A Nationwide Danish Comparative Effectiveness Study of GLP-1 RA, SGLT2i and DPP-4i Treatment on Risk of Stroke, Myocardial Infarction and Mortality in Type 2 Diabetes

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.