular hypertrophy, or carotid atherosclerosis had a higher risk of developing diabetes, regardless of their initial metabolic status, age, and body mass index [3]. According to our research, among Kyrgyzstan residents, the greatest contribution to the risk of developing DM 2 is also made by hypertension [4].
In type 2 diabetes, the main starting point for increasing blood pressure is insulin resistance (IR), compensatory hyperinsulinemia, and hypersympathicotonia, which, like hypertension, usually precedes the clinical manifestation of diabetes. IR provokes an increase in the stiffness and rigidity of the vascular wall, which leads to the development of hypertension. According to the study by Atherosclerosis Risk in Communities (ARIC), vascular wall stiffness was a predictor of hypertension: when the elasticity of the vascular wall decreased by one standard deviation, the risk of hypertension increased by 15% [5].
Hyperinsulinemia provides an increase in blood pressure as it follows: insulin increases the activity of the sympathoadrenal system; insulin increases the reabsorption of sodium and fluid in the proximal tubules of the kidneys; insulin, as a mitogenic factor, increases the proliferation of vascular smooth muscle cells, which narrows their lumen; insulin blocks the activity of Na+-K+-ATPase and Ca2+-Mg2+-ATPase, thereby increasing the intracellular content of Na+ and Ca2+ and increasing the sensitivity of blood vessels to the effects of
vasoconstrictors. The discovery of local tissue factors of RAAS found in the cells of the kidneys, heart, brain, vascular endothelium, and other tissues was a key moment in understanding the significance of activation of the RAAS system in the development of pathology of various organs. In experimental and clinical studies, it has been established that these factors are hyperactivated in hypertension (6). Therefore, today it is impossible to imagine a therapeutic practice without the use of RAAS blockers. According to the IDF, RAAS blockers - inhibitors of the an-hypotension converting enzyme (ACE) and angiotensin receptor blockers of type 1 (ARB) (I, A) — are the only recommended drugs as a measure of hemodynamic nephroprotection in patients with type 2 diabetes [7,8]. These drugs can slow down the progression of nephropathy and provide regression of albuminuria and proteinuria.
A fairly fundamental question for most practitioners remains the question of the relationship between ACE and ARB (especially when choosing treatment for patients with hypertension) since until recently it's been believed that these classes of drugs have the same pharmacological properties. The ARB group was positioned as an alternative of the iACE and was recommended for use only in cases of dry cough when using the iACE. But at the present stage ARBS or sartans have several advantages over ACE inhibitors as it is has been convincingly having been proved: they are more specifically and effectively suppress the cardiovascular effects of RAAS activation. The hypotensive effect of ARBS is primarily associated with the suppression of the vasoconstrictive action of angiotensin II,
implemented through the receptors of the blood vessel walls. Besides, angiotensin II receptor blockade leads to a decrease in aldosterone secretion, a decrease in sodium and water reabsorption in the proximal segment of the renal tubules. Sartans block only ATI-receptors while maintaining the ability to circulate at II to interact with AT2-receptors, which is accompanied by vasodilation, antiproliferation and contributes to additional organ protective effects, and this, in return, inhibits the progression of the disease (7).
Thus, the mechanism of the antihypertensive action of ARBS is directly related to the blockade of ATI -receptors, and indirectly — to the stimulation of AT2-receptors. ARBS can penetrate the blood-brain barrier and inhibit the activity of presynaptic ATI receptors of sympathetic neurons that regulate the release of norepinephrine. Therefore, it is impossible to exclude the presence of Central mechanisms of the antihypertensive action of ARBS. Due to the lack of effect on the bradykinin-kallikrein-kinin system, the main distinguishing feature of ARBS was a high safety and a small number of side effects, comparable to placebo. The absence of coughing and a negligible number of allergic reactions are the absolute advantages of sartans over ACE inhibitors (8).
Achieving the target blood pressure (BP) is one of the strategies for preventing cardiovascular complications in patients with diabetes. Effective reduction of blood pressure in patients with DM is no less significant for reducing the risk of complications than careful control of glycemia. In this regard, we are interested in the possibilities of Rotazar (irbesartan) concerning blood pressure control, which has not been studied so far in Kyrgyzstan in patients with DM.
Rotazar an antihypertensive drug, a selective antagonist of the angiotensin II receptor (type ATI), is directly active, not a metabolite. The drug is rapidly absorbed from the digestive tract, regardless of the intake of food, has a long duration of action, has the lowest level of binding to plasma proteins for its class of preparations, which allows reducing interaction with other drugs that have a high ability to bind to proteins. The absolute bioavailability of Rotazar is on average 60-80%. The preparation can be used in cases of severe renal impairment and patients undergoing hemodialysis, and long-term therapy with the drug contributes to long-term
nephroprotection [9].
The study aimed to evaluate the effectiveness and safety of using Rotazar in patients with type 2 diabetes mellitus who have uncontrolled arterial hypertension.
Methods and results
An open study of the efficacy and safety of 12-week Rotazar therapy included 20 patients (16 women and 4 men), all patients were diagnosed with diabetes and hypertension with a lack of achievement of target blood PRESSURE. All patients gave written informed consent to participate in this study. The diagnosis of hypertension is verified according to generally accepted criteria. In addition to the standard examination of glycemic indicators, patients were examined for creatinine, potassium, uric acid, blood lipids, ECG, andbloodPRESSURE. In patients, the degree of DM control was also assessed by the level of glycemia and the concentration of glycosylated hemoglobin (HbAlc): fasting glycemia < 7 mmol/1 and HbAlc <7% were considered control criteria. All patients received Metformin as an oral hypoglycemic drug, 7 of them in combination with insulin therapy, the rest with sulfonylureas.
Initially, we considered the target clinical blood pressure for patients with type 2 diabetes TO be< 140/85 mmHg. However, in terms of achieving the target blood pressure figures, there has been a slight shift in emphasis over the past year. If previous guidelines postulated that to prevent nephropathy, the target blood pressure figures for DM should be within the range of <140/85 mmHg (I, A) [10], it is currently considered that patients with hypertension in combination with DM should have a target systolic blood pressure (SAD) of <130 mmHg (I, a), for persons over 65 years of age 130-139 mmHg, and the target diastolic blood pressure (dB) <80 mmHg (I, a)[ll]. Therefore, we set the ESC/ESH recommendations for 2018 as the target clinical blood pressure indicators for the observed individuals. Statistical data processing was performed using the program Microsoft Excel, 2007. To compare the data, we used the student's paired criterion (t-criterion).
Out of 20 patients examined, 6 had ischemic heart diseases, 3 had chronic heart failures, 7 had diabetic nephropathy, 9 had polyneuropathy, and 2 had diabetic retinopathy. Thirteen patients were obese
(BMI > 30 kg/m2), four were overweight (BMI > 25 kg/m2). The abdominal type of obesity was detected in the majority of patients. The average age of men was 60.8+3.8 years, women-62.7+1.5 years.
The duration of DM was 9.2±1.3 years (coefficient of variation 62.36%), and the duration of AH — 7.0±1.06 years, respectively (coefficient of variation 65.38%). 1st degree of arterial hypertension was in 5 patients, 2nd degree—in 9 and 3 degree-in 6 people. Initially, all patients had uncontrolled hypertension, although they received antihypertensive treatment. The spectrum of previous antihypertensive drugs (AGD) in the examined population was represented by the following groups: monotherapy with ACE - 4 inhibitors (20%), valsartan - 2 (10%), 14 (70%) -combined two-and three-component therapy with ACE inhibitors in combination with other AGD (beta-blockers, calcium channel blockers, diuretics).
Blood pressure in patients was measured three times during a visit to the doctor, while taking antihypertensive medications after a 10-minute rest in a sitting position, on the dominant arm, the average of three measurements was taken for the level of blood pressure at this visit. The tests were performed before the start of treatment with Rotazar, after 6 weeks, a month, and after 3 months at the final visit. Of concomitant therapy was allowed the use of Gl-polymetallic therapy.
Tables 1 and 2 showed the initial indicators of the examination of patients with diabetes and hypertension and data on the background of treatment with Rotazar. As can be seen from the table, at the time of inclusion in the study, the average systolic blood pressure (SAD) was 153.5±3.4, and the average diastolic blood PRESSURE (DAP) was 90.7±4.2 mmHg. All subjects had uncontrolled AH against the
Table 1. Indicators of examination of patients with type 2 diabetes and hypertension (total number) pefore and during treatment with Rotazar (after 6 and 12 weeks)__
Indicators Source data M±m n=20 After 6 weeks M±m, n=20 After 12 weeks M±m, n=20
Average systolic blood pressure (mmHg.) 153.5±3.4 137.5±4.2 131.2±4.2*
Average diastolic blood pressure (mmHg.) 90.7±4.2 84.5±1.67 81.5±1.0*
Cholesterol (mmol /1) 3.8±0.22 4.1±0.14 4.5±0.5
Fasting blood glucose (mmol /1) 9.0±0.78 8.4±0.64 7.8±0.44
Glomerular filtration rate (ml / min) 71.8±4.3 - 69.8±4.9
BMI 29.9±0.82 - -
waist size (cm) 101.3±1.7 - -
*p < 0.001-confidence indicator, equal to the original data
background of previously assigned AGP with free combinations. All patients who previously received monotherapy with different AGPS were transferred to Rotazar. Patients, who were receiving combined AGP, ACE inhibitors are replaced with Rotazar. The
study drug was recommended to be taken 1 time a day in the morning at a dose of 150 mg. In the absence of achieving the target blood pressure in one patient at the visit after 4 weeks, the dose was increased to 300 mg, 3 patients were transferred to
Table 2. Dynamics of blood pressure indicators of patients receiving Rotazar in the form of monotherapy and combined with other AGP. ___
type of therapy Average systolic BP (mmHg) M±m P Average diastolic BP (mmHg) M±m P
Source data on other AGD After 12 weeks on Rotazar Source data on other AGD After 12 weeks on Rotazar
Monotherapy n=6 154±4.47 128±2.23 <0.001** 91±3.7 81±1.3 <0.05*
Combination therapy n= 14 155±4.6 133±3.4 <0.001** 91.4±2.4 82.2±1.6 <0.01**
*-the confidence score in comparison with the original data
Rotazar plus (irbesartan 150 mg, hydrochlorothiazide 12.5 mg). After 6 and 12 weeks of antihypertensive therapy, the studies mentioned above were repeated.
As can be seen from the table, at the end of 12 weeks of Rotazar therapy, significant changes in the main indicators of the office blood pressure profile were detected, which were manifested by a statistically significant decrease in SBP to 131.2±4.2 and DBP to 81.5±1.0 mm Hg (p < 0.001 compared to the baseline).
As can be seen from Table 2, in the group of patients transferred from AGP monotherapy of other groups to Rotazar, blood pressure indicators decreased after three months from SBP 154±4.47 to 128±2.23 mm Hg (p<0.001), and the DBP figures from 91±3.7 to 81±1.3 mm Hg (p<0.05). Rotazar monotherapy was prescribed to patients with grade 1 hypertension, almost all patients reached the target values of blood pressure. When measured clinically, blood pressure did not decrease to less than 120/80 mm Hg.
Most patients received a combination of AGD in combination with Rotazar, revealed positive dynamics: the average blood pressure also decreased after three months from SBP 155±4.6 to 133±3.4 mm Hg(p<0.001), and the DBP figures from 91.4±2.4 to 82.2±1.6 mm Hg (p<0.01) (tab.2). out of 14 patients, 4 people's blood pressure decreased to 120/80 mm Hg, 5 - to 130/80 mm Hg, 2-to 140/80 mm Hg. However, in 3 patients, blood pressure indicators did
not reach the target values: although 2 patients showed a noticeable positive trend (one had initial data of 200/100 mm HG, after 12 weeks -160/100 mm Hg. St, in the second patient, respectively, blood PRESSURE decreased from 150/100 mm Hg to 140/90), in 1 patient, blood PRESSURE indicators remained the same (150/90 mm Hg).
Thus, according to our research, all patients with grade 1 hypertension reached the target blood pressure values (100%) for Rotazar monotherapy, and in patients with grade 2-3 hypertension who received combined therapy with Rotazar, the target blood pressure level was reached in 78.6%. In total, the positive dynamics of blood pressure was detected in 85% of the patients we observed. In the clinical measurement of blood pressure, none of the patients had a decrease of less than 120/80 mm Hg. Negative dynamics in blood biochemical parameters (cholesterol, GFR, blood glucose) were not recorded in any of the patients. We have also not registered any significant side effects that require discontinuation of the drug.
Conclusion: the therapeutic regimen with the use of Rotazar as a monotherapy and in combination with other drugs in patients with type 2 diabetes with uncontrolled hypertension l-2-3rd degree has high antihypertensive efficacy, allowing you to reach target values of BP in 85% of patients after 12-week treatment, with a satisfactory safety profile and metabolic neutrality.
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