Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding: Novo Nordisk

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Дисциплинарные взыскания как средство стимулирования труда

Сардінов, Р. Т. Дисциплінарні стягнення як засіб стимулювання праці / Р. Т. Сардінов // Вісник Харківського національного університету внутрішніх справ. – 2012. – № 3 (58). – С. 315-320.Досліджено стимулюючу роль дисциплінарних стягнень. Визначено поняття «дисциплінарне стягнення». Подано пропозиції щодо вдосконалення законодавства, яке регламентує дисциплінарні стягнення.The stimulant role of disciplinary penalties is investigational. A concept «Disciplinary penalty» is certain. The suggestions on the improvement of legislation regulating disciplinary penalties are given.Исследована стимулирующая роль дисциплинарных взысканий. Определено понятие «дисциплинарное взыскание». Предоставлены предложения по усовершенствованию законодательства, регламентирующего дисциплинарные взыскания

Поощрения в национальном законодательстве

Сардінов, Р. Т. Заохочення за національним законодавством [Електронний ресурс] / Р. Т. Сардінов // Форум права. – 2012. – № 3. – С. 642-646. – Режим доступу: http://www.nbuv.gov. ua/e-journals/FP/2012-3/12crtznz.pdf.Досліджено роль заохочень у стимулюванні праці. Надано власне визначення поняття «заохочення». Визначено фактори, від яких залежить дієвість та ефективність заохочень.The role of encouragements in boost of transactions is researched. Characteristic determination of concept «encouragement» is given. Factors on which one an effectiveness and performance of encouragements depends are spotted.Исследуется роль поощрений в стимулировании труда. Предоставляется собственное определение понятия «поощрение». Определяются факторы, от которых зависит действенность и эффективность поощрений

Особенности применения дисциплинарных взысканий к должностным лицам таможенной службы Украины

Сардінов, Р. Т. Особливості застосування дисциплінарних стягнень до посадових осіб митної служби України / Р. Т. Сардінов // Вісник Харківського національного університету внутрішніх справ. – 2013. – № 2 (61). – С. 283-290.Досліджено норми Закону України «Про Дисциплінарний статут митної служби України» від 6 вересня 2005 р. № 2805-IV, які встановлюють порядок застосування дисциплінарних стягнень, та сформульовано рекомендації щодо їх удосконалення. The norms of the Law of Ukraine «About Disciplinary Statute of the Customs of Ukraine» dated from September 6, 2005, # 2805-IV, which govern the order of disciplinary penalties’ implementation, are researched. It is emphasized that the norms of Art. 22 of the Disciplinary Statue consolidate acts that indicate about nonperformance or improper performance of the duties by customs’ officials. Исследованы нормы Закона Украины «О Дисциплинарном уставе таможенной службы Украины» от 6 сентября 2005 г. № 2805-IV, которые устанавливают порядок применения дисциплинарных взысканий, и даны рекомендации по их усовершенствованию

Единство и дифференциация правового регулирования поощрений в трудовом праве

Сардинов, Р. Единство и дифференциация правового регулирования поощрений в трудовом праве / Р. Сардинов // Legea si viata = Закон и Жизнь : междунар. науч.-практ. журн. – 2013. – № 10/3. – P. 184-187.Исследуются нормы национального законодательства в сфере применения поощрений. Обосновывается, что институту поощрений в трудовом праве присуща такая характерная особенность как единство и дифференциация. Предоставляются рекомендации по усовершенствованию соответствующего национального законодательства. В частности, предлагается с целью обеспечения работодателя максимальными инструментарием для поощрения добросовестных работников предусматривать на предприятиях, учреждениях и организациях максимально объемный перечень поощрений. The article examines the norms of national legislation in the field of application of incentives. It is substantiated that the institution of incentives in labor law is characterized by such a characteristic feature as unity and differentiation. Recommendations for improving the relevant national legislation are provided. In particular, it is proposed to provide the employer with the maximum tools for encouraging conscientious workers to provide for the largest list of incentives at enterprises, institutions and organizations. Досліджуються норми національного законодавства в сфері застосування заохочень. Обґрунтовується, що інституту заохочень в трудовому праві властива така характерна особливість як єдність і диференціація. Надаються рекомендації щодо вдосконалення відповідного національного законодавства. Зокрема, пропонується з метою забезпечення роботодавця максимальними інструментарієм для заохочення добросовісних працівників передбачати на підприємствах, установах і організаціях максимально об'ємний перелік заохочень

Early drop in systolic blood pressure and worsening renal function in acute heart failure: Renal results of Pre-RELAX-AHF

Aims We aimed to determine the relation between baseline systolic blood pressure (SBP), change in SBP, and worsening renal function (WRF) in acute heart failure (AHF) patients enrolled in the Pre-RELAX-AHF trial. Methods and resultsThe Pre-RELAX-AHF study enrolled 234 patients within 16 h of admission (median 7 h) for AHF and randomized them to relaxin given intravenous (i.v.) for 48 h or placebo. Blood pressure was measured at baseline, at 3, 6, 9, 12, 24, 36, and 48 h and at 3, 4, and 5 days after enrolment. Worsening renal function was defined as a serum creatinine increase of &lt;0.3 mg/dL by Day 5. Worsening renal function was found in 68 of the 225 evaluable patients (30). Patients with WRF were older (73.5 ± 9.4 vs. 69.1 ± 10.6 years; P 0.003), had a higher baseline SBP (147.3 ± 19.9 vs. 140.8 ± 16.7 mmHg; P 0.01), and had a greater early drop in SBP (37.9 ± 16.0 vs. 31.4 ± 12.2 mmHg; P 0.004). In a multivariable model, higher age, higher baseline creatinine, and a greater early drop in SBP, but not baseline SBP, remained independent predictors of WRF. Furthermore, WRF was associated with a higher Day 60 (P 0.01), and Day 180 (P 0.003) mortality. ConclusionsWorsening renal function in hospitalized AHF patients is related to a poor clinical outcome and is predicted by a greater early drop in SBP. © 2011 The Author

Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: Results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes

BACKGROUND: A fixed-ratio combination of the basal insulin analogue insulin degludec and the glucagon-like peptide-1 (GLP-1) analogue liraglutide has been developed as a once-daily injection for the treatment of type 2 diabetes. We aimed to compare combined insulin degludec-liraglutide (IDegLira) with its components given alone in insulin-naive patients. METHODS: In this phase 3, 26-week, open-label, randomised trial, adults with type 2 diabetes, HbA1c of 7-10% (inclusive), a BMI of 40 kg/m(2) or less, and treated with metformin with or without pioglitazone were randomly assigned (2:1:1) to daily injections of IDegLira, insulin degludec, or liraglutide (1\ub78 mg per day). IDegLira and insulin degludec were titrated to achieve a self-measured prebreakfast plasma glucose concentration of 4-5 mmol/L. The primary endpoint was change in HbA1c after 26 weeks of treatment, and the main objective was to assess the non-inferiority of IDegLira to insulin degludec (with an upper 95% CI margin of 0\ub73%), and the superiority of IDegLira to liraglutide (with a lower 95% CI margin of 0%). This study is registered with ClinicalTrials.gov, number NCT01336023. FINDINGS: 1663 adults (mean age 55 years [SD 10], HbA1c 8\ub73% [0\ub79], and BMI 31\ub72 kg/m(2) [4\ub78]) were randomly assigned, 834 to IDegLira, 414 to insulin degludec, and 415 to liraglutide. After 26 weeks, mean HbA1c had decreased by 1\ub79% (SD 1\ub71) to 6\ub74% (1\ub70) with IDegLira, by 1\ub74% (1\ub70) to 6\ub79% (1\ub71) with insulin degludec, and by 1\ub73% (1\ub71) to 7\ub70% (1\ub72) with liraglutide. IDegLira was non-inferior to insulin degludec (estimated treatment difference -0\ub747%, 95% CI -0\ub758 to -0\ub736, p<0\ub70001) and superior to liraglutide (-0\ub764%, -0\ub775 to -0\ub753, p<0\ub70001). IDegLira was generally well tolerated; fewer participants in the IDegLira group than in the liraglutide group reported gastrointestinal adverse events (nausea 8\ub78 vs 19\ub77%), although the insulin degludec group had the fewest participants with gastrointestinal adverse events (nausea 3\ub76%). We noted no clinically relevant differences between treatments with respect to standard safety assessments, and the safety profile of IDegLira reflected those of its component parts. The number of confirmed hypoglycaemic events per patient year was 1\ub78 for IDegLira, 0\ub72 for liraglutide, and 2\ub76 for insulin degludec. Serious adverse events occurred in 19 (2%) of 825 patients in the IDegLira group, eight (2%) of 412 in the insulin degludec group, and 14 (3%) of 412 in the liraglutide group. INTERPRETATION: IDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycaemic control compared with its components given alone

Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes.

BACKGROUND: A fixed-ratio combination of the basal insulin analogue insulin degludec and the glucagon-like peptide-1 (GLP-1) analogue liraglutide has been developed as a once-daily injection for the treatment of type 2 diabetes. We aimed to compare combined insulin degludec-liraglutide (IDegLira) with its components given alone in insulin-naive patients. METHODS: In this phase 3, 26-week, open-label, randomised trial, adults with type 2 diabetes, HbA1c of 7-10% (inclusive), a BMI of 40 kg/m(2) or less, and treated with metformin with or without pioglitazone were randomly assigned (2:1:1) to daily injections of IDegLira, insulin degludec, or liraglutide (1·8 mg per day). IDegLira and insulin degludec were titrated to achieve a self-measured prebreakfast plasma glucose concentration of 4-5 mmol/L. The primary endpoint was change in HbA1c after 26 weeks of treatment, and the main objective was to assess the non-inferiority of IDegLira to insulin degludec (with an upper 95% CI margin of 0·3%), and the superiority of IDegLira to liraglutide (with a lower 95% CI margin of 0%). This study is registered with ClinicalTrials.gov, number NCT01336023. FINDINGS: 1663 adults (mean age 55 years [SD 10], HbA1c 8·3% [0·9], and BMI 31·2 kg/m(2) [4·8]) were randomly assigned, 834 to IDegLira, 414 to insulin degludec, and 415 to liraglutide. After 26 weeks, mean HbA1c had decreased by 1·9% (SD 1·1) to 6·4% (1·0) with IDegLira, by 1·4% (1·0) to 6·9% (1·1) with insulin degludec, and by 1·3% (1·1) to 7·0% (1·2) with liraglutide. IDegLira was non-inferior to insulin degludec (estimated treatment difference -0·47%, 95% CI -0·58 to -0·36, p<0·0001) and superior to liraglutide (-0·64%, -0·75 to -0·53, p<0·0001). IDegLira was generally well tolerated; fewer participants in the IDegLira group than in the liraglutide group reported gastrointestinal adverse events (nausea 8·8 vs 19·7%), although the insulin degludec group had the fewest participants with gastrointestinal adverse events (nausea 3·6%). We noted no clinically relevant differences between treatments with respect to standard safety assessments, and the safety profile of IDegLira reflected those of its component parts. The number of confirmed hypoglycaemic events per patient year was 1·8 for IDegLira, 0·2 for liraglutide, and 2·6 for insulin degludec. Serious adverse events occurred in 19 (2%) of 825 patients in the IDegLira group, eight (2%) of 412 in the insulin degludec group, and 14 (3%) of 412 in the liraglutide group. INTERPRETATION: IDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycaemic control compared with its components given alone