Sustained glucagon-like peptide-1 receptor agonist treatment improves glycemic control and reduces all-cause mortality compared to dipeptidyl peptidase-4 inhibitors: A real-world target trial emulation in type 2 diabetes.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) improve glycemic outcomes in people with type 2 diabetes, but their generalizability to routine clinical practice remains uncertain. AIM: To evaluate the real-world effectiveness of sustained GLP-1 RA use on haemoglobin A1c (HbA1c) over 1 to 4.5 years, using dipeptidyl peptidase 4 inhibitors (DPP-4is) as an active comparator. METHODS: Using Danish nationwide registries (2012-2022), we emulated a target trial assessing the glycemic effectiveness of GLP-1 RAs. The primary outcome was the probability of improvement in defined HbA1c categories within 1 year. Longitudinal Targeted Minimum Loss-based Estimation was used to estimate the primary outcome under sustained use of GLP-1 RA and DPP 4i, controlling for baseline and time-varying confounding. RESULTS: We included 16 619 GLP-1 RA initiators and 34 196 DPP-4i initiators, each with 2.8 HbA1c measurements per patient-year. At 1 year, the probability of any HbA1c improvement was 82.7% (95% CI: 82.0% to 83.4%) under sustained GLP-1 RA versus 67.1% (95% CI: 66.5% to 67.6%) under DPP-4i, an absolute difference of 15.7% (95% CI: 14.8% to 16.5%). GLP-1 RA treatment was also associated with a lower all-cause mortality risk, with absolute reductions of 0.4% (95% CI: 0.1% to 0.7%) at 1 year and 1.1% (95% CI: 0.3% to 2.0%) at 3 years. CONCLUSION: Within the limitations of this nationwide study and the available data, sustained GLP-1 RA therapy provided superior glycemic control and was associated with a modest mortality benefit compared with DPP-4i therapy.