Association of polymorphic loci of susceptibility to diabetes mellitus type 2 in various ethnic groups of the Russian Federation

The multifactorial nature of type 2 diabetes mellitus (T2D) was confirmed by numerous researches. The first investigations devoted to molecular-genetic mechanisms of T2D were carried out on the basis of linkage disequilibrium (LD) studying and later the candidate genes of T2D have begun investigated. We have analyzed the literature data including the case-control studies in populations of Russia. There were revealed 33 genes and 65 polymorphic markers in the analyzed works. The analysis of association of T2D in the ethnic groups of Russian Federation was carried out on following genes: ABCC8, ADIPOQ, ADIPOR1, ADIPOR2, C2CD4A/C2CD4A, CDKAL1, ­CDKN2A/2B, CCL11, CCL20, CCL5, CYBA, FABP2, FTO, GCLC, GPX2, GSTP1, GSTT1, HHEX/IDE, IGF2BP2, IRS1, KCNJ11, KCNQ1, LPL, LRP5, MC4R, PPARG, SLC2A2, SLC30A8, SLC30A8, TCF7L2, TMEM18, WFS1, ZFAND6. The major of studies are replicative, i.e. repeating previous investigations of foreign authors, and were performed on Russian, Tatar and Yakut populations. At the same time not all the loci of genetic susceptibility have demonstrated the association with T2D in the population of Russia. In this work the systematic review of studies of molecular-genetic markers of T2D in the ethnic groups of Russian Federation was made for the first time

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Analiz assotsiatsiy polimorfizma S1159A gena interleykina 12V s sakharnym diabetom 1 tipa v etnicheskikh gruppakh Bashkortostana

Цель. Анализ ассоциаций полиморфизма С1159А гена ИЛ12B c развитием СД 1 в трех этнически однородных группах (русские, башкиры, татары), проживающих на территории республики Башкортостан. Материалы и методы. В исследовании приняли участие 313 пациентов в возрасте от 7 до 71 года (татар ? 127, русских ? 110, башкир ? 66). ДНК выделяли методом фенольно-хлороформной экстракции. У всех пациентов, включенных в исследование, а также у всех лиц группы сравнения был исследован полиморфизм С1159А гена ИЛ12B. Сравнение групп по частотом аллелей и генотипов проводили с использованием точного двустороннего критерия Фишера. Результаты. В этнической группе башкир среди пациентов с поздним началом заболевания по сравнению с другими пациентами с большей частотой обнаруживается генотип АС (53,6% и 33,3% соответственно, p=0,074). в группе этнических русских аллель С чаще встречается у больных с поздней манифестацией СД 1 (30,5% против 17,1% в подгруппе пациентов с началом диабета в возрасте до 16 лет, p=0,047). Заключение. У этнических русских наблюдается выраженная тенденция к возрастанию частоты генотипа СС и достоверно большая частота аллеля С среди больных с поздней манифестацией СД 1. Необходимы дополнительные исследования для подтверждения ассоциации полиморфизма С1159А гена ИЛ12B с СД 1 с поздней манифестацией у этнических русских

Opyt primeneniya ingibitora angiotenzinprevrashchayushchego fermenta spiraprila u bol'nykh gipertonicheskoy bolezn'yu v sochetanii s sakharnym diabetom 2 tipa

Цель. Оценка влияния иАПФ спираприла на плазменно-тромбоцитарный гемостаз, углеводный обмен и липидный профиль у больных ГБ, ассоциированной с СД 2. Материалы и методы. Под динамическим наблюдением находилось 33 больных СД 2 и ГБ (1-я ст. ? 2 (6,06%), 2-я ст. ? 9 (27,27%), 3-я ст. ? 22 (66,67%) больных). Контрольную группу составили 35 больных гипертонической болезнью (1-я ст. ? 4 (11,43 %), 2-я ст. ? 14 (40 %), 3-я ст. ? 17 (48,57%)) без СД. Антропометрическое исследование включало измерение массы тела, объема талии (ОТ) и бедер (ОБ), расчет ОТ/ОБ, индекса массы тела (ИМТ). Содержание глюкозы в крови определялось глюкозооксидазным методом в капиллярной крови натощак, через 1 и 2 часа в ходе стандартного перорального глюкозотолерантного теста с 75 г глюкозы. Исследовались липидный спект, экскреция альбумина, коагуляцинное звено гемостаза, тромбоцитарное звено гемостаза. Результаты. МАУ (экскреция альбумина >20 мг/л) исходно диагностирована у 28 больных (84,85%). Через 4 недели лечения спираприлом у 93,94% больных отмечалось уменьшение уровня экскреции альбумина с мочой. У обследованных больных СД 2 с ГБ отмечены нарушения во всех звеньях гемостаза, но, в отличие от контрольной группы, были менее выражены нарушения спонтанной агрегации тромбоцитов. У больных СД с ГБ гиперкоагуляция наблюдалась преимущественно по внешнему пути свертывания крови. Заключение. У больных СД и ГБ повышен тромбогенный потенциал крови. В результате лечения спираприлом отмечена положительная динамика ? активация фибринолитической системы, снижение спонтанной агрегации тромбоцитов и нормализация в коагуляционном звене гемостаза. На фоне терапии спираприлом наблюдается улучшение показателей углеводного и липидного обмена. Спираприл обладает нефропротективным эффектом, что проявилось снижением уровня МАУ. Лечение спираприлом не влияло на динамику массы тела, ИМТ, отношения ОТ/ОБ

Polimorfizm gena glavnogo kompleksa gistosovmestimosti klassa II DRB1 i risk razvitiya sakharnogo diabeta tipa 1 v etnicheskikh gruppakh Bashkortostana

Цель: исследования состояла в изучении роли по? лиморфизма гена HLA класса II DRB1 в формировании наследственной предрасположенности к СД ти? па 1. Объем и методы: Обследовано 186 больных СД типа 1. Контрольная группа была сформирована из 71 мужчины и 100 женщин без клинических признаков диабета. Образцы ДНК были получены из венозной крови методом фенольно-хлороформной экстракции. Результаты: при сравнении полученных нами результатов с данными других авторов обращает на себя внимание тот факт, что в популяциях башкир, русских и татар Башкортостана выявлены те же самые специфичности риска (DRB1*04 и DRB1*17) и антириска (DRB1*15), что и в других популяциях eвропеоидов и монголоидов

Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials

Background: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. Methods: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). Findings: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference −0·2 ETDRS letters [−2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [−0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [−1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [−1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). Interpretation: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. Funding: F Hoffmann-La Roche