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Cited by 82Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsAcute Ischemic Stroke Management

Benefits of GLP-1 (Glucagon-Like Peptide 1) Receptor Agonists for Stroke Reduction in Type 2 Diabetes: A Call to Action for Neurologists

Goldenberg, Ronald M., Cheng, Alice Y.Y., Fitzpatrick, Tess, Gilbert, Jeremy D., Verma, Subodh, Hopyan, Julia J.·2022·Stroke
DOI 10.1161/strokeaha.121.038151
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Abstract

People living with diabetes are at higher risk for stroke and have a poorer prognosis following a stroke event than those without diabetes. Data from cardiovascular outcome trials and meta-analyses indicate that GLP-1RAs (glucagon-like peptide 1 receptor agonists) reduce the risk of stroke in individuals with type 2 diabetes. Accordingly, many guidelines now recommend the addition of GLP-1RAs to ongoing antihyperglycemic regimens to lower the risk of stroke in type 2 diabetes. The current work summarizes evidence supporting the use of GLP-1RAs for stroke reduction in people with type 2 diabetes and offers 2 new resources for neurologists who are considering GLP-1RAs for their patients—a list of frequently asked questions with evidence-based answers on safely initiating and managing GLP-1RAs, and a practical decision-making algorithm to assist in using GLP-1RAs as part of a stroke reduction strategy.

Integrity signals

Registry

Crossref · 10.1161/strokeaha.121.038151

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 69 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    GLP-1 receptor agonists reduce the risk of stroke in people with type 2 diabetes.

    “Data from cardiovascular outcome trials and meta-analyses indicate that GLP-1RAs (glucagon-like peptide 1 receptor agonists) reduce the risk of stroke in individuals with type 2 diabetes.”
    • Also stated in: § Nonstandard Abbreviations and Acronyms · hedged
      “Emerging evidence has suggested that GLP-1RAs reduce the incidence of stroke in people with T2DM.”
    • Also stated in: § Meta-Analyses of GLP-1 Receptor Agonists and Stroke · plain
      “We performed a meta-analysis that included all 8 CVOTs using the Cochrane Collaboration's Review Manager Software Package (RevMan 5.3) and found significant decreases versus placebo in fatal/nonfatal stroke (HR, 0.83 [95% CI, 0.76-0.92]),nonfatal stroke (HR, 0.84 [95% CI, 0.76-0.93]),but no reduction in fatal stroke (HR, 0.80 [95% CI, 0.63-1.03]; Figure 2).”
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  • Premisecitation

    In SGLT2i CVOTs, people with T2DM and stroke experienced similar cardiorenal benefits as the rest of the populations.

    “Notably, although the SGLT2is do not appear to reduce stroke, people with T2DM and stroke were included in the SGLT2i CV outcome trials (CVOTs) and that subgroup experienced similar cardiorenal benefits as the rest of the populations.25,26”
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  • Premisecitation

    In REWIND, the impact of dulaglutide on stroke did not differ according to sex, age, history of CVD, HbA1c, systolic blood pressure, or use of statins or renin-angiotensin-aldosterone system inhibitors.

    “The impact of dulaglutide on stroke not differ according to sex, age, history of CVD, HbA1c, systolic blood pressure, or use of statins or renin-angiotensinaldosterone system inhibitors.”
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  • Premisecitation

    Independent of other factors, the risk of ischemic stroke is approximately twice as high in people with diabetes as in those without.

    “Independent of other factors, the risk of ischemic stroke is approximately twice that in people with diabetes compared with those without.3”
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  • Premisecitation

    In the nonacute setting, intensive glycemic control with mainly non-GLP-1RA antihyperglycemic agents in T2DM can lower the risk of microvascular and certain macrovascular complications.

    “In the nonacute setting, meta-analyses indicate that intensive glycemic control with mainly non-GLP-1RA antihyperglycemic agents in T2DM can lower the risk of microvascular and certain macrovascular complications.21”
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    Findingown data

    The authors' meta-analysis including all 8 CVOTs found significant decreases versus placebo in fatal/nonfatal stroke (HR 0.83 [95% CI, 0.76-0.92]) and nonfatal stroke (HR 0.84 [95% CI, 0.76-0.93]), but no reduction in fatal stroke (HR 0.80 [95% CI, 0.63-1.03]).

    “We performed a meta-analysis that included all 8 CVOTs using the Cochrane Collaboration's Review Manager Software Package (RevMan 5.3) and found significant decreases versus placebo in fatal/nonfatal stroke (HR, 0.83 [95% CI, 0.76-0.92]),nonfatal stroke (HR, 0.84 [95% CI, 0.76-0.93]),but no reduction in fatal stroke (HR, 0.80 [95% CI, 0.63-1.03]; Figure 2).”
    Quote in the paperSubstantial claim

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    Premisecitation

    In PROactive, the main secondary composite endpoint of nonfatal MI, nonfatal stroke, and all-cause death was reduced with pioglitazone (HR 0.84 [95% CI, 0.72-0.98]; P=0.027), but the individual outcome of stroke was not.

    “The main secondary composite end point of nonfatal MI, nonfatal stroke and all-cause death was reduced with pioglitazone (HR, 0.84 [95% CI, 0.72-0.98];P=0.027) but the individual outcome of stroke was not.27”
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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Diabetes is associated with premature vascular aging and is a strong risk factor for stroke.

    “Diabetes is associated with premature vascular aging and is a strong risk factor for stroke.”
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    Premisecitation

    Despite improvements in screening and expanded treatment options, the prevalence of stroke in people with diabetes has remained relatively stable, indicating a persistent care gap.

    “Despite improvements in screening for diabetes and an expanded diabetes and stroke reduction armamentarium, the prevalence of stroke in individuals with diabetes has remained relatively stable, 6 underscoring a persistent care gap.”
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    Premisecitation

    In REWIND, disabling stroke (modified Rankin Scale score ≥3) was reduced by 26%, but among those who had a stroke, there was no difference in the distribution of stroke severity scores between dulaglutide and placebo.

    “Disabling stroke, defined as a modified Rankin Scale score of ≥3, was reduced by 26%, but in those who had a stroke, there was no difference in the distribution of stroke severity scores between dulaglutide and placebo.37”
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    Premisecitation

    In the acute/subacute phase, hospitalized patients with both diabetes and stroke are more likely to have complications such as urinary tract infection and pneumonia and have higher mortality.

    “In the acute/subacute phase, hospitalized patients with both diabetes and stroke are more likely to suffer from complications such as urinary tract infection and pneumonia and have higher mortality rates.4”
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    Premisecitation

    In REWIND, fatal/nonfatal stroke was significantly reduced by 24% and ischemic stroke by 25%, but the decrease in fatal stroke or hemorrhagic stroke did not achieve statistical significance.

    “Although fatal/nonfatal stroke was significantly reduced by 24% and ischemic stroke by 25%, the decrease in fatal stroke or hemorrhagic stroke did not achieve statistical significance.37”
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    Premisecitation

    Intensive glycemic control reduces nonfatal MI and the composite of cardiovascular death, nonfatal MI, and nonfatal stroke, but does not reduce stroke alone.

    “The risk of nonfatal myocardial infarction (MI) and the composite of cardiovascular death, nonfatal MI, and nonfatal stroke were reduced, whereas the risk of stroke on its own was not.9,21”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hypertension and dyslipidemia are often comorbid in diabetes and further increase stroke risk.

    “Risk factors for atherosclerotic disease such as hypertension and dyslipidemia are often comorbid in diabetes 1 and further increase the risk of stroke.”
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    Interpretationcitation

    While achieving lower glycemic levels alone does not appear to reduce stroke risk, a multifactorial approach can reduce many complications of T2DM, including stroke, with long-lasting effects.

    “Thus, while achieving lower glycemic levels on its own does not appear to reduce stroke risk, when used as part of a multifactorial approach, many complications of T2DM, including stroke, can be reduced with long-lasting effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SGLT2 inhibitors reduce cardiorenal outcomes including MACE, hospitalization for heart failure, and kidney endpoints across a spectrum of people with T2DM, but do not reduce stroke.

    “SGLT2is (sodium-glucose-transporter-2 inhibitors) reduce cardiorenal outcomes including the composite of major adverse cardiovascular events (MACE), hospitalization for heart failure and kidney end points across a spectrum of people with T2DM, but not stroke.23,24”
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    Premisenone given

    GLP-1RA therapy directly improves endothelial function, promotes angiogenesis, cerebral blood flow, and neurogenesis, and decreases neuronal damage, amyloid plaque build-up, and infarct volume within the cerebral circulation.

    “GLP-1RA therapy also directly improves endothelial function, promotes angiogenesis, cerebral blood flow, and neurogenesis alongside decreasing neuronal damage as well as amyloid plaque build-up and infarct volume within the cerebral circulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The retinopathy increase with semaglutide was not replicated in other semaglutide trials, other GLP-1RA trials, or meta-analyses of GLP-1RA trials.

    “This was not replicated in other semaglutide trials, other GLP-1RA trials nor meta-analyses of GLP-1RA trials.62”
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  • Classified as probably not a substantial claim.

    Premisecitation

    The Diabetes, Cardiorenal, and Metabolic task force endorses the use of a long-acting GLP-1RA for primary and secondary prevention of stroke/TIA in diabetes.

    “the Diabetes, Cardiorenal, and Metabolic task force endorses the use of a long-acting GLP-1RAs for primary and secondary prevention of stroke/TIA in diabetes 55”
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    Premisecitation

    Earlier meta-analyses of 4 to 7 CVOTs reported similar declines in fatal/nonfatal stroke, decreases in nonfatal stroke across 7 CVOTs, but no reduction in fatal stroke when meta-analyzing 5 or 6 studies.

    “Earlier studies reported similar declines in fatal/nonfatal stroke in meta-analyses of 4 to 7 CVOTs, decreases in nonfatal stroke across 7 CVOTs, but no reduction in fatal stroke when meta-analyzing 5 or 6 studies.9,23,[48][49][50][51]”
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    Premisecitation

    Dulaglutide can be prescribed in severe renal impairment with cautions; subcutaneous semaglutide is not recommended in end-stage kidney disease.

    “Dulaglutide can be prescribed in severe renal impairment with cautions; sc semaglutide is not recommended in end-stage kidney disease.38,39,46,67”
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    Premisecitation

    GLP-1RAs lower stroke indirectly by reducing blood pressure, promoting weight loss, and enhancing HbA1c control.

    “GLP-1RAs further lower stroke by indirectly reducing blood pressure, promoting weight loss, and enhancing HbA1c control.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In another meta-analysis of 8 CVOTs, nonfatal stroke was reduced by 16% (HR 0.84 [95% CI, 0.76-0.94]), but fatal/nonfatal stroke and fatal stroke were not reported.

    “In another meta-analysis of 8 CVOTs, nonfatal stroke was reduced by 16% (HR, 0.84 [95% CI, 0.76-0.94]),but the outcomes of fatal/nonfatal stroke and fatal stroke were not reported.47”
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    Premisecitation

    The 2020 Canadian Stroke Best Practices update, 2021 Spanish Society of Neurology consensus statement, 2021 AHA/ASA guideline, and Diabetes, Cardiorenal, and Metabolic Diseases Multispecialty Task Force all endorse GLP-1RAs for reducing stroke risk in individuals with T2DM.

    “In the same vein, the 2020 Canadian Stroke Best Practices update for secondary prevention of stroke, 8 2021 Spanish Society of Neurology consensus statement, 9 2021 American Heart Association/American Stroke Association Guideline for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack, 7 and the Diabetes, Cardiorenal, and Metabolic Diseases Multispecialty Task Force 55”
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    Premisecitation

    A meta-analysis of 8 completed CVOTs with GLP-1RAs revealed statistically significant reductions in fatal/nonfatal stroke versus placebo (HR 0.83 [95% CI, 0.76-0.92]) as well as decreases in MACE, cardiovascular death, fatal/nonfatal MI, and hospitalization for heart failure.

    “A meta-analysis of the 8 completed CVOTs with GLP-1RAs revealed statistically significant reductions in the combined outcome of fatal/nonfatal stroke versus placebo (HR, 0.83 [95% CI, 0.76-0.92])as well as decreases in MACE, cardiovascular death, fatal/nonfatal MI, and hospitalization for heart failure.13”
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  • Classified as probably not a substantial claim.

    Premisecitation

    Diabetes Canada recommends the use of GLP-1RAs to provide cardiovascular protection in those with CVD or risk factors.

    “Diabetes Canada recommends the use of GLP-1RAs to provide cardiovascular protection in those with CVD or risk factors.54”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    In SUSTAIN-6, retinopathy was increased with subcutaneous semaglutide (HR 1.76 [95% CI, 1.11-2.78]; P=0.02), but mainly among those with preexisting retinopathy, rapid HbA1c lowering, and very high baseline HbA1c levels.

    “In SUSTAIN-6, retinopathy was increased with sc semaglutide (HR, 1.76 [95% CI, 1.11-2.78];P=0.02), but mainly among those who had preexisting retinopathy, rapid HbA1c lowering and very high baseline HbA1c levels.”
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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The lack of heterogeneity for stroke reduction in REWIND and SUSTAIN-6 for the subgroups with prior stroke/TIA and prior MI/stroke respectively is sufficient evidence to recommend dulaglutide or semaglutide for stroke reduction in those with prior stroke.

    “we deem the lack of heterogeneity for stroke reduction in REWIND and SUSTAIN-6 for the subgroups with prior stroke/TIA and prior MI/ stroke respectively as sufficient evidence to recommend dulaglutide or semaglutide for stroke reduction in those with prior stroke.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The Canadian Stroke Best Practices recommends GLP-1RAs for patients with stroke and T2DM who have not met glycemic targets with standard antihyperglycemic agents.

    “Specifically, the Canadian Stroke Best Practices recommends GLP-1RAs for patients with stroke and T2DM who have not met their glycemic targets with standard antihyperglycemic agents 8”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisenone given

    At the molecular and cellular levels, GLP-1RAs diminish oxidative stress, reduce apoptosis, and limit the formation and accumulation of advanced glycation end-products, which help attenuate the proinflammatory components of cerebral atherosclerosis.

    “At the molecular and cellular levels, GLP-1RAs diminish oxidative stress, reduce apoptosis, and limit the formation and accumulation of advanced glycation end-products, all of which help attenuate the proinflammatory components of cerebral atherosclerosis.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In SUSTAIN-6, there was no significant decrease in fatal/nonfatal stroke or fatal stroke alone, and only 5 participants experienced a fatal stroke.

    “There was no significant decrease in the outcomes of fatal/nonfatal stroke or fatal stroke alone, and only 5 study participants experienced a fatal stroke.29,40,41”
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  • The paper relies on this without support.

    GLP-1 receptor agonists can be safely started at any point during the patient journey.

    “underscore that GLP-1RAs can be safely started at any point during the patient journey.”
1 of 1

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Real-world cohort cites a diabetes guideline

    Minor

    The claim about a cohort of 557,109 people cites reference 53, which the reference list identifies as a Diabetes Canada guideline. The listed routine-care comparison is reference 52.

  • Network meta-analysis cites a routine-care study

    Minor

    The text attributes a result from a network meta-analysis of 176 trials to reference 52, but reference 52 is listed as a study of patients in routine care, not a network meta-analysis of trials.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 11

  1. Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and management of diabetes in Canada. Can J Diabetes. 2018;42:S1–S325.
  2. Bhatt, DL, Brinton, EA, Miller, M, Steg, PG, Jacobson, TA, Ketchum, SB, Doyle, RT, Juliano, RA, Jiao, L, Granowitz, C, et al. Substantial cardiovascular benefit from icosapent ethyl in patients with diabetes: REDUCE-IT DIABETES. American Diabetes Association’s 80th Scientific Sessions Virtual. Late Breaking Poster Presentations: Acute and Chronic Complications. Diabetes. 2020;69:4–LB. · DOI
  3. Eli Lilly Canada Inc. PrTRULICITY® Product Monograph. September 11, 2020.
  4. Eli Lilly and Company. TRULICITY® Prescribing Information. September 2020.
  5. Food and Drug Administration. New drug application 209637 for semaglutide injection. Endocrinologic and Metabolic Drugs Advisory Committee Meeting Briefing Document. 2017:1–152.
  6. Novo Nordisk. Semaglutide subcutaneous once-weekly - Treatment to improve glycemic control in adults with Type 2 diabetes mellitus. Endocrinologic and Metabolic Drugs Advisory Committee Meeting Briefing Document. 2017:1–158.
  7. Strain, WD, Holst, AG, Rasmussen, S, Saevereid, HA, James, MA. Effects of liraglutide and semaglutide on stroke subtypes in patients with type 2 diabetes: a post hoc analysis of the LEADER, SUSTAIN 6 and PIONEER 6 trials. 56th EASD Annual Meeting of the European Association for the Study of Diabetes, Virtual Meeting. OP 47 Thinking about diabetes complications in the brain. Diabetologia. 2020;63:258.
  8. Nuffield Dept of Population Health (University of Oxford). Major new study could help protect millions of people with type 2 diabetes from cardiovascular disease. University of Oxford News and Events. 2021
  9. Novo Nordisk Inc. OZEMPIC® Prescribing Information. January 2020.
  10. Reid, TS. Statement of clarification—Reid TS: practical use of glucagon-like peptide-1 receptor agonist therapy in primary care. Clin Diabetes. 2014;32:58–59.
  11. Novo Nordisk Inc. PROZEMPIC® Product Monograph. September 07, 2021.

Cited by

Sorted by citations

Authors
Goldenberg, R. M., Cheng, A. Y. Y., Fitzpatrick, T., Gilbert, J. D., Verma, S., & Hopyan, J. J.
Affiliations
  • LMC Diabetes & Endocrinology (Canada) (CA)
  • St. Michael's Hospital (CA)
  • Mackenzie Health, Canada (T.F.).
  • Sunnybrook Health Science Centre (CA)
ORCID
Venue
Stroke
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2022-05
Volume
53
Issue
5
Pages
1813-1822
ISSN
  • 0039-2499 (ISSN-L)
  • 1524-4628
DOI
10.1161/strokeaha.121.038151
OpenAlex
W4220671970
Cited by
82
References
55
Citations by year
2026: 23 · 2025: 13 · 2024: 31 · 2023: 11 · 2022: 4
FWCI
2.10
Type
journal article
Language
en
Open access
closed
Locations
  • Stroke (publishedVersion)
  • PubMed (publishedVersion)
Funders
University of Toronto
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
Keywords
GLP-1 receptor agonists, type 2 diabetes, stroke prevention, cardiovascular outcome trials, antihyperglycemic therapy, neurologist role, decision-making algorithm, frequently asked questions
MeSH terms
Glucagon-Like Peptide-1 Receptor, Neurologists, Glucagon-Like Peptide-1 Receptor Agonists, Diabetes Mellitus, Type 2, Humans, Stroke, Glucagon-Like Peptide 1

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