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A Nationwide Danish Comparative Effectiveness Study of GLP-1 RA, SGLT2i and DPP-4i Treatment on Risk of Stroke,
Sidsel Hastrup1, Jakob N Hedegaard2, Grethe Andersen1,3
1Department of Neurology, Danish Stroke Center, Aarhus University Hospital, Aarhus, Denmark.
Aims:
Cardiovascular outcome trials have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce the risk of major adverse cardiovascular events, whereas dipeptidyl peptidase-4 inhibitors (DPP-4i) have not shown cardiovascular benefits. We aimed to compare the effectiveness in routine clinical settings of incident use of either GLP-1 RA, SGLT2i or DPP-4i among type 2 diabetes on the stroke risk and as secondary outcomes myocardial infarction and all-cause mortality.
Methods:
A nationwide population-based cohort study consisted of persons with type 2 diabetes who were new users of a GLP-1 RA, SGLT2i or DPP-4i and without prior stroke from 2014 to 2020 in Denmark using an active comparator design. They were followed from initiation of medication up to a maximum of 2 years for incident outcomes. Estimates were adjusted for age, sex, calendar year of initiation, socio-economic factors, medication and co-morbidity.
Results:
The study included 19,999 new users of a GLP-1 RA; 24,702 of a SGLT2i and 41,943 of a DPP-4i. The new users of GLP-1 RA had a lower incidence of stroke when compared to new users of DPP-4i, adjusted hazard rate ratios (aHRR): 0.69 95% confidence interval (0.53-0.91). There was no significant difference in stroke incidence between the new users of SGLT2i versus DPP4-4i and SGLT2i versus GLP-1 RA: aHRR 0.80 (0.64-1.01) and 1.17 (0.87-1.57). The new users of GLP-1 RA and SGLT2i had lower risk of mortality in comparison with new users of DPP-4i. The risk of myocardial infarction was not significantly different between the compared groups.
Conclusions:
New users of GLP-1 RA with type 2 diabetes had a lower risk of first stroke and new users of GLP-1 RA and SGLT2i had lower mortality. These data could help guide the choice of glucose-lowering medications in persons with type 2 diabetes.
Insights
New users of glucagon-like peptide-1 receptor agonists (GLP-1 RA) significantly lowered stroke risk compared to dipeptidyl peptidase-4 inhibitors (DPP-4i). GLP-1 RA and sodium-glucose cotransporter 2 inhibitors (SGLT2i) also reduced mortality risk in type 2 diabetes patients.
Area of Science:
- Endocrinology
- Cardiology
- Pharmacology
Background:
- Cardiovascular outcome trials show GLP-1 RAs and SGLT2is reduce major adverse cardiovascular events, unlike DPP-4is.
- Type 2 diabetes management requires careful consideration of cardiovascular risk reduction.
Purpose of the Study:
- To compare the real-world effectiveness of GLP-1 RAs, SGLT2is, and DPP-4is on stroke risk in type 2 diabetes.
- To evaluate the secondary outcomes of myocardial infarction and all-cause mortality associated with these glucose-lowering medications.
Main Methods:
- Nationwide population-based cohort study in Denmark (2014-2020) including new users of GLP-1 RA, SGLT2i, or DPP-4i without prior stroke.
- Active comparator design with up to 2 years of follow-up for incident outcomes.
- Adjusted analyses for age, sex, calendar year, socio-economic factors, medication, and comorbidities.
Main Results:
- 19,999 GLP-1 RA, 24,702 SGLT2i, and 41,943 DPP-4i new users were included.
- GLP-1 RA users showed a significantly lower stroke incidence compared to DPP-4i users (aHRR: 0.69; 95% CI: 0.53-0.91).
- No significant stroke difference was found between SGLT2i and DPP-4i users, or between SGLT2i and GLP-1 RA users. Both GLP-1 RA and SGLT2i users had lower mortality risk versus DPP-4i users.
Conclusions:
- New users of GLP-1 RAs in type 2 diabetes demonstrated a reduced risk of first stroke.
- GLP-1 RAs and SGLT2is were associated with lower all-cause mortality compared to DPP-4is.
- Findings can inform clinical decisions regarding glucose-lowering medication choices for type 2 diabetes patients with cardiovascular considerations.
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