Vol 22, No 6 (2019)

Original Studies
An economic value of the glycated hemoglobin test in diabetes mellitus type 2 diagnosis
Shestakova M.V., Kolbin A.S., Karpov O.I., Galstyan G.R., Mayorov A.Y., Arepeva M.A., Kurylev A.A., Proskurin M.A.

BACKGROUND: Diagnostic of diabetes mellitus type 2 (DM2T) in time is very actual for treatment and prevention of potential complications of illness. Fasting blood glucose test (FBG) is a widely used method of primary DM2T diagnose. Glycated hemoglobin (HbA1c) test is an alternative and used more rarely due to expensive.

AIM: Modelling of comparative expenditures for DM2T control in cases of primary diagnostic by HbA1c test or FBG test usage in 20-years horizon.

METHODS: Retrospective analysis of aggregated epidemiological Russian NATION study data in 810 patients with prediabetes and DM2T with both analysis performed, with sensitivity and specificity of each is detected. The simulation model of DM2T outcomes has been used for Health Technology assessment (direct and indirect costs of Diabetes control during 20 years). Three algorithms of the DM2T treatment were investigated for understanding of expenditures in case on diagnostic on-time and case of late verification with metformin, gliflozines, gliptins, Glucagon-like peptide-1 receptor agonists, basal insulin analogs and their combinations.

RESULTS: FBG test has more negative results for DM2T diagnostics in compare with HbA1c analysis (77,4% and 36,5% accordingly). Amount of false negative results in FBG test in 3 times more often occurred in comparison with HbA1c. HbA1c test in 3 times more precisely than FBG test for carbon metabolism abnormalities detection. Diagnostic in time with HbA1c test in compare with late process of illness detection by FBG can cut common expenditures on 26,3-27,7% depending on treatment option due to macrovasular complications decreasing. Disability rate is expected decrease on 21% to 20-th year in case of diagnostic with HbA1c performing instead FBG test.

CONCLUSION: HbA1c test has diagnostic advantages in compare with FBG test for primary investigation (dispanserization). Direct and indirect expenditures in average for one patient with DM2T on 20-years horizon including cost of drugs, analysis, complications, disabilities are less in case of diagnostic in time with HbA1c test in comparison with late diagnostics in case of FBG test execution.

Diabetes mellitus. 2019;22(6):504-514
Clinical and laboratory characteristics of the patterns of chronic kidney disease in patients with type 2 diabetes
Klimontov V.V., Korbut A.I., Fazullina O.N., Vinogradov I.V., Romanov V.V.

BACKGROUND: A growing body of evidence demonstrates increasing prevalence of normoalbuminuric chronic kidney disease (NA-CKD) in subjects with type 2 diabetes (T2D), while proportion of albuminuric pattern is decreasing.

AIMS: To determine the clinical and laboratory parameters associated with different patterns of CKD in patients with T2D.

METHODS: This observational, single-center, cross-sectional study included 360 patients with T2D duration ≥10 years. Patients with urinary albumin/creatinine ratio (UACR) <3 mg/mmol and estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2 were classified as no-CKD group (n=89). Patients with UACR <3 mg/mmol and eGFR <60 ml/min/1.73 m2 formed NA-CKD group (n=111). Individuals with eGFR ≥60 ml/min/1.73 m2 and UACR mg/mmol ≥3 were recorded as albuminuric with preserved renal function (A-CKD–, n=87). Patients with eGFR <60 ml/min/1.73 m2 and UACR mg/mmol ≥3 mg/mmol were considered as albuminuric CKD group (A-CKD+, n=73). Urinary nephrin and podocin, the podocyte injury markers, and whey acidic protein four-disulfide core domain protein 2 (WFDC-2), a marker of tubulointerstitial involvement, was assessed by ELISA and compared to control (20 non-diabetic subjects).

RESULTS: Age ≥65 years (p=0.0001), duration of T2D ≥15 years (p=0.0009), female sex (p=0.04), and therapy with diuretics (p=0.0005) were found as risk factors for NA-CKD. The risk factors for A-CKD were male sex (p=0.01), smoking (p=0.01), waist-to-hip ratio >1 (p=0.01) and HbA1c levels >8% (p=0.005). The duration of T2D ≥15 years (p=0.01) and the use of dihydropyridine calcium channel blockers (p=0.01) were associated with A-CKD+. In T2D groups, the urinary excretion of nephrin and podocin was increased (all p<0.001), more markedly in albuminuric individuals (p<0.01 vs. NA-CKD). WFDC-2 excretion was increased in men from all diabetic groups (p<0.05) and in women with decreased eGFR only (p<0.05 vs. the control and NA-CKD).

CONCLUSIONS: The CKD patterns in T2D are heterogeneous according to their clinical and laboratory characteristics. The changes in the excretion of nephrin and podocin indicate the association of albuminuric patterns with podocyte injury. A decrease in eGFR in women with T2D is associated with an increase in urinary excretion of WFDC-2, tubulointerstitial fibrosis marker.

Diabetes mellitus. 2019;22(6):515-525
Evaluation of glycaemic profile variability as a basis for insulin therapy strategy in pregnant women with type 1 diabetes
Tiselko A.V., Yarmolinskaya M.I., Misharina E.V., Milyutina Y.P.

BACKGROUND: Patients with any form of diabetes during pregnancy should achieve the target (close to physiological) values of glycaemia, the main condition for a safe course and outcomes of pregnancy. To accomplish this task, effective and safe methods of insulin therapy should be selected.

AIM: To determine the glycaemic profile and pregnancy outcomes in women with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) and multiple insulin injections (MII).

METHODS: A continuous glucose monitoring (CGM) of 100 pregnant women with type 1 diabetes treated with CSII and 100 women treated with MII was conducted to assess the effectiveness of these insulin therapy regimens in achieving target blood glucose values.

RESULTS: HbA1c levels were significantly lower during the first, second, and third trimesters in patients treated with CSII than those treated with MII. Glucose variability has already improved since the second trimester of pregnancy in women treated with CSII, which was not observed in those treated with MII. The period of hyperglycaemia according to the results in pregnant women treated with CSII was 25 [13; 38] %, which was lower than those treated with MII, 41 [18; 54] %. No risk of obstetric and perinatal complications was observed with the duration of the hyperglycaemic state of <25% of the CGM time, whereas the risk of neonatal hypoglycaemia appeared with the duration of the hypoglycaemic state of a mother with type 1 diabetes of >0.2%. The relationship between glucose variability in terms of MAGE and MODD and the risk of developing macrosomia has been observed, and the dependence of glucose variability (MODD and CONGA) and the risk of neonatal hypoglycaemia and preeclampsia have also been confirmed.

CONCLUSION: Comprehensive assessment of the glycaemic profile when using CSII, confirmed the advantages of using CSII in pregnant women with type 1 diabetes to achieve the target glycaemia values, to reduce glucose variability and duration of hypoglycaemic episodes, which led to decreased frequency of obstetric and perinatal complications.

Diabetes mellitus. 2019;22(6):526-535
The clinical and epidemiological characteristics of hypogonadism in men with type 2 diabetes mellitus
Mel'nichenko G.A., Shestakova M.V., Rozhivanov R.V.

BACKGROUND: Male hypogonadism is a frequent complication of diabetes mellitus (DM) type 2; therefore, a study of its clinical and epidemiological characteristics is of interest.

AIMS: Assessment of clinical and epidemiological characteristics of hypogonadism in men with diabetes mellitus type 2.

METHODS: A full-design, cross-sectional, screening, multicenter, non-interventional study included men with diabetes mellitus type 2. The study was conducted from November 2017 to January 2019.Medical history assessment, sexological testing, estimation of luteinizing hormone (LH), sex hormone-binding globulin; total testosterone and glycated hemoglobin were performed. Free testosterone was calculated by the Vermeullen method. Comparison of groups was carried out using Yates’s corrected version of chi-squared test, Mann-Whitney U-test, and Spearman’s rank correlation method was also used. Differences were considered statistically significant with p <0,05.

RESULTS: The age of 554 men included in the study was 55 [50; 58] years, total testosterone level was 12,5 [9,1; 16,4] nmol/L; free testosterone was 0,266 [0,205; 0,333] nmol/L; HbA1c 7,2 [6,2; 8,9] %. Hypogonadism syndrome was detected in 181 men (32,7%). Total testosterone level in these patients was 7,8 [6,5; 9,4] nmol/L, and free testosterone level was 0,182 [0,152; 0,217] nmol/L. In patients without hypogonadism, these parameters were 14,7 [12,4; 18,0] nmol/L and 0,308 [0,265; 0,362] nmol/L, respectively. In most cases, patients with hypogonadism had normal, but lower LH levels of 3,3 [2,2; 4,9] U/L compared with patients without hypogonadism 3,8 [2,7; 4,9], p = 0,022. Most often, normogonadotropic hypogonadism was detected (89,5%). Statistically significant negative correlations were found between total testosterone levels and body mass index (r = -0,24; p <0,001), and waist circumference (r = -0,21; p<0,001). The prevalence of decreased libido in patients with hypogonadism (66,8%) is statistically significantly higher than that in men without hypogonadism (56,3%, p = 0,022).

CONCLUSIONS: The prevalence of hypogonadism syndrome in men with diabetes mellitus type 2 is 32,7%. This type of hypogonadism is characterized by normal LH values.

Diabetes mellitus. 2019;22(6):536-541
Testosterone deficiency and non-alcoholic fatty liver disease in men with type 2 diabetes mellitus
Khripun I.A., Vorobyev S.V., Allahverdieva Y.

BACKGROUND: Current studies investigated diseases associated with testosterone (T) deficiency; however, data on the combination of non-alcoholic fatty liver disease (NAFLD) with hypogonadism and diabetes mellitus (DM) in men are extremely limited.

AIMS: To evaluate the effects of hypogonadism on the formation and progression of NAFLD in men with type 2 DM.

METHODS: The study included 90 men with type 2 DM [age 54 (49–57) years]. Patients underwent clinical examinations, biochemical analysis (alanine aminotransferase (ALT), aspartate aminotransferase, gamma-glutamyl transpeptidase (GGTP), fasting glucose, immunoreactive insulin, HOMA index, HbA1c, lipid profile), immune enzyme analysis (luteinising hormone, total T, sex hormone binding globulin, resistin, adiponectin, leptin) and magnetic resonance imaging with liver fat fraction determination were performed. Patients were divided into two groups: 1–32 eugonadal patients and 2–58 men with newly diagnosed hypogonadism.

RESULTS: Increased insulin resistance, hyperinsulinemia, hypertriglyceridemia were observed in men with hypogonadism compared to eugonadal patients. Along with biochemical signs of impaired liver function, such as an increase in liver enzyme concentrations of ALT by 24.5% (p = 0.02), GGTP by 60.5% (p = 0.001), de Rytis coefficient by 60.4% (p = 0.047), of men in the 2nd group, the liver fat fraction also increased, which together indicates NAFLD progression. The proton density of the liver fat fraction according to MRI was 4.12 [2.25–5.30] % in the 1st group and 10.30 [7.78; 14.44] % in the 2nd group (p=0.001). This was accompanied by an increase in fat production of resistin by 2 times and leptin by 12 times (p <0.001) in patients of group 2 compared to 1.

CONCLUSIONS: The combination of type 2 DM with hypogonadism in men leads not only to deterioration of carbohydrate and lipid metabolism but also to disturbance of liver function: increased ALT, GGTP concentrations and liver fat. Increased secretion of leptin and resistin in the adipose tissue is assumed to be a pathogenetically associated with the development of carbohydrate and lipid metabolism disorders, NAFLD and T deficiency.

Diabetes mellitus. 2019;22(6):542-549
Systems of continuous subcutaneous insulin infusion to maintain metabolic compensation for type 1 diabetes mellitus among children and adolescents
Bashnina E.B., Tsargasova I.M., Klitsenko O.A.

BACKGROUND: Insulin pumps (IP) are a widespread treatment for type 1 diabetes mellitus (T1D) in children because of its several advantages over multiple insulin injection regimens (MII). However, the long-term effectiveness of continuous subcutaneous insulin infusion (CSII) in achieving and maintaining sustained metabolic compensation remains controversial.

OBJECTIVE: To determine the factors affecting the long-team effectiveness of CSII in children and adolescents with T1DM in real clinical practice.

METHODS: Data of 239 children and adolescents treated with CSII for ≥3 years were examined during the registration of patients receiving insulin pump therapy in Saint-Petersburg was formed. HbA level changes over time were analysed before switching to CSII and were assessed depending on sex and age, baseline HbA level and factors as the frequency of using continuous glucose monitoring (CGM), temporary transitions from CSII to MII with injection pens and use of bolus calculators (BC).

RESULTS: The final HbA value showed no significant changes as compared with the HbA level before switching to CSII (baseline, 7.82±1.46%; final, 7.93±1.30%). Approximately 42% of patients had HbA level of <7.5%. Better results were observed in the 4.5–7-year age group, where 67% of patients had HbA level of <7.5%; in 12–18-year age group, only 35% of patients reached the target HbAlevel. Majority of patients with baseline HbA level of <7.5% remained within the target level during the final examination, whereas only 23% of patients with HbA level of ≥7.5% before switching to CSII reached the target level. Better glycaemic control was also observed in patients treated with CSII regularly, as compared to patients who periodically switched to MII with the injection pen (p<0.05). HbA appeared to be lower in the group of 12–18-year-old adolescents who used CGM regularly, as compared to the group not treated with CGM (p<0.05).

CONCLUSION: Children and adolescents treated with CSII for ≥3 years did not experience a significant improvement in metabolic control. However, the influence of factors in maintaining the metabolic control, such factors as the patient’s age, initial HbA level, CGM use and frequency, and the presence or absence of changes in insulin therapy regimen is observed.

Diabetes mellitus. 2019;22(6):550-558
Pilot study of the safety and efficacy of angiogenic therapy in diabetic foot syndrome
Plaksa I.L., Mzhavanadze N.D., Kalinin R.E., Suchkov I.A., Bakunov M.U., Krivichin V.T., Matveev S.A., Isaev A.A., Deev R.V.

BACKGROUND: The syndrome of diabetic foot remains the main cause of non-traumatic amputation of the lower extremity in the world. Even with the provision of comprehensive medical care in the conditions of a specialized center, 10-15% of patients do not succeed in healing the ulcerative defect due to the ischemic component.

AIMS: The objective of this study is evaluation of safety and efficacy of pl-VEGF165 transfer in patients with neuroischemic type of diabetic foot syndrome.

METHODS: The pilot study included 35 diabetic patients with neuroischemic foot ulcers (Wagner stage 1-2) who were not candidates for revascularization procedures (NCT02538705). The patients were closely monitored after repeated pl-VEGF165 intramuscular gene transfer (2,4 mg) at 1, 3, and 6 months after treatment. The primary efficacy endpoint was the surface area of the ulcers (sq.cm), the secondary endpoints were transcutaneous oxygen tension (Tcp02), ankle-brachial index (ABI), neuropathy disability score (NDS), neuropathy symptoms score (NSS), and Michigan neuropathy screening instrument (MNSI). Adverse events were monitored throughout the study.

RESULTS: The use of pl-VEGF165 as part of complex treatment allowed to achieve wound healing in 65,7% of patients with chronic ulcerative defects, the safety of the target limb was 84%. Carrying out therapeutic angiogenesis as a part of the combined therapy ensured a reduction in the average area of the resistant to treatment defects from 3.6 [1.0; 7.05] cm2 to 0.0 [0.0;2.0] cm2 (p=0,001), which correlated with an increase in the TcPo2 index by 15% from 35 [29.5; 40.5] to 40.5 [36.0; 46.5] mm Hg (p= p=0,005) and in the ABI by 16% from 0.96 [0.82;1.08] to 1.11 [0.85; 1.24] (p=0,062). The decrease in the signs of diabetic neuropathy was determined - the scores of NSS scales and VAT decreased from 6,5 [5.75; 8.0) to 6.0 [5.25; 7.0] (p=0,004) and from 9.0 [8.0; 13.5] to 8.0 [7.0; 12.7] (p=0,001), respectively. No adverse effects associated with the use of pl-VEGF165 were recorded.

CONCLUSIONS: Thus, preliminary results of the pilot study show that the use of pl-VEGF165 gene transfer in combination therapy allows for complete healing of neuroischemic diabetic foot ulcers in the majority of patients.

Diabetes mellitus. 2019;22(6):559-567
Genetic polymorphism of renin-angiotensin-aldosterone system in type 2 diabetes and in combination with arterial hypertension among Dagestan inhabitants
Saidov M.Z., Mammaev S.N., Magadova H.M., Balamirzoeva R.M., Magomedova Z.S., Magomedova Z.S., Gamzaeva A.U.

BACKGROUND: Type 2 diabetes and arterial hypertension are frequent comorbidities under which activation the renin-angiotensin-aldosterone system is important pathogenetic link. The functional state of the RAAS is genetically determined. Genetic polymorphisms of the RAAS system associated with the development of both type 2 diabetes and arterial hypertension have been identified and mapped. Associations of polymorphic variants of the RAAS genes with type 2 diabetes and arterial hypertension among the inhabitants of Dagestan have not been studied.

AIM: Studying the association of the most relevant polymorphic variants of the C521T and T704C AGT gene, as well as the A1166C AGTR1 gene with type 2 diabetes and when combining type 2 diabetes with arterial hypertension among Dagestan inhabitants.

METHODS: We examined 16 patients with type 2 diabetes, 59 patients with type 2 diabetes combined with arterial hypertension and 51 patients with arterial hypertension, all residents of Dagestan. The control group included 47 healthy persons of the same age group. SNP polymorphisms were investigated by the method of allele-specific Real-Time PCR. The C521T and T704C polymorphisms of the AGT gene and the A1166C polymorphism of the AGTR1 gene were studied.

RESULTS: In the group of patients with a combination type 2 diabetes with arterial hypertension, the genotype CT of the C521T polymorphism of the AGT gene is less common compared to the control (23% vs. 43%, χ2 = 3,868, p = 0,049), OR score – 0,4 (0,2-0,9 ). The situation is similar with the TC genotype of the T704C polymorphism of the AGT gene (39% versus 61%, χ2 = 4,282, p = 0,039). OR was 0,4 (0,2–0,8).On the contrary, in the same patients, but the carriers of the homozygous CC genotype of the T704C polymorphism of the AGT gene, OR exceeded one and made 2.5 (1.02-5.9), the frequency of occurrence was 42% vs. 23%, χ2 = 3,363, p = 0,05. The frequency of the mutant allele C of the A1166C polymorphism of the AGTR1 gene in patients with arterial hypertension alone was 31% vs. 14%, χ2 = 5.496, p = 0,019, OR – 2,5 (1,2-5,0). The frequency of the wild allele A in these same patients was 69% versus 84%, χ2 = 5,496, p = 0,019, OR – 0,4 (0,2-0,8). A similar situation is determined with the AA genotype (52% versus 73%, χ2 = 3,609, p = 0,05), OR = 0,4 (0,1-0,9).

CONCLUSIONS: The association of the C521T and T704C polymorphisms, as well as the A1166C candidate genes AGT and AGTR1 with type 2 diabetes and arterial hypertension, is an important component in assessing the susceptibility to the development of these diseases in Dagestan residents.

Diabetes mellitus. 2019;22(6):568-576
Phenotypes of prediabetes: pathogenesis and consequences for prediction and prevention of type 2 diabetes and cardiovascular diseases
Stefan N.

The prevalence of type 2 diabetes is increasing world-wide. Thus, it is necessary to better understand its pathogenesis, the risk of diabetes-associated complications and effective treatment strategies. Because type 2 diabetes is a very heterogenous disease, both, related to its pathogenesis and risk of complications, phenotyping strategies in diabetes may help to tailor the preventive strategies based on the individual’s risk. As the the hyperglycemic state of prediabetes is already associated with an increased risk of cardiometabolic diseases it is necessary to investigate the impact of phenotypes for predictive and preventive outcomes already in this early state of hyperglycemia. In this review artice I discuss how important phenotypes of prediabetes, such as nonalcoholic fatty liver disease, visceral obesity, insulin secretion defect and insulin resistance can be used to improve the prediction and prevention of type 2 diabetes and cardiovascular disease.

Diabetes mellitus. 2019;22(6):577-581
Type 2 diabetes mellitus in elderly patients treated with endocrinologists in clinical practice
Biryukova E.V.

A large-scale epidemic of type 2 diabetes mellitus (T2DM) is observed with advanced ageing worldwide. The prevalence of T2DM significantly increases with age. Therefore, this review aimed to summarise the data on T2DM in advanced and older aged patients. The primary geriatric syndromes, which should be considered for the management of older patients (cognitive impairment, sarcopenia, orthostatic hypotension, falls, urinary incontinence, senile asthenia, etc.), are presented. The causes of the high risk for hypoglycaemia in elderly patients are analysed. Improving the treatment for T2DM is a priority of modern medicine. Using antihyperglycaemic therapy is especially difficult in this population due to the high risk of hypoglycaemia and the multi-organ pathology leading to polypharmacy. Therefore, special attention is paid to treatment recommendations. Hypoglycaemic drugs used in elderly patients should be low risk of hypoglycaemia, without nephro- and hepatic toxicity, safe for cardiovascular organs, easy to administer. Furthermore, advantages and limitations of using various groups of hypoglycaemic drugs in elderly patients are discussed. DPP-4 inhibitors are also considered in detail. Modern data on mechanisms of hypoglycaemic action of DPP-4 inhibitors are presented. Possibilities of using sitagliptin in elderly patients were also considered. Finally, evidence-based studies demonstrating the obvious advantages of sitagliptin for the treatment of T2DM in the elderly and advanced aged population are discussed.

Diabetes mellitus. 2019;22(6):582-591
DECLARE-TIMI 58 trial in the context of EMPA-REG OUTCOME and CANVAS
Shestakova M.V.

The article discussed results of the DECLARE-TIMI 58 study in the aspects of the previously finished trials (EMPA-REG OUTCOME and CANVAS).

All three SGLT2i demonstrated the reduction of the risk of hospitalization for heart failure, as well as the risk of progression chronic kidney disease. At the same time, the patient populations are different. In EMPA-REG OUTCOME almost all the patients had previously diagnosed cardiovascular disease; in CANVAS 44.4% of patients did not have a confirmed cardiovascular disease, but had cardiovascular risk factors, and in DECLARE TIMI 58 there were 59% of such patients.

Assessment of the published data suggests that the risk of a combined cardiovascular endpoint, including death from cardiovascular causes, myocardial infarction, and stroke, seems to be most pronounced in patients who already have established cardiovascular disease, and this effect is achieved mainly by reducing cardiovascular mortality. In the population of patients with type 2 diabetes who do not have cardiovascular disease, but who have cardiovascular risk factors, this effect is not detected.

Contrary, risk-reduction of hospitalization for CHF and slowing the progression of CKD is manifested both in a population of patients with established cardiovascular disease and in the population of patients with multiple cardiovascular risk factors.

In this regard, DECLARE-TIMI 58, as well as previously published data, open up new option for an earlier start of SGLT-2i for primary prevention and/or slowing the progression of nephropathy, reducing the risk of heart failure, and its prevention, as well as reduction of cardiovascular morbidity and mortality in patients with type 2 diabetes, regardless of the presence or absence of cardiovascular pathology in the anamnesis.

Diabetes mellitus. 2019;22(6):592-601

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