AIM: To assess the occurrence of atrial fibrillation or atrial flutter (atrial arrhythmias [AA]) in patients with type 2 diabetes treated with once-weekly subcutaneous dulaglutide versus placebo. MATERIALS AND METHODS: Patients without electrocardiographic (ECG)-confirmed AA at baseline and randomized in the REWIND trial were assessed for the development of AA based on an annual ECG. Additional analyses included whether dulaglutide compared with placebo reduced the composite outcome of AA or death, AA or cardiovascular death, AA or stroke and AA or heart failure. RESULTS: Among 9543 participants (mean age 66 ± 7 years, with cardiovascular risk factors and 31% with previous cardiovascular disease) without AA at entry in the trial, 524 patients (5.5%) had at least one episode of AA during the median 5.4 years of follow-up. Incident AA occurred in 269 of the 4769 participants allocated to dulaglutide (5.6%), at a rate of 10.7 per 1000 person-years, versus 255 of the 4774 allocated to placebo (5.3%), at a rate of 10.5 per 1000 person-years (P = .59). There was also no effect of dulaglutide on the composite outcome of AA and death or AA and heart failure. CONCLUSION: This post hoc analysis of data from the REWIND trial showed that treatment with dulaglutide was not associated with a reduced incidence of AA in this at-risk group of patients with type 2 diabetes.

• Klíčová slova
• atrial fibrillation, atrial flutter, dulaglutide, glucagon-like peptide-1 receptor agonists, type 2 diabetes,
• MeSH
• diabetes mellitus 2. typu * komplikace   farmakoterapie   epidemiologie   MeSH
• fibrilace síní * komplikace   farmakoterapie   epidemiologie   MeSH
• glukagonu podobné peptidy analogy a deriváty   MeSH
• hypoglykemika MeSH
• imunoglobuliny - Fc fragmenty škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• rekombinantní fúzní proteiny škodlivé účinky   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• dulaglutide MeSH Prohlížeč
• glukagonu podobné peptidy MeSH
• hypoglykemika MeSH
• imunoglobuliny - Fc fragmenty MeSH
• rekombinantní fúzní proteiny MeSH

AIMS: Dulaglutide, a once weekly GLP-1 receptor agonist, is approved at two doses (1.5 and 0.75 mg) for treatment of type 2 diabetes (T2D). Two higher doses of dulaglutide (3.0 and 4.5 mg) were evaluated for safety and efficacy to determine whether these doses warrant further study for improved control of glucose and body weight. MATERIALS AND METHODS: This 18-week, double-blind, phase 2 trial randomized 318 patients with T2D using ≥1500 mg metformin, to receive subcutaneous injection of placebo (n = 82), dulaglutide 1.5 mg (n = 81), dulaglutide 3.0 mg (n = 79) or dulaglutide 4.5 mg (n = 76). The primary objective was superiority of dulaglutide doses over placebo in reduction of HbA1c at 18 weeks. Secondary objectives included superiority of dulaglutide over placebo in change from baseline in body weight and fasting serum glucose (FSG) at 18 weeks. Investigational doses of dulaglutide were compared to the 1.5 mg dose as an exploratory objective. RESULTS: HbA1c reduction at 18 weeks was significantly greater with dulaglutide vs placebo (placebo, -0.44% ± 0.10% [-4.8 ± 1.1 mmol/mol]; dulaglutide 1.5 mg, -1.23% ± 0.10% [-13.5 ± 1.1 mmol/mol]; dulaglutide 3.0 mg, -1.31% ± 0.10% [-14.3 ± 1.1 mmol/mol]; dulaglutide 4.5 mg, -1.40% ± 0.10% [-15.3 ± 1.1 mmol/mol]; P < 0.001, each dose), as were changes in body weight (placebo, -1.6 ± 0.39 kg; dulaglutide 1.5 mg, -2.8 ± 0.39 kg; dulaglutide 3.0 mg, -3.9 ± 0.39 kg; dulaglutide 4.5 mg, -4.1 ± 0.41 kg; P < 0.001, each dose). All three dulaglutide doses significantly reduced FSG from baseline (1.5 mg, -36.2 ± 4.7 mg/dL [-2.0 ± 0.3 mmol/L]; 3.0 mg, -34.5 ± 4.5 mg/dL [-1.9 ± 0.3 mmol/L]; 4.5 mg, -38.0 ± 4.7 mg/dL [-2.1 ± 0.3 mmol/L]) vs placebo (-12.4 ± 4.5 mg/dL [-0.7 ± 0.3 mmol/L]) (P < 0.001, all). Safety profiles of the higher doses were consistent with the established safety profile for dulaglutide. Gastrointestinal events were mostly mild to moderate, and was dose-related for nausea. CONCLUSION: All three dulaglutide doses were superior to placebo in improving glycaemic control and reducing body weight in participants with T2D using metformin. The potential for doses of dulaglutide of 3.0 and 4.5 mg to provide additional glycaemic benefit and weight reduction with an acceptable safety profile, compared with the 1.5 mg dose, warrants further study in a phase 3 trial.

• Klíčová slova
• GLP-1, dulaglutide, type 2 diabetes,
• MeSH
• diabetes mellitus 2. typu krev   farmakoterapie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• glukagonu podobné peptidy aplikace a dávkování   analogy a deriváty   MeSH
• glykovaný hemoglobin účinky léků   MeSH
• hmotnostní úbytek účinky léků   MeSH
• hypoglykemika aplikace a dávkování   MeSH
• imunoglobuliny - Fc fragmenty aplikace a dávkování   MeSH
• kombinovaná farmakoterapie MeSH
• krevní glukóza účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metformin aplikace a dávkování   MeSH
• rekombinantní fúzní proteiny aplikace a dávkování   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• dulaglutide MeSH Prohlížeč
• glukagonu podobné peptidy MeSH
• glykovaný hemoglobin MeSH
• hypoglykemika MeSH
• imunoglobuliny - Fc fragmenty MeSH
• krevní glukóza MeSH
• metformin MeSH
• rekombinantní fúzní proteiny MeSH

Dulaglutide is a frequently used GLP-1 analogue and one of the most potent antidiabetic drugs. Practical aspects of treatment with dulaglutide are presented in this article, together with new data from AWARD-11 study with higher concentrations of dulaglutide, especially the effects on diabetes control, body weight and side effects.

• Klíčová slova
• GLP1 receptor agonists, diabetes, dulaglutide, heart failure, pharmacotherapy,
• MeSH
• diabetes mellitus 2. typu * farmakoterapie   MeSH
• glukagonu podobné peptidy analogy a deriváty   MeSH
• glukagonu podobný peptid 1 MeSH
• glykovaný hemoglobin analýza   MeSH
• hypoglykemika škodlivé účinky   MeSH
• imunoglobuliny - Fc fragmenty MeSH
• lidé MeSH
• motivace * MeSH
• receptor pro glukagonu podobný peptid 1 MeSH
• rekombinantní fúzní proteiny MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dulaglutide MeSH Prohlížeč
• glukagonu podobné peptidy MeSH
• glukagonu podobný peptid 1 MeSH
• glykovaný hemoglobin MeSH
• hypoglykemika MeSH
• imunoglobuliny - Fc fragmenty MeSH
• receptor pro glukagonu podobný peptid 1 MeSH
• rekombinantní fúzní proteiny MeSH

BACKGROUND: Cardiovascular outcome trials have suggested that glucagon-like peptide 1 (GLP-1) receptor agonists might reduce strokes. We analysed the effect of dulaglutide on stroke within the researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial done at 371 sites in 24 countries. Men and women (aged ≥50 years) with established or newly detected type 2 diabetes whose HbA1c was 9·5% or less (with no lower limit) on stable doses of up to two oral glucose-lowering drugs with or without basal insulin therapy were eligible if their body-mass index was at least 23 kg/m2. Participants were randomly assigned (1:1) to weekly subcutaneous injections of either masked dulaglutide 1·5 mg or the same volume of masked placebo (containing the same excipients but without dulaglutide). Randomisation was done by a computer-generated random code with an interactive web response system with stratification by site. Participants, investigators, the trial leadership, and all other personnel were masked to treatment allocation until the trial was completed and the database was locked. During the treatment period, participants in both groups were instructed to inject study drug on the same day at around the same time, each week. Strokes were categorised as fatal or non-fatal, and as either ischaemic, haemorrhagic, or undetermined. Stroke severity was assessed using the modified Rankin scale. Participants were seen at 2 weeks, 3 months, 6 months, and then every 3 months for drug dispensing and every 6 months for detailed assessments, until 1200 confirmed primary outcomes accrued. The primary endpoint was the first occurrence of any component of the composite outcome, which comprised non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular or unknown causes. All analyses were done according to an intention-to-treat strategy that included all randomly assigned participants, irrespective of adherence. The trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, we screened 12 133 patients, of whom 9901 with type 2 diabetes and additional cardiovascular risk factors were randomly assigned to either dulaglutide (n=4949) or an equal volume of placebo (n=4952). During a median follow-up of 5·4 years, cerebrovascular and other cardiovascular outcomes were ascertained and adjudicated. 158 (3·2%) of 4949 participants assigned to dulaglutide and 205 (4·1%) of 4952 participants assigned to placebo had a stroke during follow-up (hazard ratio [HR] 0·76, 95% CI 0·62-0·94; p=0·010). Dulaglutide reduced ischaemic stroke (0·75, 0·59-0·94, p=0·012) but had no effect on haemorrhagic stroke (1·05, 0·55-1·99; p=0·89). Dulaglutide also reduced the composite of non-fatal stroke or all-cause death (0·88, 0·79-0·98; p=0·017) and disabling stroke (0·74, 0·56-0·99; p=0·042). The degree of disability after stroke did not differ by treatment group. INTERPRETATION: Long-term dulaglutide use might reduce clinically relevant ischaemic stroke in people with type 2 diabetes but does not affect stroke severity. FUNDING: Eli Lilly and Company.

• MeSH
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• cévní mozková příhoda prevence a kontrola   MeSH
• diabetes mellitus 2. typu krev   farmakoterapie   patofyziologie   MeSH
• diabetické angiopatie krev   farmakoterapie   patofyziologie   MeSH
• dvojitá slepá metoda MeSH
• glukagonu podobné peptidy analogy a deriváty   terapeutické užití   MeSH
• glykovaný hemoglobin účinky léků   MeSH
• hypoglykemika terapeutické užití   MeSH
• imunoglobuliny - Fc fragmenty terapeutické užití   MeSH
• inkretiny terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• rekombinantní fúzní proteiny terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• dulaglutide MeSH Prohlížeč
• glukagonu podobné peptidy MeSH
• glykovaný hemoglobin MeSH
• hemoglobin A1c protein, human MeSH Prohlížeč
• hypoglykemika MeSH
• imunoglobuliny - Fc fragmenty MeSH
• inkretiny MeSH
• rekombinantní fúzní proteiny MeSH

BACKGROUND: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). INTERPRETATION: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. FUNDING: Eli Lilly and Company.

• MeSH
• cévní mozková příhoda prevence a kontrola   MeSH
• diabetes mellitus 2. typu komplikace   farmakoterapie   MeSH
• dvojitá slepá metoda MeSH
• glukagonu podobné peptidy analogy a deriváty   terapeutické užití   MeSH
• hypoglykemika terapeutické užití   MeSH
• imunoglobuliny - Fc fragmenty terapeutické užití   MeSH
• infarkt myokardu prevence a kontrola   MeSH
• kardiovaskulární nemoci mortalita   prevence a kontrola   MeSH
• lidé středního věku MeSH
• lidé MeSH
• rekombinantní fúzní proteiny terapeutické užití   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• dulaglutide MeSH Prohlížeč
• glukagonu podobné peptidy MeSH
• hypoglykemika MeSH
• imunoglobuliny - Fc fragmenty MeSH
• rekombinantní fúzní proteiny MeSH

BACKGROUND: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING: Eli Lilly and Company.

• MeSH
• albuminurie prevence a kontrola   MeSH
• diabetes mellitus 2. typu farmakoterapie   MeSH
• diabetické nefropatie prevence a kontrola   MeSH
• dvojitá slepá metoda MeSH
• glukagonu podobné peptidy analogy a deriváty   terapeutické užití   MeSH
• hodnoty glomerulární filtrace účinky léků   MeSH
• hypoglykemika terapeutické užití   MeSH
• imunoglobuliny - Fc fragmenty terapeutické užití   MeSH
• kreatinin moč   MeSH
• lidé středního věku MeSH
• lidé MeSH
• rekombinantní fúzní proteiny terapeutické užití   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• dulaglutide MeSH Prohlížeč
• glukagonu podobné peptidy MeSH
• hypoglykemika MeSH
• imunoglobuliny - Fc fragmenty MeSH
• kreatinin MeSH
• rekombinantní fúzní proteiny MeSH

BACKGROUND: Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related cardiovascular morbidity are common, and current pharmacological strategies for their management are unsatisfactory. Glucagon-like 1 peptide receptor agonists (GLP-1 RAs) are approved for the treatment of type 2 diabetes and obesity hold promise for the management of antipsychotic-associated adverse metabolic effects. METHODS: To characterize the molecular effects and identify biomarkers for GLP-1 RA preventive treatment, Sprague-Dawley female rats were treated with long-acting formulations of the antipsychotic olanzapine and the GLP-1 RA dulaglutide for 8 days. A pair-feeding protocol evaluated the combined effects of dulaglutide and food restriction on an olanzapine-induced metabolic phenotype. Body weight and food consumption were recorded. Biochemical analysis included a lipid profile, a spectrum of gastrointestinal and adipose tissue-derived hormones, and fibroblast growth factor 21 serum levels. RESULTS: Olanzapine induced hyperphagia, weight gain, increased serum triglycerides and HDL cholesterol. Food restriction affected the OLA-induced phenotype but not serum markers. Dulaglutide led to a modest decrease in food intake, with no effect on weight gain, and did not reverse the OLA-induced changes in serum lipid parameters. Concomitant dulaglutide and food restriction resulted in weight loss, decreased feed efficiency, and lower total and HDL cholesterol. CONCLUSIONS: A combined strategy of dulaglutide and food restriction manifested a massive synergistic benefit. GLP-1RAs represent a promising strategy and deserve thorough future research. Our findings underline the potential importance of lifestyle intervention in addition to GLP-1 RA treatment.

• Klíčová slova
• Antipsychotic, GLP-1 receptor agonist, Olanzapine, metabolic adverse effects, Schizophrenia,
• MeSH
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• antipsychotika farmakologie   škodlivé účinky   MeSH
• benzodiazepiny farmakologie   škodlivé účinky   MeSH
• glukagonu podobné peptidy * analogy a deriváty   farmakologie   MeSH
• hmotnostní přírůstek účinky léků   MeSH
• imunoglobuliny - Fc fragmenty * farmakologie   MeSH
• kalorická restrikce metody   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• olanzapin * farmakologie   škodlivé účinky   MeSH
• potkani Sprague-Dawley * MeSH
• přijímání potravy účinky léků   MeSH
• receptor pro glukagonu podobný peptid 1 metabolismus   MeSH
• rekombinantní fúzní proteiny * farmakologie   MeSH
• tělesná hmotnost účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• antipsychotika MeSH
• benzodiazepiny MeSH
• dulaglutide MeSH Prohlížeč
• glukagonu podobné peptidy * MeSH
• imunoglobuliny - Fc fragmenty * MeSH
• olanzapin * MeSH
• receptor pro glukagonu podobný peptid 1 MeSH
• rekombinantní fúzní proteiny * MeSH

OBJECTIVE: Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. RESEARCH DESIGN AND METHODS: Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection. RESULTS: Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81-1.05) vs. 0.78 (CI 0.61-0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin. CONCLUSION: This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy.

• Klíčová slova
• Cardiovascular disease, GLP-1-based therapy, Metformin, Morbidity, Mortality,
• MeSH
• diabetes mellitus 2. typu * komplikace   farmakoterapie   epidemiologie   MeSH
• glukagonu podobné peptidy analogy a deriváty   MeSH
• hypoglykemika terapeutické užití   MeSH
• imunoglobuliny - Fc fragmenty MeSH
• kardiovaskulární nemoci * epidemiologie   prevence a kontrola   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metformin * terapeutické užití   MeSH
• nemoci cév * MeSH
• receptor pro glukagonu podobný peptid 1 MeSH
• rekombinantní fúzní proteiny MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• dulaglutide MeSH Prohlížeč
• glukagonu podobné peptidy MeSH
• hypoglykemika MeSH
• imunoglobuliny - Fc fragmenty MeSH
• metformin * MeSH
• receptor pro glukagonu podobný peptid 1 MeSH
• rekombinantní fúzní proteiny MeSH

AIMS: People with diabetes are at high risk for cardiovascular events including heart failure (HF). We examined the effect of the glucagon-like peptide 1 agonist dulaglutide on incident HF events and other cardiovascular outcomes in those with or without prior HF in the randomized placebo-controlled Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. METHODS AND RESULTS: The REWIND major adverse cardiovascular event (MACE) outcome was the first occurrence of a composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes). In this post-hoc analysis, a HF event was defined as an adjudication-confirmed hospitalization or urgent evaluation for HF. Of the 9901 participants studied over a median follow-up of 5.4 years, 213/4949 (4.3%) randomly assigned to dulaglutide and 226/4952 (4.6%) participants assigned to placebo experienced a HF event (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.77-1.12; p = 0.456). In the 853 (8.6%) participants with HF at baseline, there was no change in either MACE or HF events with dulaglutide as compared to participants without HF (p = 0.44 and 0.19 for interaction, respectively). Combined cardiovascular death and HF events were marginally reduced with dulaglutide compared to placebo (HR 0.88, 95% CI 0.78-1.00; p = 0.050) but unchanged in patients with and without HF at baseline (p = 0.31). CONCLUSIONS: Dulaglutide was not associated with a reduction in HF events in patients with type 2 diabetes regardless of baseline HF status over 5.4 years of follow-up.

• Klíčová slova
• Clinical trial, Dulaglutide, GLP-1, Glucagon-like peptide 1 receptor agonist, Heart failure, Heart failure hospitalization, Major adverse cardiovascular events,
• MeSH
• diabetes mellitus 2. typu * komplikace   farmakoterapie   epidemiologie   MeSH
• hypoglykemika terapeutické užití   škodlivé účinky   MeSH
• inkretiny terapeutické užití   MeSH
• kardiovaskulární nemoci * epidemiologie   MeSH
• lidé MeSH
• srdeční selhání * farmakoterapie   epidemiologie   chemicky indukované   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• hypoglykemika MeSH
• inkretiny MeSH

The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.

• Klíčová slova
• GLP-1 receptor agonist, antidiabetic drug, cardiovascular disease, clinical trial, diabetes complications,
• MeSH
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• diabetes mellitus 2. typu krev   komplikace   farmakoterapie   metabolismus   MeSH
• diabetická kardiomyopatie epidemiologie   mortalita   prevence a kontrola   MeSH
• diabetické angiopatie epidemiologie   mortalita   prevence a kontrola   MeSH
• glukagonu podobné peptidy aplikace a dávkování   škodlivé účinky   analogy a deriváty   terapeutické užití   MeSH
• glykovaný hemoglobin analýza   MeSH
• hypoglykemika aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• imunoglobuliny - Fc fragmenty aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• injekce subkutánní MeSH
• inkretiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• kardiovaskulární nemoci komplikace   epidemiologie   mortalita   prevence a kontrola   MeSH
• kombinovaná farmakoterapie škodlivé účinky   MeSH
• léky s prodlouženým účinkem aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mortalita MeSH
• multicentrické studie jako téma MeSH
• následné studie MeSH
• randomizované kontrolované studie jako téma MeSH
• receptor pro glukagonu podobný peptid 1 metabolismus   MeSH
• rekombinantní fúzní proteiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• rizikové faktory MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• výzkumný projekt MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• dulaglutide MeSH Prohlížeč
• GLP1R protein, human MeSH Prohlížeč
• glukagonu podobné peptidy MeSH
• glykovaný hemoglobin MeSH
• hemoglobin A1c protein, human MeSH Prohlížeč
• hypoglykemika MeSH
• imunoglobuliny - Fc fragmenty MeSH
• inkretiny MeSH
• léky s prodlouženým účinkem MeSH
• receptor pro glukagonu podobný peptid 1 MeSH
• rekombinantní fúzní proteiny MeSH