Impact of high glucose levels and glucose lowering on risk of ischaemic stroke: a Mendelian randomisation study and meta-analysis
Open accessAbstract
Aims/hypothesis It is unclear whether glucose per se has a causal impact on risk of stroke and whether glucose-lowering drugs reduce this risk. This is important for the choice of treatment for individuals at risk. We tested the hypotheses that high plasma glucose has a causal impact on increased risk of ischaemic stroke, and that glucose-lowering drugs reduce this risk.Methods Using a Mendelian randomisation design, we examined 118,838 individuals from two Copenhagen cohorts, the Copenhagen General Population Study and the Copenhagen City Heart Study, and 440,328 individuals from the MEGASTROKE study. Effects of eight glucose-lowering drugs on risk of stroke were summarised by meta-analyses.Results In genetic, causal analyses, a 1 mmol/l higher plasma glucose had a risk ratio of 1.48 (95% CI 1.04, 2.11) for ischaemic stroke in the Copenhagen studies. The corresponding risk ratio from the MEGASTROKE study combined with the Copenhagen studies was 1.74 (1.31, 2.18). In meta-analyses of glucose-lowering drugs, the risk ratio for stroke was 0.85 (0.77, 0.94) for glucagon-like peptide-1 receptor agonists and 0.82 (0.69, 0.98) for thiazolidinediones, while sulfonylureas, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors, α-glucosidase inhibitors, meglitinides and metformin individually lacked statistical evidence of an effect on stroke risk.Conclusions/interpretation Genetically high plasma glucose has a causal impact on increased risk of ischaemic stroke. Treatment with glucose-lowering glucagon-like peptide-1 receptor agonists and thiazolidinediones reduces this risk. These results may guide clinicians in the treatment of individuals at high risk of ischaemic stroke.
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Hyperglycemia has a causal impact on increased risk of ischemic stroke.
“Hyperglycemia has a causal impact on increased risk of ischemic stroke [19].”
From Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms (2022) · cites this paper as [19]
Only 1 of the 5 thiazolidinedione studies was performed in a population of only those with T2DM.
“However, only 1 of the 5 studies was performed in a population of only those with T2DM.”
From Benefits of GLP-1 (Glucagon-Like Peptide 1) Receptor Agonists for Stroke Reduction in Type 2 Diabetes: A Call to Action for Neurologists (2022) · cites this paper as [23]
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”
From Benefits of GLP-1 (Glucagon-Like Peptide 1) Receptor Agonists for Stroke Reduction in Type 2 Diabetes: A Call to Action for Neurologists (2022) · cites this paper as [23]
In a meta-analysis of 48 randomized trials with 8 classes of antihyperglycemic therapies reporting stroke outcomes, statistically significant reductions in stroke were found only with GLP-1RAs and thiazolidinediones.
“In a meta-analysis of 48 randomized trials with 8 classes of antihyperglycemic therapies that reported stroke outcomes (Figure S1), statistically significant reductions in stroke were only found with the GLP-1RAs and thiazolidinediones.23”
From Benefits of GLP-1 (Glucagon-Like Peptide 1) Receptor Agonists for Stroke Reduction in Type 2 Diabetes: A Call to Action for Neurologists (2022) · cites this paper as [23]
A meta-analysis of 5 thiazolidinedione studies including stroke outcomes demonstrated a relative risk of 0.82 (95% CI, 0.69-0.98).
“A meta-analysis of 5 thiazolidinedione studies that included stroke outcomes demonstrated a relative risk of 0.82 (95% CI, 0.69-0.98).23”
From Benefits of GLP-1 (Glucagon-Like Peptide 1) Receptor Agonists for Stroke Reduction in Type 2 Diabetes: A Call to Action for Neurologists (2022) · cites this paper as [23]
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]”
From Benefits of GLP-1 (Glucagon-Like Peptide 1) Receptor Agonists for Stroke Reduction in Type 2 Diabetes: A Call to Action for Neurologists (2022) · cites this paper as [23]
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- Authors
- Benn, M., Emanuelsson, F., Tybjærg-Hansen, A., & Nordestgaard, B. G.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Benn, Marianne
- Venue
- Diabetologia
- Published
- 2021-03-25
- Volume
- 64
- Issue
- 7
- Pages
- 1492-1503
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W3137082679
- Cited by
- 41
- References
- 44
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 15 · 2023: 9 · 2022: 6 · 2021: 1
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Herlev and Gentofte Hospital (NA)
- The Danish Council for Independent Research, Medical Sciences (DFF-4183-00171)
- Rigshospitalets Forskningsfond (NA)
- Topics
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- ischemic stroke, plasma glucose, hyperglycemia, antidiabetic drugs, GLP-1 receptor agonists, thiazolidinediones, stroke risk reduction, type 2 diabetes, SGLT2 inhibitors, DPP-4 inhibitors, sulfonylureas, metformin, alpha-glucosidase inhibitors, meglitinides
- MeSH terms
- Ischemic Stroke, Glycemic Control, Blood Glucose, Brain Ischemia, Diabetes Mellitus, Type 2, Humans, Hyperglycemia, Hypoglycemic Agents, Risk Factors, Stroke, Mendelian Randomization Analysis
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