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BACKGROUND: According to research, only 38% of patients reach glycated hemoglobin targets. It is possible to improve the effectiveness of medical care for children with T1D using modern technologies, including continuous glucose monitoring (CGM). AIMS: To evaluate the effectiveness of outpatient monitoring of children and adolescents with T1D with regular use of professional continuous glucose monitoring. METHODS: The inclusion criteria: age 812 years; T1D at least 1 year; insulin therapy by multiple injections of insulin; inadequate glycemic control of T1D: НbА1с level of 7.5% and higher and / or children and adolescents with frequent episodes of hypoglycemia (usually 4 times a week) or with a history of severe hypoglycemia; signed informed consent. All patients initially and 12 weeks after inclusion in the study conducted a study of the level of НbА1с, and also performed CGM for 6 days. Based on the results of CGM, glycemia indicators and daily doses of insulin were recorded, treatment was evaluated and corrected, and recommendations for self-monitoring were made. Glucose monitoring was carried 120144 hours using the blind method iPro2 (Medtronic, USA). RESULTS: In all, 99 children aged 818 years were included in the study in all centers. The decrease in the level of НbА1с by the end of the study was 0.72%, while the proportion of patients who reached the target level of НbА1с (defined as 7.5%) was statistically significantly higher at the end of the study (15.5% and 2%, respectively; p0.05). During the study, patients showed a trend towards a decrease in the average level and variability of glycemia by the end of the study, however, statistical significance was achieved only in relation to the average level of glycemia (p=0.04). Conducted insulin therapy, determined by the average daily doses of long-acting and short-acting insulin, did not statistically significantly change at the end of the study. The frequency of DKA episodes and severe hypoglycemia did not statistically significantly differ from the initial level. CONCLUSIONS: For children with poor glycemic control of T1D, the use of professional CGM is effective in terms of glycemic control and a safe method.

Public organization “Russian Association of Endocrinologists”. Clinical guidlines.

Public organization “Russian Association of Endocrinologists”. Clinical guidlines.

June 19, 2018 the meeting of the Scientific Advisory Board took place in Moscow, chaired by Professor G.R. Galstyan, (co-chair - A.V. Zilov) devoted to the discussion of the possibilities of improving the results of treatment of diabetes mellitus (DM) by consideration of «variability of glycemia» (VG) as an additional criterion of the glycemic control effectiveness (especially of insulin therapy) as well as one of the goals of treatment in patients with unstable glycemia. The purpose of the working meeting was to develop a strategy for the introduction of VG as a predictor and an additional criterion in assessing the effectiveness and safety of hypoglycemic therapy to improve the pharmacotherapy of diabetes and reduce cardiovascular and total mortality. Aims: - to conduct a comprehensive data analysis of the relationship between VG and adverse DM outcomes, such as hypoglycemia, micro-and macrovascular complications, cardiovascular and total mortality; - to accumulate and analyze published data and the experience of decrease of VG and improving outcomes of diabetes on the background of different versions of insulin therapy; - to compare existing methods of glycaemia monitoring and VG assessment, their validity and availability in real practice in the context of limited budget; - to analyze the informativeness, clinical and prognostic significance of various parameters of VG assessment and determine their reasonable «minimum» for a comprehensive assessment of VG as a criterion for evaluating the effectiveness of treatment of DM and predictors of negative diabetes outcomes. The following reports were heard during the discussion: Glycemic variability: clinical and prognostic value. Types of glycemic variability. (Alexey V. Zilov, MD, PhD in Medicine, Assistant Professor). Methods of assessment of variability of glycemia in clinical trials and routine practice (Tatiana N. Markova, MD, PhD in Medicine, Professor). Current international and national recommendations on glycemic monitoring (Gagik R. Galstyan, MD, PhD in Medicine, Professor). Peculiarities of glycemic variability and its evaluation among children and adolescents (Alisa V. Vitebskaya, MD, PhD in Medicine).19 июня 2018 г. в Москве состоялось заседание Научно-консультативного совета под председательством д.м.н., профессора Г.Р. Галстяна и к.м.н., доцента А.В. Зилова, посвященное обсуждению возможностей улучшения результатов лечения сахарного диабета (СД) путем использования вариабельности гликемии (ВГ) в качестве дополнительного критерия эффективности контроля гликемии (в первую очередь, на фоне инсулинотерапии), а также одной из целей лечения у пациентов с нестабильной гликемией. Целью рабочей встречи была выработка стратегии внедрения ВГ в качестве предиктора и дополнительного критерия при оценке эффективности и безопасности сахароснижающей терапии с целью совершенствования фармакотерапии СД и снижения общей и сердечно-сосудистой смертности при этом заболевании. Задачи: – провести комплексный анализ данных о взаимосвязи между ВГ и неблагоприятными исходами СД, такими как гипогликемия, микро- и макрососудистые осложнения СД, сердечно-сосудистая и общая смертность; – аккумулировать и проанализировать опубликованные данные и имеющийся опыт снижения ВГ и улучшения исходов СД на фоне различных вариантов инсулинотерапии; – сравнить существующие методики мониторинга гликемии и оценки ВГ, их валидность и доступность в реальной практике в условиях ограниченных ресурсов здравоохранения; – проанализировать информативность, клиническую и прогностическую значимость различных параметров оценки ВГ и определить их обоснованный «минимум» для комплексной оценки ВГ в качестве критерия оценки эффективности лечения СД и предикторов негативных исходов СД. В рамках дискуссии были заслушаны следующие доклады: – Вариабельность гликемии: Клиническое и прогностическое значение. Виды вариабельности гликемии. (к.м.н., доцент Зилов А.В.). – Методы оценки вариабельности гликемии в клинических исследованиях и рутинной практике (д.м.н., профессор Маркова Т.Н.). – Действующие международные и национальные рекомендации по мониторингу гликемии (д.м.н., профессор Галстян Г.Р.). – Особенности вариабельности гликемии и ее оценки у детей и подростков (к.м.н. Витебская А.В.).

The Scientific Advisory Board, chaired by Professor G. R. Galstyan (cochair - A.V. Zilov), met in Moscow on 19 June 2018 to discuss the possibilities of improving the results of diabetes mellitus (DM) treatment by considering glycaemic variability (GV) as an additional criterion for effective glycaemic control (especially in patients receiving insulin therapy) and as one of the goals of treatment in patients with unstable glycaemia. The purpose of the working meeting was to develop a strategy for the introduction of GV as a predictor and as an additional criterion for assessing the effectiveness and safety of hypoglycaemic therapy to improve the pharmacotherapy of diabetes and reduce cardiovascular and total mortality. The aims of the working meeting were to conduct a comprehensive data analysis of the relationship between GV and hypoglycaemia; to gather and analyse published data and the experience of decrease in GV and improved outcomes of diabetes against the background of different types of insulin therapy; to compare existing methods of glycaemia monitoring and GV assessment and examine their validity and availability in real practice in the context of limited budget and to analyse the informativeness and clinical and prognostic significance of various parameters of GV assessment and to determine their reasonable ‘minimum’ for a comprehensive assessment of GV as a criterion for evaluating the effectiveness of DM treatment and the predictors of negative diabetes outcomes. The following reports were presented during the discussion: ‘Glycemic variability: clinical and prognostic value. Types of glycemic variability’ (Candidate of Medical Sciences, assistant Professor Zilov A.V.); ‘Methods of assessment of variability of glycemia in clinical trials and routine practice’ (PhD, Professor Markova T. N.); ‘Current international and national recommendations on glycemic monitoring’ (PhD, Professor Galstyan G. R.) and ‘Peculiarities of glycemic variability and its evaluation among children and adolescents’ (Candidate of Medical Sciences Vitebskaya A.V.).

BACKGRAUND: A closed-loop glucose control system or artificial pancreas consists of three components a Continuous Glucose Monitor (CGM), infusion pumps to deliver hormone(s) and a sophisticated dosing algorithm to control hormone delivery. In the past years, numerous studies with closed-loop system devices were conducted with gradual shift to out-of-hospital environment and with lengthening study duration. AIMS: To compare efficacy and safety of closed-loop insulin pump use in children with type 1 diabetes mellitus in compare with conventional insulin treatment (continuous subcutaneous insulin infusion (CSII) with our without CGM) based on randomized control trials data (RCT). METHODS: In the systematic review we have include 28 randomized controlled trials results indexed in PubMed, Medline databases published till 15 June 2017. The efficacy on metabolic control in this study evaluated by the proportion of time within target range (preferably 70 to 180 mg/dl if reported) and mean (median) glucose based on sensor measurements, and the safety evaluated by time in hypoglycemia (below 70 mg/dl if reported). RESULTS: Increased time in range in the night period was observed in all RCT. Only 3 RCT showed decrease of the time in range within 24 h evaluation period. In one RCT the significant positive differences have been shown in the time in range for dual hormone closed-loop glucose control system in compare with insulin-only artificial pancreas. Mean glycaemia and glucose variability changes were not in the same manner in different RCT, both in the night only and in 24 h estimation period. Night hypoglycemia duration decreased in most RCT with closed-loop control in compare with CSII, and increased only in 2 RCT. When all-day estimation period the time in hypoglycemia changed not in the same manner in different RCT. Valuable methodology differences of the glycaemic control estimation within observed RCT brought significant complications in the data analysis and made impossible the results quantitative estimation to prepare a metaanalysis. CONCLUSIONS: Much work has been done to develop effective and safe artificial pancreas, but not all RCTs confirmed advantages of closed-loop glucose control in compare with CSII in children and adolescents in real life. More research with prospective randomized control design required to prove benefits of closed-loop glucose control. Further RCTs should have an uniform methodology for glycemic control assessment and long duration that will allow to use cumulative measures in a closed-loop efficacy estimation (HbA1c).

Background. Insulin pump therapy in increasingly frequently used in the Russian Federation in recent years, which requires an evaluation of the treatment in order to improve its efficacy and safety. Objective — the study was aimed at complex monitoring (long-term efficacy and safety, state of medical care, factors associated with metabolic control, and factors hindering its use) of the continuous subcutaneous insulin infusion (CSII) in children, adolescents, and young adults with type 1 diabetes mellitus (DM1) from various regions of the Russian Federation. Material and methods. Data of 395 DM1 children and adolescents from 60 regions of the Russian Federation were collected from the pediatric CSII register of the Endocrinology Research Center. The following data were analyzed in different age groups (0 to 7 years, 8 to 11 years, 12 to 17 years, and 18 to 25 years): glycemic control, the incidence of acute complications, discontinuation of CSII, characteristic features of blood glucose monitoring, and supplies coverage. Results. Initiation of CSII is accompanied by decrease in HbA1c level with the lowest values within the period from 6 to 24 months (–0.7±1.5% compared to the baseline level). However, 6 years after CSII initiation, HbA1c values do not differ significantly from the baseline values. The target HbA1c level (less than 7.5%) is observed in 43.6% of children aged 0 to 7 years, 32.7% of children aged 8 to 11 years, 24.2% of adolescents aged 12 to 17 years, and 28% of young adults aged 18 to 25 years. Regular self-monitoring of glycemia, 4 and more times per day, was performed by 83% of patients, while the frequency of continuous glucose monitoring (CGM) was low, 12.7% in the whole population. The incidence of acute complications in children and adolescents under 18 years did not differ significantly and the lowest incidence was observed in the age group 18 to 25 years. The effectiveness of CSII depended on the frequency of self-monitoring, CGM use, and supplies coverage. CSII discontinuation rate was 4.6 cases per 100 patient-years. The main reasons for discontinuation of CSII included the inconvenience of its use and the cost of supplies. Conclusions. Many children and the majority of adolescents with DM1, who use CSII, did not reach target HbA1c level despite the adequate self-monitoring. Many patients do not use CGM and refuse CSII. This necessitates the efforts to improve the efficacy and overcome barriers to the use of CGM and CSII.

Wolcott-Rallison syndrome is a rare autosomal recessive disease characterized by neonatal diabetes mellitus in combination with osteodysplasia and liver failure. This disease is the most common cause of neonatal diabetes mellitus in consanguineous families. Wolcott-Rallison syndrome is associated with mutations in the EIF2AK3, the gene encoding a transmembrane enzyme PERK (pancreatic endoplasmic reticulum kinase) which inhibits the synthesis of proteins in the event of misfolding in the endoplasmic reticulum. In addition to the core symptoms patients may develop multisystemic clinical manifestation including acute renal and liver failure, short stature, exocrine pancreatic insufficiency, neuro-motor deficit, hypothyroidism, anemia, neutropenia, recurrent hypoglycemia. The disease is characterized by high mortality, more than 50% of patients die from fulminant liver failure. The awareness of Wolcott-Rallison syndrome is extremely low due to the rarity of detection, however in view of the severity of the disease and the unfavorable prognosis patients with this syndrome require timely diagnosis and care of well-organized team of specialists.

Background: he obesity epidemic has led to an increase in the incidence of type 1 diabetes mellitus (T1DM) on the background of overweight. The combination of T1DM and obesity can lead to an erroneous diagnosis of type 2 diabetes (T2DM). Methods: The study included 35 adolescents with T1DM. Inclusion criteria were obesity at onset, high titer of diabetes-associated autoantibodies, and insulin requirement less than 0.5 U/kg with a diabetes duration of more than 6 months. We assessed the level of HbA1c, fasting level of insulin and c-peptide, and level during the Mixed-Meal Tolerance Test, the immunological status of GADA, IA-2, ZnT8, ICA. Results: The age of onset was 12.7 years [10.6; 14.5], the tanner stage of puberty was 4 [3; 5]. Sex distribution: boys (n = 25) - 71.5%, girls (n = 10) - 28.5%. HbA1c at the time of onset equaled 8,9% [7.4; 10.45]. Ketosis/diabetic ketoacidosis was registered in 47.8%. The duration of the diabetes was 1.7 years at the moment of examination [0.7; 2.9]. The fasting level of C-peptide - 1.37 mμg/ml [1.0.9; 2.19], insulin level (n = 26) - 13.93 uU/ml [9.57; 19.77]. The maximum level of stimulated secretion of C-peptide (n = 21) - 5.13 mμg/ml [3.05; 6.07], of insulin secretion (n = 21) - 58.59 uU/ml [31.02; 79.74]. Higher HOMA of insulin resistance (n = 25) was detected in 72% of the examined patients. In the study of pancreatic autoantibodies, an increase in ICA was detected in 57% (median of titer 1.68 [0.28;11.7]), IA-2 - 67% (192.8 ME/ml [65; 310.1]), GAD - 59% (90.25 ME/ml [32.27; 214.6]), ZnT8 - 82% (350.5 [90.4; 506.05]). The presence of 2 or more autoantibodies is found in 94% of cases. Dyslipidemia was observed in 34.8%, arterial hypertension was identified in 23% of patients. Received therapy: insulin 82%; metformin 0.02%; metformin + insulin 5.7%. Median daily dose per patient was 0.3 U/kg [0.2; 0.5]. Conclusion: T1DM in adolescents with obesity and overweight has a similar clinical picture both with T1DM (insulin dependence, high titer of autoantibodies, ketosis) and T2DM (slow progression of the disease, low insulin requirement, preserved secretion of c-peptide, and insulin for more than 1.5 years). We hypothesize that obesity and insulin resistance may contribute to DM onset at an earlier date, even if a satisfactory function of pancreatic beta-cells is still preserved. Given that the onset of the disease in our group falls on adolescence it seems that pubertal insulin resistance also contributes to the features of the course of the disease. Understanding the role of obesity in the progression of disorders of carbohydrate metabolism will allow postponing the acute manifestation of the disease and initiation of insulin therapy through lifestyle modifications in patients at risk. A long period of preserved insulin secretion opens up the possibility of new personalized therapies.

Background: The data of the register is the main source of up-to-date information about patients with diabetes mellitus (DM). It’s very important for improving the quality of medical care organization. Aims: to analyze the main epidemiological DM characteristics in Russian Federation (RF) (prevalence, incidence, mortality) in children and adolescents, to assess the dynamics of these parameters for the period 2013 – 2016, to analyze the status of compensation for carbohydrate metabolism, therapy of DM1, prevalence of diabetic complications and the reasons for hospitalizations in these age groups. Materials and methods: The database of Federal DM registry of 81 regions was included in the online system. Results: The total number of patients under the age of 18 with DM in RF on 31.12.2016 was 33081 people, there were 95,9% (31727 people) with DM1 and 4,1% (1354 patients) with DM2. The prevalence of DM1 in 2013–2016 in children: 81.0 – 91.4 / 100 ths., in adolescents – 212,8–209,5 / 100 ths. The DM1 incidence/100 thousand population in 2016 in children was 14,2/100 ths., in adolescents 10,0/100 ths. HbA1c levels in DM1 was in children: 9% in 35% of the patients; in adolescents 9% in 45% of the patients. Among complications in children and adolescents with DM1, diabetic neuropathy is the most often recorded (in 10,9% of cases and 40,8%, respectively); among DM2 patients, diabetic neuropathy is registered in 4,7% and 8,8% in children and adolescents, respectively. There are associated diseases in DM2 patients – arterial hypertension and dyslipidemia. 43,8% of children and 49,2% of adolescents were hospitalized in the anamnesis, most hospitalizations in 2016 (children 71,9%, adolescents 67,1%) were due to diabetes. Conclusions: It is established that in the dynamics of 2013–2016 the prevalence of DM1 in children continues to increase, with relatively stable indicators in adolescents. According to the register, during last two years there has been a decrease in the incidence of DM1 and, on the contrary, an increase in the prevalence/incidence of DM2 in children. Significant interregional differences in the level of incidence/prevalence have been established, especially in regions located in various geographic regions of the RF. The frequency of diabetic complications in children and adolescents with diabetes varies. There is an association of hospitalizations with higher HbA1c level. In the structure of therapy of this age group the ratio of insulin therapy in syringes-pens and pump therapy is 80.9% / 15.1% according to the register.

RATIONALE: Continuous subcutaneous insulin infusion (CSII) is an effective method for optimizing glycemic control in children with type 1 diabetes mellitus (DM1). However, the use of CSII does not always result in adequate glycemic control. Telehealth can be applied as one of the methods to improve the effectiveness of treatment.AIMS: To evaluate the use of remote medical support of children and adolescents with DM1 and its influence on glycemic control, quality of life, and incidence of acute complications of DM1.MATERIALS AND METHODS: We conducted a 24-week multi-institutional prospective open-label controlled clinical trial. 180 children and adolescents were included in this study and divided into the following categories: 1) age 8–18 years; 2) DM1 at least 1 year; 3) pump insulin therapy Medtronic Paradigm (Medtronic MiniMed, USA) at least 6 months; 4) self-monitoring of glycemia at least 4 times a day and replacement of the insulin pump infusion system at least once every 3 days; 5) inadequate glycemic control of DM1: the level of glycated hemoglobin (HbA1c) 7.5% or higher. Patients were assigned to a remote consultation group (RC; n=100) or a traditional control group (TC; n=80). All patients were trained on the basic principles of DM1 and CSII, and we measured initial HbA1c, then after 12 and 24 weeks, also registered and analyzed glycemic indicators and daily doses of insulin, evaluated and corrected the treatment. Patients or their parents in the RC group sent pump data via the Internet to the pump insulin therapy center at least once every 2 weeks at home and received treatment recommendations in response.RESULTS: The total number of patients included in the study in all institutions was 180 children at 8–18 years. Patients in both groups did not differ in age, gender, duration of DM1 and CSII, and HbA1c level. The total amount of remote consultations for all institutions was 949. The decrease in the level of HbA1c by the end of the study against the initial one was statistically significantly greater in the RC group: 1.17% compared to 0.59% in the TC group (p1c (CONCLUSIONS: Remote monitoring in children with DM1 resulted in significant improvements in glycemic control (HbA1c, glycemic variability, and hypoglycemic frequency). The accumulation of evidence on the effectiveness and safety of telehealth in DM should contribute to implementing this approach in practical health care.

Insulin pump therapy (continuous subcutaneous insulin infusion, CSII) and continuous glucose monitoring (CGM) are high-tech treatment and diagnostic tools for diabetes patients management which are actively used worldwide. CSII initiation and pump-users supervision became a part of routine clinical practice in Russia along with the CGM. Present project of clinical guidelines is based on international and domestic experience in CSII and CGM for diabetes treatment. Guidelines should ensure uniformity of CGM and CSII usage in Russia by health care professionals and diabetes patients and provide them an international experience to guarantee height performance of the technology. This article contains a preliminary version of the guidelines (draft) prepared for further expert’s discussion and review. The final version of the clinical guidelines will be sent to the Ministry of Health of the Russian Federation for approval.

The present study included 71 patients with type 2 diabetes mellitus (41 boys and 30 girls) at the age from 9 to 18 (mean 15.2 (13.6; 16.5)) years, duration of the disease 5.0 (2.5; 9) years, and the HbA1c level of 9.1% (7.0; 10.2). All the patients underwent continuous ECG monitoring with the assessment of the cardiac rhythm variability (CRV) characteristics and the QT interval duration over 24 hours. These studies were supplemented by cardiovascular tests and the PWC170 test with the evaluation of CRV and the heart rate (HR) during testing and the rehabilitation period. Autonomous dysfunction was documented in 22 (30.9%) patients. It was shown that the children and adolescents presenting with the cardiovascular form of autonomous neuropathy (KAH+) had lower CRV values during physical exercises than the patients without KAH+ , and their CRV and HR characteristics failed to be fully normalized after the cessation of loading. This fact may be responsible for the high cardiovascular morbidity and mortality rate among the patients with DM1 in the mature age.

Aim. The aim of this study was to investigate cardiac autonomic function as assessed by ST dynamics during and post-exercise in children and adolescents with type 1 diabetes mellitus (T1DM). Materials and methods. The study included 71 young patients with T1DM. The patients were aged 9?18 years and had no history of macrovascular disease or renal disease, including microalbuminuria. Cardiac autonomic function was assessed using cardiovascular tests and 24-h ECG monitoring with automatic calculation of QT interval and heart rate variability parameters. Each patient underwent the physical working capacity 170 test. Results. The prevalence of cardiovascular autonomic neuropathy (CAN) was 30.9%. The frequency of asymptomatic ST-segment depression increased during exercise in 10 (45.5%) patients with CAN (CAN+) compared with 9 (18.4%) patients without CAN (CAN-; p=0.042). During the recovery period, asymptomatic ST-segment depression was present in the first minute in 8 (36.4%) CAN+ patients compared with 1 (2%) CAN- patient (p=0.0003) and in the second minute in 5 (22.7%) CAN+ patients compared with 1 (2%) CAN- patient (p=0.0095). Conclusion. Children and adolescents with T1DM and impaired autonomic function have increased prevalence of asymptomatic ST-segment depression during and post-exercise. The presence of cardiovascular risk factors in children and adolescents with T1DM and CAN may contribute to the increased cardiovascular morbidity and mortality during adulthood in patients with T1DM.

Diabetes mellitus (DM) is characterised by relative or absolute insulin deficiency. The currently available treatment methods for DM cannot provide normal blood glucose level without hypo- or hyperglycaemia episodes, thus failing to completely prevent the development of diabetic complications. Replacement of ?-cells (transplantation of the pancreas or ?-cells) is accompanied by complications and requires life-long immunosuppressive therapy that is not always followed by restoration of insulin independence; there is also a substantial deficit of donors. Stem cells do not cause such negative effects and can be used in therapy to avoid such problems. Allogeneic stem cell transplantation is complicated by immune rejection of a transplant, whereas the use of embryonic stem cells is associated with ethical concerns, complicated cell line selection, and risk of teratoma formation. The present review focuses on therapeutic pathways of autologous transplantation of tissue stem cells in order to restore the ?-cell pool, for immune reconstitution and modulation of the immune response in DM patients.

In this study, we investigated the relationship between the blood glucose level and the length of the QT-interval as well as the influence of locomotor activity on these characteristics in children and adolescents presenting with type 1 diabetes mellitus during the long-term monitoring of ECG, the level of glycemia, and locomotor activity. The daily dynamics of these parameters was elucidated along with the measurements of the lengths of QT and RR intervals. Specifically, the correlation between the length of the QTc interval and the blood glucose level appears from the fact that the maximum QTc length occurred when glycemia dropped below 4 mmol/l. It also significantly increased at glycemia in excess of 16 mmol/l (and up to 21 mmol/l). Moreover the length of the QTc interval directly depended on the duration of the disease. The locomotor activity was shown to significantly affect the blood glucose level within 3-4 hours after its onset.

Aim: this study the changes of blood pressure (BP), heart rate variability (HRV) characteristics, average weighed rhythmogram variation (AWRV) and QTc in patients with metabolic syndrome (MC) and arterial hypertension (AH) before and after therapy of betablocker, metformin and their combination. Materials: 51 patients with МС and AH were enrolled in the study. The patients were randomization on 3 groups: the monotherapy of nebivolol (N) 5 mg/days (n=18), the monotherapy of metformin (M) 1700 mg/days (n=15) and nebivolol+metformin combination therapy (N+M) (n=18). The estimated variables included of BP, HRV, AWRV and QTc before and after 24 weeks of the treatment. Results: after 24 weeks of the N treatment QTc interval change from 44823 ms to 43317ms (p 0.05). Treatment of M changes AWRV from 872234 ms to 761195 (p>0.05), QTc from 44825 ms to 43427 ms (p