Cardiovascular outcomes in sustained use of glucagon like peptide inhibitors: a trial inspired population vs. a broad population

Abstract Background In type 2 diabetes, cardiovascular outcome trials have significantly influenced clinical practice, yet less than half of the patients receiving these therapies in real-world settings would have met the inclusion criteria for these trials. Aim To apply a target trial emulation framework to evaluate the impact of sustained treatment with glucagon-like peptide-1 (GLP1-RA) versus dipeptidyl peptidase-4 inhibitor (DPP4i) on major adverse cardiovascular events (MACE) over three years in (1) a population adhering to trial-like inclusion and exclusion criteria and (2) a broader real-world population receiving these therapies, excluding the trial-inspired population. Methods Using Danish nationwide registries, we identified new users of GLP1-RA or DPP4i for type 2 diabetes between 2012 and 2022. The trial-inspired population included patients aged 50 years or older with at least one of the following: heart failure, ischemic heart disease, stroke, or chronic kidney disease. Alternatively, patients aged 60 or older were eligible if they had hypertension or chronic obstructive pulmonary disease. Additionally, all patients were required to have an HbA1c of at least 53 mmol/mol in the year preceding treatment initiation. Not including the trial-inspired population, the broad population was defined by the same HbA1c threshold but included all patients prescribed GLP1-RA or DPP4i as second-line or add-on glucose-lowering therapy without further restrictions. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke (MACE). Patients were followed for up to three years or until the occurrence of MACE, all-cause mortality, emigration, three-year follow-up completion, or December 31, 2022. A causal inference approach using longitudinal targeted maximum likelihood estimation was applied to estimate the average treatment effect incorporating information on pre-and post-baseline confounders. Results In the trial-inspired population, 6,619 patients initiated GLP1-RA, while 19,211 initiated DPP4i. Sustained GLP1-RA use was associated with an absolute 3-year MACE risk of 8.2% (95% CI: 6.6% to 9.8%) and an absolute risk reduction of 1.8% (95% CI: 0.0% to 3.5%) compared to DPP4i. In the broad population, 10,872 patients initiated GLP1-RA, and 16,743 initiated DPP4i. Here, sustained GLP1-RA use was associated with an absolute 3-year MACE risk of 5.3% (95% CI: 4.3% to 6.4%) and an absolute risk reduction of 0.1% (95% CI: -0.3% to 0.2%) compared to DPP4i. Conclusion The cardiovascular benefits of GLP1-RA observed in clinical trials appear to extend to real-world patients who meet similar eligibility criteria. However, in a broad, less-selected population these benefits are negligible. This suggests that patient characteristics and real-world treatment factors may influence the magnitude of cardiovascular risk reduction.