Can sustained use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) deliver durable glycemic improvement in routine clinical care when compared with dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors)? A nationwide Danish registry analysis published in Diabetes, Obesity, and Metabolism addressed this question by emulating a target trial in people with type 2 diabetes.

The study drew on nationwide health registries from 2012 through 2022 and included 16,619 individuals who initiated GLP-1 RA therapy and 34,196 who initiated DPP-4 inhibitor therapy. The primary outcome was the probability of improvement across predefined haemoglobin A1c (HbA1c) categories within 1 year. Longitudinal Targeted Minimum Loss-based Estimation accounted for baseline and time-varying confounders under sustained treatment strategies.

After 1 year, the probability of any HbA1c improvement was 82.7% (95% confidence interval [CI], 82.0% to 83.4%) with sustained GLP-1 RA therapy compared with 67.1% (95% CI, 66.5% to 67.6%) with DPP-4 inhibitor therapy, yielding an absolute difference of 15.7% (95% CI, 14.8% to 16.5%). GLP-1 RA use was also associated with lower all-cause mortality, 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.

Within the constraints of this observational emulation, sustained GLP-1 RA therapy was associated with greater HbA1c improvement and modest differences in mortality compared with DPP-4 inhibitor therapy.