TY - JOUR
T1 - Impact of high glucose levels and glucose lowering on risk of ischaemic stroke
T2 - a Mendelian randomisation study and meta-analysis
AU - Benn, Marianne
AU - Emanuelsson, Frida
AU - Tybjærg-Hansen, Anne
AU - Nordestgaard, Børge G.
PY - 2021
Y1 - 2021
N2 - 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. Graphical abstract: [Figure not available: see fulltext.]
AB - 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. Graphical abstract: [Figure not available: see fulltext.]
KW - Anti-diabetes drugs
KW - Diabetes mellitus
KW - Glucose
KW - Glucose lowering
KW - Ischaemic cerebrovascular disease
KW - Ischaemic stroke
KW - Meta-analysis
U2 - 10.1007/s00125-021-05436-0
DO - 10.1007/s00125-021-05436-0
M3 - Journal article
C2 - 33765180
AN - SCOPUS:85103207340
VL - 64
SP - 1492
EP - 1503
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
ER -