Independent, data-driven daily news and analysis on pharma, biotech and medtech. 11 Similar results have been noted with other GLP-1 agents as well. Listing a study does not mean it … The heterogeneity of patient characteristics and reported renal outcomes, which hinders comparisons between trials and drug classes, is highlighted. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. We did exploratory analyses of the prospectively defined renal effects of dulaglutide and their relation to glucose and blood pressure lowering within the REWIND trial. Also at ADA, Lilly presented results from an exploratory analysis of Rewind showing that Trulicity reduced renal events by 15% versus placebo. Study design and participants REWIND was a multicentre, randomised, double­blind, And the MACE benefit was driven by a non-fatal stroke; there was no significant reduction in non-fatal heart attack or cardiovascular death with Trulicity. Patients were randomized in a 1:1 fashion to either dulaglutide 1.5 mg once weekly (n = 4,949) or matching placebo (n = 4,952). Dulaglutide is a novel drug for the treatment of type 2 diabetes and functions as a GLP-1 agonist. But Lilly could have done with a stronger result in Rewind to stay ahead of the competition. 49,51 But, in the end, data from the Rewind cardiovascular outcomes study of Lilly’s type 2 diabetes drug Trulicity disappointed. Novo has said it is planning a much bigger CV outcomes study of oral sema, but this would take several years to complete. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. 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 … Semaglutide, a GLP-1 analogue with an extended half-life of approximately 1 week (which permits once-weekly subcutaneous administration),4 is currently in development but not yet approved for the treatment of type 2 diabetes. Lancet 2019;394:121-30. The primary composite outcome was a composite of non-fatal MI, non-fatal stroke, and death from CV- or unknown causes. The size of the study is robust with a recruitment of 9,901 participants (mean age 66) occurred in 370 sites located in 24 countries. Regulatory guidance specifies the need to establish the cardiovascular safety of new therapies for type 2 diabetes in order to rule out excess cardiovascular risk.5 The preapproval Trial to Evaluate Cardiovascular and … The full data were presented yesterday at the ADA meeting in San Francisco and published simultaneously in The Lancet. The primary composite outcome (first occurrence of vascular death, non-fatal myocardial infarction or non-fatal stroke) occurred at statistically lower rates in the dulaglutide treatment group compared to placebo. Hertzel C Gerstein. "The REWIND trial was an ambitious study that conclusively assessed the effects of dulaglutide on people with type 2 diabetes both with and without prior cardiovascular disease (CVD)," said Gerstein. There was also a significant reduction in nonfatal strokes. REWIND is the longest cardiovascular outcome trial in the GLP-1 receptor agonist class (median 5.4 years) and consisted primarily of people without established CV disease. Additionally, they highlighted the fact that participants in the REWIND trial were at lower risk of CV events than participants in the previous studies. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Editorial Comment: Verma S, Mazer CD, Perkovic V. Is it time to REWIND the cardiorenal clock in diabetes? In addition, the drug had a moderate effect on the composite renal outcome, and reduced new macroalbuminuria in this patient population. The renal benefits noted in this trial are similar to those noted with SGLT-2 inhibitors, and may be due to a combination of better glycemic and blood pressure control, although other undefined mechanisms are also likely to be responsible. All rights reserved. This study is registered with ClinicalTrials.gov, number NCT01394952. The prespecified primary microvascular outcome in our trial was a composite of nephropathy and retinopathy outcomes. However, Bernstein analysts do not see this as a given. The FREEDOM-CVO and REWIND trials included injection-free GLP-1 RA with osmotic mini-pump and patients without established cardiovascular background respectively, whereas the PIONEER 6 study investigated oral semaglutide. Against these competitors, Trulicity comes off worse on cardiovascular outcomes. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Lancet. ACROSS T2D is the global Academy for Cardiovascular Risks, Outcomes and Safety Studies in Type 2 Diabetes (T2D) The Sustain 6 trial of the former did not include a prespecified superiority analysis, while the Pioneer 6 study of the latter did not meet superiority, although it was a small trial and Novo had long played down expectations (Novo’s next big diabetes bet heads to regulators, 26 November 2018). In fact, the risk reduction was the same for both the primary and secondary prevention cohorts, a slightly puzzling finding. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. But on cardiovascular outcomes Trulicity, which is given via a once-weekly subcutaneous injection, appears similar to Novo Nordisk’s once-daily injectable, Victoza. 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. Download PDF. The primary composite outcome (MACE-3) occurred in 594 (12.0%) participants assigned to Trulicity + standard of care and 663 (13.4%) participants assigned to placebo + standard of care (hazard ratio [HR] 0.88, ... (REWIND) trial on the cardiovascular effects of dulaglutide. 4 years. However, in contrast to the other CV outcomes trials of GLP-1 receptor agonists, the REWIND trial included a substantial proportion of patients without established CV disease (68.5%), which provided more information as to whether GLP-1 receptor agonists may be beneficial in a primary prevention setting. These are really important findings and suggest that dulaglutide may need to be considered for the management of type 2 diabetes in similar high-risk patients going forward. But, numerically speaking, the results made Trulicity look normal against its GLP1 agonist peers. Trulicity has so far been holding firm against Ozempic, helped by formulary coverage and price. However, the cardiovascular outcomes data were the main event, and Lilly’s stock opened down 2% this morning. This was not because Rewind was a failure – as previously reported, the trial found a significant reduction in cardiovascular adverse events in patients receiving the drug versus those on placebo. In addition, several secondary outcomes were analysed, comprising a composite clinical microvascular outcome which included diabetic retinopathy or renal disease. November 5, 2018. These events were seen in 12% of patients in the Trulicity cohort and 13.4% in the placebo group; although Trulicity was deemed superior, Bernstein described the p value of 0.026 as “not overly compelling” and the overall … The REWIND trial showed that dulaglutide is superior to placebo in improving glycemic control and reducing CV events in patients with type 2 diabetes and higher CV risk. But the picture is complicated further, as neither Ozempic nor oral sema can be considered superior to placebo here. We use cookies on this website. Lancet 2019;394:95-7. Epub 2019 Jun 9. 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. The primary outcome, CV death, MI, or stroke for dulaglutide vs. placebo, was 12.0% vs. 13.4% (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.79-0.99; p = 0.026 for superiority) CV death for dulaglutide vs. placebo: 6.4% vs. 7.0% (p = 0.21) Nonfatal MI for dulaglutide vs. placebo: 4.1% vs. 4.3% (p = 0.65) The primary endpoint of Rewind was the first occurrence of a major cardiovascular outcome, defined as cardiovascular death, non-fatal heart attack, or non-fatal stroke. Methods Study design and participants REWIND was a multicentre, randomised, double-blind, Congenital Heart Disease and Pediatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Pulmonary Hypertension and Venous Thromboembolism, CardioSource Plus for Institutions and Practices, Nuclear Cardiology and Cardiac CT Meeting on Demand, Annual Scientific Session and Related Events, ACC Quality Improvement for Institutions Program, National Cardiovascular Data Registry (NCDR), Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes, Evaluation of Lixisenatide in Acute Coronary Syndrome, Exenatide Study of Cardiovascular Event Lowering, Congenital Heart Disease and     Pediatric Cardiology, Invasive Cardiovascular Angiography    and Intervention, Pulmonary Hypertension and Venous     Thromboembolism, Stable doses of two oral glucose-lowering drugs, If age ≥50 years, then had to have concomitant vascular disease (a previous myocardial infarction [MI], ischemic stroke, revascularization, hospital admission for unstable angina, or imaging evidence of myocardial ischemia), If age ≥55 years, then had to have concomitant myocardial ischemia; coronary, carotid, or lower extremity artery stenosis exceeding 50%; left ventricular hypertrophy; estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m, If age ≥60 years, then had to have ≥2 of the following: tobacco use, dyslipidemia, hypertension, or abdominal obesity, Coronary or cerebrovascular event within the previous 2 months, CV death for dulaglutide vs. placebo: 6.4% vs. 7.0% (p = 0.21), Nonfatal MI for dulaglutide vs. placebo: 4.1% vs. 4.3% (p = 0.65), Nonfatal stroke for dulaglutide vs. placebo: 2.7% vs. 3.5% (p = 0.017), All-cause mortality: 10.8% vs. 12.0% (p = 0.067), Chronic heart failure hospitalization/urgent visit: 4.3% vs. 4.6% (p = 0.46), Composite microvascular outcome (eye or kidney): 18.4% vs. 20.6% (p = 0.002), Severe hypoglycemic event: 1.3% vs. 1.5% (p = 0.38), Acute pancreatitis: 0.5% vs. 0.3% (p = 0.11); pancreatic cancer: 0.4% vs. 0.2% (p = 0.22), Median reduction in hemoglobin A1c: 0.61%, Composite renal outcome (new macroalbuminuria, sustained decline in eGFR ≥30% chronic renal replacement therapy): 17.1% vs. 19.6% (HR 0.85, 95% CI 0.77-0.93; p = 0.0004), New macroalbuminuria: 8.9% vs. 11.3% (p < 0.0001), Sustained decline in eGFR ≥50%: 1.2% vs. 2.2% (p = 0.0002). Methods: 40 participants will be randomised to receive either the Rewind Technique immediately, or after an 8 week wait. Less than emphatic cardiovascular outcomes data leave Lilly looking vulnerable to Novo Nordisk’s competing drugs. Gerstein HC, Colhoun HM, Dagenais GR, et al. The sample size in REWIND is the largest second only to the recently published EXSCEL trial among studies that evaluated antidiabetic medication in CVD outcome. © 2021 American College of Cardiology Foundation. In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. Both medications were administered as a subcutaneous injection. It was billed as one of the big events of this year’s American Diabetes Association meeting. Oncology decisions ahead for the FDA, Novo’s next big diabetes bet heads to regulators, presented results from an exploratory analysis, p<0.001 for noninferiority, testing for superiority vs placebo not prespecified, p<0.001 for noninferiority, did not meet superiority vs placebo. These drugs reduce hyperglycemia in patients with type 2 diabetes and are also known to cause slight reductions in weight and blood pressure. 49–51 Mortality outcomes in some of these trials are encouraging, yet the results are inconsistent. Ozempic’s label does not currently include a cardiovascular benefit claim, and oral sema looks unlikely to get one unless Novo can convince the FDA to accept pooled data from Sustain 6 and Pioneer 6. REWIND’s primary CV outcome was the first occurrence of MACE, the composite of CV death or non-fatal myocardial infarction or non-fatal stroke. A plus for Lilly was that Rewind showed a benefit in patients both with and without existing cardiovascular disease; 69% of trial subjects had cardiovascular risk factors but no underlying disease. Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Hypertension, Keywords: Albuminuria, Angina, Unstable, Brain Ischemia, Constriction, Pathologic, Diabetes Mellitus, Type 2, Dyslipidemias, Glomerular Filtration Rate, Glucagon-Like Peptide 1, Hemoglobin A, Glycosylated, Heart Failure, Hyperglycemia, Hypertension, Hypertrophy, Left Ventricular, Hypoglycemic Agents, Myocardial Infarction, Myocardial Ischemia, Metabolic Syndrome X, Obesity, Pancreatic Neoplasms, Pancreatitis, Primary Prevention, Renal Insufficiency, Stroke, Tobacco Use. Incretin in Diabetes (REWIND) trial was designed to assess whether the addition of dulaglutide to the diabetes medication regimen of middle­aged and older people with type 2 diabetes safely reduces the incidence of cardiovascular outcomes compared with placebo. ADA 2019 – Rewind makes Lilly’s Trulicity look average, AHA 2020 – sotagliflozin wins come too late for Lexicon, AHA 2018 – Astrazeneca takes heart from partial Farxiga victory, Heart benefit now a baseline for Invokana and all diabetes drugs, ADA – Canvas paints a mixed picture for J&J’s Invokana, 2020 wins top of the froths for biotech stocks, Go or no go? The primary outcome, CV death, MI, or stroke for dulaglutide vs. placebo, was 12.0% vs. 13.4% (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.79-0.99; p = 0.026 for superiority). The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction (MI), non-fatal stroke, or death from CV causes (including unknown causes). INDIANAPOLIS, Nov. 5, 2018 /PRNewswire/ -- Trulicity ® (dulaglutide) significantly reduced major adverse cardiovascular events (MACE), a composite endpoint of cardiovascular (CV) death, non-fatal myocardial infarction (heart attack) or non-fatal stroke, meeting the primary efficacy objective in … However, the outcome was consistent with the overall effect size from a meta-analysis of all previous GLP-1 receptor agonist trials. The primary outcome will be PTSD symptom severity as measured by the Clinician-Administered PTSD Scale for DSM5 (CAPS-5) at 8 and 16 weeks post-randomisation. 2019 Jul 13;394(10193):121-130. doi: 10.1016/S0140-6736(19)31149-3. True, cross-trial comparisons should always be treated with caution. While all participants had CV risk factors, only 31 percent of study participants had established CV disease. Secondary outcomes, for dulaglutide vs. placebo: Renal outcomes, for dulaglutide vs. placebo: The results of this trial indicate that once-weekly dulaglutide administered via subcutaneous injection is superior to placebo in improving glycemic control and reducing CV events in patients with type 2 diabetes and higher CV risk. Although it also raises the possibility of some geographical variation of effect, this variation loses statistical significance after accounting for the seven subgroups that were assessed … Prof Hertzel C Gerstein, MD . Correspondence. Lancet 2019;394:131-8. However, pulse can increase with the use of these agents, but in this trial, suggests no adverse CV consequences. And Victoza is no longer Trulicity’s most relevant rival – Lilly’s drug is now squaring up against Novo’s newer once-weekly injectable semaglutide, branded Ozempic, and could soon be competing with the Danish group’s even more convenient oral semaglutide, which is set for a US approval decision by September. The company probably did not help itself by setting expectations high, describing Rewind’s results as “compelling” when it toplined the data in November. The goal of the trial was to assess the cardiovascular (CV) safety of dulaglutide, a glucagon-like peptide-1 (GLP-1) agonist, in patients with type 2 diabetes mellitus at higher risk for CV events. These events were seen in 12% of patients in the Trulicity cohort and 13.4% in the placebo group; although Trulicity was deemed superior, Bernstein described the p value of 0.026 as “not overly compelling” and the overall data as underwhelming. This was driven primarily by a reduction in the individual component of non-fatal stroke. Ongoing cardiovascular and renal outcome studies such as Dapa-CKD, EMPA-KIDNEY, EMPEROR-Preserved and EMPEROR-Reduced are also discussed. separate analyses of the components of this outcome. Only 31 percent of REWIND trial participants had established CV disease. The primary endpoint of Rewind was the first occurrence of a major cardiovascular outcome, defined as cardiovascular death, non-fatal heart attack, or non-fatal stroke. The REWIND trial aimed to assess whether dulaglutide could reduce major cardiovascular events (MACE) and other serious outcomes in people with T2D, when added to their anti-hyperglycemic regimen. By using this site, you agree that we may store and access cookies on your device. If Lilly can get a cardiovascular claim added to Trulicity’s label on the back of Rewind, which could happen in the first half of next year, the company's chances of fending off Novo will get a boost. Correspondence to: Prof Hertzel C Gerstein, Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, L8S 4K1, Canada. Consistent with the findings from three cardiovascular outcomes trials of other GLP-1 receptor agonists,5, 6, 27, 30 the REWIND trial raises the possibility of a greater effect on stroke than on myocardial infarction. Dulaglutide reduced the prespecified composite renal outcome of new-onset macroalbuminuria, eGFR decline of 30% or more, or chronic renal replacement therapy, … Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
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