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
- 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
- receptor pro glukagonu podobný peptid 1 agonisté 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
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
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
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.
- 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 agonisté 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
V posledních letech nabývá na intenzitě diskuse, která se týká způsobu léčby a terapeutických cílů u diabetu 2. typu. Poprvé od ukončení studie UKPDS (United Kingdom Prospective Diabetes Study) a studie DIS (Diabetes Interventions Study) se uskutečnilo hned několik velkých klinických studií, které mají odpovědět na otázku, zda a do jaké míry může úprava zvýšených hodnot glykémie snížit kardiovaskulární riziko. Jde o vysoce aktuální a závažnou otázku, vzhledem k alarmujícím počtům úmrtí z kardiovaskulárních příčin, k nimž dochází u pacientů s diabetem 2. typu. Není sporu, že u těchto pacientů s vysokým rizikem musí být léčba zaměřena jak na metabolické, tak na kardiovaskulární faktory.
Die Diskussion um Therapie und Therapieziele beim Typ-2-Diabetes ist in der jüngsten Vergangenheit neu entbrannt: erstmals seit UKPDS (United Kingdom Prospective Diabetes Study) und der Diabetesinterventionsstudie (DIS) haben gleich mehrere große Untersuchungen Stellung zur umstrittenen Frage genommen, ob und in welchem Ausmaß die Absenkung erhöhter Blutzuckerwerte das Risiko für Herz-Kreislauf-Ereignisse reduziert. Eine hochaktuelle und zentrale Frage, wenn man an die alarmierenden Zahlen kardiovaskulärer Todesfälle unter Typ-2-Diabetikern denkt. Die Notwendigkeit einer doppelten Fokussierung auf metabolische und kardiovaskuläre Komponenten in dieser Hochrisikogruppe ist unstrittig.
- MeSH
- analýza přežití MeSH
- cévní endotel účinky léků MeSH
- diabetes mellitus 2. typu farmakoterapie krev mortalita MeSH
- diabetické angiopatie krev mortalita prevence a kontrola MeSH
- glykovaný hemoglobin metabolismus MeSH
- hypoglykemika terapeutické užití MeSH
- inzulinová rezistence MeSH
- kardiovaskulární nemoci krev mortalita prevence a kontrola MeSH
- krevní glukóza metabolismus MeSH
- krevní tlak účinky léků MeSH
- lidé MeSH
- lipoproteiny krev MeSH
- mediátory zánětu krev MeSH
- PPAR gama agonisté MeSH
- randomizované kontrolované studie jako téma MeSH
- thiazolidindiony terapeutické užití MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR)=1.11 (95% confidence interval (CI), 1.02-1.20), P=0.01). Two haplotype combinations were associated with increased risk of T2D (1-2-1/1-2-1, OR=1.20 (1.03-1.41), P=0.02; and 1-1-2/1-2-1, OR=1.26 (1.01-1.59), P=0.04) and one with decreased risk (1-1-1/2-2-1, OR=0.86 (0.75-0.99), P=0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR=1.25 (1.05-1.50), P=0.01). However, there was evidence for heterogeneity with respect to this effect (P=0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P=0.89) and strengthened the evidence for association with T2D in both the pooled (SNP-43*G, OR=1.19 (1.07-1.32), P=0.001; 1-2-1/1-2-1 haplogenotype, OR=1.46 (1.19-1.78), P=0.0003; 1-1-2/1-2-1 haplogenotype, OR=1.52 (1.12-2.06), P=0.007; and 1-1-1/2-2-1 haplogenotype, OR=0.83 (0.70-0.99), P=0.03) and the meta-analysis (SNP-43*G, OR=1.18 (1.05-1.32), P=0.005; 1-2-1/1-2-1 haplogenotype, OR=1.68 (1.33-2.11), P=0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans.
- MeSH
- běloši * genetika MeSH
- diabetes mellitus 2. typu * genetika MeSH
- haplotypy genetika MeSH
- jednonukleotidový polymorfismus * MeSH
- kalpain * genetika MeSH
- lidé MeSH
- vazebná nerovnováha * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- metaanalýza MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Atherosclerosis supplements, ISSN 1567-5688 vol. 6, issue 3, September 2005
27 s. : il. ; 28 cm
- MeSH
- hyperlipidemie terapie MeSH
- komplikace diabetu terapie MeSH
- Publikační typ
- kongresy MeSH
- sborníky MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- vnitřní lékařství
- diabetologie
European journal of clinical investigation, ISSN 0960-135X vol. 30, suppl. 2, August 2000
24 s. : il., tab. ; 30 cm
120 s. : il.
- Konspekt
- Lékařské vědy. Lékařství
- NLK Obory
- gastroenterologie
- vnitřní lékařství