GLP1-RA versus DPP4 inhibitors on cardiovascular outcomes: A three-year real-world analysis

Abstract Background Cardiovascular outcome trials of GLP1-RAs have massively impacted the clinical practice in the management of patients with type 2 diabetes. The cardiovascular protective properties of GLP1-RA compared to DPP4 have been demonstrated in an observational setting before, however recent methodological developments have enabled clinically relevant effect estimation. Aim This study aimed to evaluate the real-world cardiovascular outcomes of GLP1-RA versus DPP4 inhibitors in patients with type 2 diabetes and high cardiovascular risk. Methods In this study, we utilized the Danish nationwide registers to identify new users of GLP1-RA or DPP4 therapies from 2012 to 2022. Participants were required to be either at least 50 years of age and have one or more of the following conditions: hypertension, chronic obstructive pulmonary disease, cardiovascular disease, or chronic renal disease or be at least 60 years of age and have hypertension. Additionally, their glycated hemoglobin (HbA1c) levels needed to be 53 mmol/mol or higher within the year preceding their first prescription date for these therapies. The index date was defined as the initial prescription date, and comorbidities and medicine use were evaluated up to 10 years prior to this date. Individuals who had filled prescriptions for SGLT2 inhibitors within six months prior to their index date were excluded from the study. The outcome of interest was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE). Patients were followed for up to three years until MACE, all-cause mortality, emigration, or until the end of follow-up on December 31, 2022. To assess the three-year risk of MACE, the Aalen Johansson estimator was used. A casual inference framework was employed estimating the three-year average treatment effect using g-formula based on Cox regression with competing risk. Results A total of 26,190 individuals were included, with 19,494 initiating DPP4 inhibitor therapy and 6,696 initiating GLP1-RA therapy. The three-year risk of MACE was 8.56% (95% confidence interval [CI]: 8.11 to 9.00) for the DPP4 initiator group, compared to 4.76% (95% CI: 4.08 to 5.43) for the GLP1-RA initiator group. Emulating what would have happened had all included individuals initiated GLP1-RA treatment versus had all initiated treatment with DPP4, accounting for age, sex, income, education, degree of urbanization, diabetes duration, baseline hba1c level, co-medicine, and co-morbidities, we estimated an three-year average treatment effect of -2.05% (95% CI:-2.92;-1.18) , p-value<0.001) for GLP1-RA initiation versus DPP4 initiation for MACE. Conclusion Our findings suggest that GLP1-RA use is associated with a significantly lower risk of MACE compared to DPP4 inhibitors in a real-world population of patients with type 2 diabetes and high cardiovascular risk. This supports the cardiovascular protective role of GLP1-RA in clinical practice.