The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial

Gerstein, Hertzel C.; Hart, Robert G.; Colhoun, Helen M.; Dı́az, Rafael; Lakshmanan, Mark; Botros, Fady T.; Probstfield, Jeffrey L.; Riddle, Matthew C.; Rydén, Lars; Atisso, Charles; Dyal, Leanne; Hall, Stephanie; Avezum, Álvaro; Basile, Jan; Conget, Ignacio; Cushman, William C.; Hâncu, Nicolae; Hanefeld, Markolf; Jánský, Petr; Keltai, Mátyás; Lanas, Fernando; Leiter, Lawrence A.; López‐Jaramillo, Patricio; Muñoz, Ernesto; Pogosova, Nana; Raubenheimer, Peter; Shaw, Jonathan E.; Sheu, Wayne H‐H; Temelkova‐Kurktschiev, Theodora

doi:10.1016/s2213-8587(19)30423-1

Cited by 97 publications

(83 citation statements)

References 23 publications

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“…Whilst dulaglutide reduced the incidence of ischaemic stroke, it did not affect stroke severity. 60 Post-hoc analysis of CVOT trial data has identified sub-groups which may potentially derive greater…”

Section: Stroke Risk In Cardiovascular Outcome (Safety) Trialsmentioning

confidence: 99%

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Maskery

Hölscher

Jones

et al. 2020

J Cereb Blood Flow Metab

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Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.

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Section: Stroke Risk In Cardiovascular Outcome (Safety) Trialsmentioning

confidence: 99%

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Maskery

Hölscher

Jones

et al. 2020

J Cereb Blood Flow Metab

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“…4 5 13 14 In the same period GLP-1a, first approved in 2005, proved to be CV safe, reduced CV events and showed potential renal benefits. [15][16][17][18][19][20][21][22] Gliptins already showed CV safety in 2013, and the evidence was strengthened from 2015 to 2019, and showed renal safety. [23][24][25][26] This new evidence led to significant changes in the guidelines.…”

mentioning

confidence: 99%

Long-term trends in the prescription of antidiabetic drugs: real-world evidence from the Diabetes Registry Tyrol 2012–2018

Engler

Leo

Pfeifer

et al. 2020

BMJ Open Diab Res Care

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IntroductionPrescription patterns of antidiabetic drugs in the period from 2012 to 2018 were investigated based on the Diabetes Registry Tyrol. To validate the findings, we compared the numbers with trends of different national registries conducted in a comparable period of time.Research design and methodsMedication data, prescription patterns, age groups, antidiabetic therapies and quality parameters (hemoglobin A1c, body mass index, complications) of 10 875 patients with type 2 diabetes from 2012 to 2018 were retrospectively assessed and descriptively analyzed. The changes were assessed using a time series analysis with linear regression and prescription trends were plotted over time.ResultsSodium/glucose cotransporter 2 inhibitors (SGLT-2i) showed a significant increase in prescription from 2012 to 2018 (p<0.001), as well as metformin (p=0.002), gliptins (p=0.013) and glucagon-like peptide-1 agonists (GLP-1a) (p=0.017). Significant reduction in sulfonylurea prescriptions (p<0.001) was observed. Metformin was the most frequently prescribed antidiabetic drug (51.3%), followed by insulin/analogs (34.6%), gliptins (28.2%), SGLT-2i (11.7%), sulfonylurea (9.1%), glitazones (3.7%), GLP-1a (2.8%) and glucosidase inhibitors (0.4%).ConclusionsIn this long-term, real-world study on prescription changes in the Diabetes Registry Tyrol, we observed significant increase in SGLT-2i, metformin, gliptins and GLP-1a prescriptions. In contrast prescriptions for sulfonylureas declined significantly. Changes were consistent over the years 2012–2018. Changes in prescription patterns occurred even before the publication of international and national guidelines. Thus, physicians change their prescription practice not only based on published guidelines, but even earlier on publication of cardiovascular outcome trials.

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“…REWIND investigated the effect of dulaglutide in a population in which 68.5% (6793 patients) had not established CVD [19], and reported a 13% risk reduction of 3P-MACE (non-significant) in the multiple risk factors population [11,19]. A recent exploratory analysis [42] of REWIND reported a significantly reduced risk of non-fatal stroke (HR 0.76 [95% CI 0.61-0.95]; p = 0.017) and ischaemic stroke (HR 0.75 [95% CI 0.59-0.94); p = 0.0115), and no significant effects on fatal stroke, haemorrhagic stroke, or stroke of unknown type when comparing dulaglutide to placebo [42]. When analysing this in context of primary prevention, a significant effect was only observed for participants with previous CVD, however, a non-significant risk reduction of 20% (HR 0.80 [95% CI 0.61-1.06]) was observed in primary prevention [42].…”

Section: Primary Care In Diabetes Managementmentioning

confidence: 99%

“…A recent exploratory analysis [42] of REWIND reported a significantly reduced risk of non-fatal stroke (HR 0.76 [95% CI 0.61-0.95]; p = 0.017) and ischaemic stroke (HR 0.75 [95% CI 0.59-0.94); p = 0.0115), and no significant effects on fatal stroke, haemorrhagic stroke, or stroke of unknown type when comparing dulaglutide to placebo [42]. When analysing this in context of primary prevention, a significant effect was only observed for participants with previous CVD, however, a non-significant risk reduction of 20% (HR 0.80 [95% CI 0.61-1.06]) was observed in primary prevention [42]. Even though more studies are needed on the potential benefits of GLP-1 RAs and SGLT-2is in a primary prevention population [43,44], this is a first step towards making CVOTs, their outcomes and medications tested relevant for both broad primary and secondary prevention populations, and thus both, specialist and primary care physicians.…”

Section: Primary Care In Diabetes Managementmentioning

confidence: 99%

Report from the 5th cardiovascular outcome trial (CVOT) summit

Schnell¹,

Standl²,

Cos³

et al. 2020

Cardiovasc Diabetol

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The 5th Cardiovascular Outcome Trial (CVOT) Summit was held in Munich on October 24th-25th, 2019. As in previous years, this summit served as a reference meeting for in-depth discussions on the topic of recently completed and presented CVOTs. This year, focus was placed on the CVOTs CAROLINA, CREDENCE, DAPA-HF, REWIND, and PIONEER-6. Trial implications for diabetes management and the impact on new treatment algorithms were highlighted for diabetologists, cardiologists, endocrinologists, nephrologists, and general practitioners. Discussions evolved from CVOTs to additional therapy options for heart failure (ARNI), knowledge gained for the treatment and prevention of heart failure and diabetic kidney disease in populations with and without diabetes, particularly using SGLT-2 inhibitors and GLP-1 receptor agonists. Furthermore, the ever increasing impact of CVOTs and substances tested for primary prevention and primary care was discussed. The 6th Cardiovascular Outcome Trial Summit will be held in Munich on October 29th-30th, 2020 (https ://www.cvot.org).

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The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial

Cited by 97 publications

References 23 publications

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Long-term trends in the prescription of antidiabetic drugs: real-world evidence from the Diabetes Registry Tyrol 2012–2018

Report from the 5th cardiovascular outcome trial (CVOT) summit

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