Examinando por Autor "Dyal, Leanne"
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- PublicaciónAcceso abiertoAssociation of handgrip strength to cardiovascular mortality in pre-diabetic and diabetic patients : A subanalysis of the ORIGIN trial(2014-06-15) Lopez-Jaramillo, Patricio; Cohen, Daniel Dylan; Gómez Arbeláez, Diego; Bosch, Jackie; Dyal, Leanne; Yusuf, Salim; Gerstein, Hertzel C.; The ORIGIN Trial Investigators
- PublicaciónAcceso abiertoDulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial(ELSEVIER, 2019-07-13) Gerstein, Hertzel C.; Colhoun, Helen M.; Dagenais, Gilles R.; Diaz, Rafael; Lakshmanan, Mark; Pais, Prem; Probstfield, Jeffrey; Riesmeyer, Jeffrey S.; Riddle, Matthew C.; Rydén, Lars; Xavier, Denis; Messan Atisso, Charles; Dyal, Leanne; Hall, Stephanie; Rao-Melacini, Purnima; Wong, Gloria; Avezum, Alvaro; Basile, Jan; Chung, Namsik; Conget, Ignacio; Cushman, William C.; Franek, Edward; Hancu, Nicolae; Hanefeld, Markolf; Holt, Shaun; Jansky, Petr; Keltai, Matyas Matyas; Lanas, Fernando; Leiter, Lawrence A.; Lopez-Jaramillo, Patricio; Cardona-Munoz, Ernesto German; Pirags, Valdis; Pogosova, Nana; Raubenheimer, Peter J.; Shaw, Jonathan E.; Sheu, Wayne H-H.; Temelkova-Kurktschiev, Theodora; The REWIND Investigators; EverestBackground 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.
- PublicaciónAcceso abiertoDulaglutide and renal outcomes in type 2 diabetes. An exploratory analysis of the REWIND randomised, placebo-controlled trial(The Lancet, 2019-07-13) Gerstein, Hertzel C.; Colhoun, Helen M.; Dagenais, Gilles R.; Diaz, Rafael; Lakshmanan, Mark; Pais, Prem; Probstfield, Jeffrey; Riesmeyer, Jeffrey S.; Riddle, Matthew C.; Rydén, Lars; Xavier, Denis; Messan Atisso, Charles; Dyal, Leanne; Hall, Stephanie; Rao-Melacini, Purnima; Wong, Gloria; Avezum, Alvaro; Basile, Jan; Chung, Namsik; Conget, Ignacio; Cushman, William C.; Franek, Edward; Hancu, Nicolae; Hanefeld, Markolf; Holt, Shaun; Jansky, Petr; Keltai, Matyas; Lanas, Fernando; Leiter, Lawrence A.; Lopez-Jaramillo, Patricio; Cardona-Munoz, Ernesto German; Pirags, Valdis; Pogosova, Nana; Raubenheimer, Peter J.; Shaw, Jonathan E.; Sheu, Wayne H-H.; Temelkova-Kurktschiev, Theodora; The REWIND Investigators; EverestBackground: 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.
- PublicaciónAcceso abiertoRivaroxaban Plus Aspirin in Obese and Overweight Patients With Vascular Disease in the COMPASS Trial(JACC Journals, 2021-02-05) Guzik, Tomasz J.; Ramasundarahettige, Chinthanie; Pogosova, Nana; Lopez-Jaramillo, Patricio; Dyal, Leanne; Berkowitz, Scott D.; Muehlhofer, Eva; Bhatt, Deepak L.; Fox, Keith A.; Yusuf, Salim; Eikelboom, John W.; MasiraBackground Direct oral anticoagulants are administered in fixed doses irrespective of body weight, but guidelines recommend against their use in patients with extremes of body weight. Objectives This study determined the effects of dual-pathway inhibition antithrombotic regimen (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/day) compared with aspirin Halone across a range of patient body mass indexes (BMIs) and body weights. Methods This was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial, which included patients with chronic coronary artery disease or peripheral artery disease. Efficacy and safety outcomes were studied in relation to BMI: (normal 18.5 ≤BMI <25 kg/m2, overweight 25 ≤BMI <30 kg/m2, obese ≥30 kg/m2) and body weight (≤70 kg, 70 < weight ≤90 kg, and >90 kg; as well as ≤120 kg vs. >120 kg). Results Among 27,395 randomized patients, 6,459 (24%) had normal BMI, 12,047 (44%) were overweight, and 8,701 (32%) were obese. The combination of rivaroxaban and aspirin compared with aspirin produced a consistent reduction in the primary outcome of cardiovascular death, stroke, or myocardial infarction, irrespective of BMI or body weight. For 18.5 ≤BMI <25 kg/m2: 3.5% vs. 5.0%; hazard ratio (HR): 0.73 (95% credible interval [CrI]: 0.58 to 0.90); 25 ≤ BMI <30 kg/m2: 4.3% vs. 5.1%; HR: 0.80 (95% CrI: 0.66 to 0.96); BMI ≥30 kg/m2: 4.2% vs. 6.1%; HR: 0.71 (95% CrI: 0.57 to 0.86). For body weight ≤70 kg: 4.1% vs. 5.3%; HR: 0.75 (95% CrI: 0.62 to 0.91); 70 < weight ≤90 kg: 4.1% vs. 5.3%; HR: 0.76 (95% CrI: 0.65 to 0.89); >90 kg: 4.2% vs. 5.7%; HR: 0.74 (95% CrI: 0.61 to 0.90). Effects on bleeding, mortality, and net clinical benefit were consistent irrespective of BMI or bodyweight. Conclusions The effects of dual-pathway antithrombotic therapy are consistent irrespective of BMI or body weight, suggesting no need for dose adjustments in the ranges of weights and BMI of patients enrolled in the COMPASS trial. Further studies need to address this problem in relation to greater extremes of body weight. (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease [COMPASS]; NCT01776424)
- PublicaciónAcceso abiertoSimilar cardiovascular outcomes in patients with diabetes and established or high risk for coronary vascular disease treated with dulaglutide with and without baseline metformin(European Society of Cardiology, 2021-07-07) Ferrannini, Giulia; Gerstein, Hertzel; Colhoun, Helen Martina; Dagenais, Gilles R.; Diaz, Rafael; Dyal, Leanne; Lakshmanan, Mark; Mellbin, Linda; Probstfield, Jeffrey; Riddle, Matthew Casey; Shaw, Jonathan Edward; Avezum, Alvaro; Basile, Jan Neil; Cushman, William C.; Jansky, Petr; Keltai, Mátyás; Lanas, Fernando; Leiter, Lawrence Alan; Lopez-Jaramillo, Patricio; Pais, Prem; Pīrāgs, Valdis; Pogosova, Nana; Raubenheimer, Peter Johann; Huey-Herng Sheu, Wayne; Rydén, Lars; MasiraObjective 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.
- PublicaciónAcceso abiertoThe effect of dulaglutide on stroke(Elsevier, 2020-02-02) Gerstein, Hertzel C.; Hart, Robert; Colhoun, Helen M.; Diaz, Rafael; Lakshmanan, Mark; Botros, Fady T.; Probstfield, Jeffrey; Riddle, Matthew C.; Rydén, Lars; Messan Atisso, Charles; Dyal, Leanne; Hall, Stephanie; Avezum, Alvaro; Basile, Jan; Conget, Ignacio; Cushman, William C.; Hancu, Nicolae; Hanefeld, Markolf; Jansky, Petr; Keltai, Matyas; Lanas, Fernando; Leiter, Lawrence A.; Lopez-Jaramillo, Patricio; Cardona Muñoz, Ernesto Germán; Pogosova, Nana; Raubenheimer, Peter J.; Shaw, Jonathan E.; Sheu, Wayne H-H.; Temelkova-Kurktschiev, Theodora; EverestBackground 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.
- PublicaciónAcceso abiertoTotal cardiovascular or fatal events in people with type 2 diabetes and cardiovascular risk factors treated with dulaglutide in the REWIND trail(Cardiovascular Diabetology, 2020-11-01) Dagenais, Gilles R.; Rydén, Lars; Leiter, Lawrence A.; Lakshmanan, Mark; Dyal, Leanne; Probstfield, Jeffrey L.; Atisso, Charles Messan; Shaw, Jonathan E.; Conget, Ignacio; Cushman, William C.; Lopez-Jaramillo, Patricio; Lanas, Fernando; Cordona Munoz, Ernesto German; Pirags, Valdis; Pogosova, Nana; Basile, Jan; Sheu, Wayne H. H.; Temelkova-Kurktschiev, Theodora; Raubenheimer, Peter J.; Keltai, Matyas; Hall, Stephanie; Pais, Prem; Colhoun, Helen M.; Riddle, Matthew C.; Gerstein, Hertzel C.; EverestBackground The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants Methods We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models. Results Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82–0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80–0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87–0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82–0.99) p = 0.028]. Conclusions These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk.