Comparative Effectiveness and Safety of Once-Weekly Injectable Semaglutide Versus Dulaglutide in Individuals with Type 2 Diabetes Managed in UK Primary Care: A Population-Based Cohort Study

Background The SUSTAIN-7 trial demonstrated greater HbA1c and bodyweight reductions with once-weekly semaglutide versus dulaglutide in type 2 diabetes, but strict eligibility criteria limit external validity. We evaluated the comparative real-world effectiveness and safety of these agents in UK primary care. Methods Using the IQVIA Medical Research Data (IMRD) incorporating data from THIN, a Cegedim Database, we included adults with type 2 diabetes initiating semaglutide or dulaglutide between 01-Jan-2019 and 01-Dec-2022, followed through 30-Jun-2023. Co-primary outcomes were 1-year changes in HbA1c and bodyweight, estimated using a new-user, active-comparator cohort design with marginal structural models and inverse probability of treatment weighting. Treatment heterogeneity was assessed in the primary per-protocol analysis by SUSTAIN-7 trial-eligibility. Safety events were assessed while-on-treatment. Findings Among 6616 new users, 4636 (70.1%) remained on-treatment and 1980 (29.9%) discontinued early. Semaglutide new users (n = 1901) achieved greater 1-year reductions than dulaglutide new users (n = 2735) in HbA1c (estimated treatment difference [ETD] −0.22 percentage points [95% CI −0.30, −0.15]) and bodyweight (ETD −1.92 kg [95% CI −2.91, −0.93]). While semaglutide's benefits were preserved across the 87.7% (n = 4064) not meeting SUSTAIN-7 trial-eligibility (HbA1c: ETD −0.23 percentage points [95% CI −0.31, −0.15]; bodyweight: ETD −2.01 kg [95% CI −3.07, −0.95]), reductions in HbA1c and bodyweight were greater among trial-eligible individuals (12.3%; n=572) for both agents (trial-eligible [semaglutide/dulaglutide] versus non-eligible [semaglutide/dulaglutide] individuals, HbA1c: −1.10/−1.02 versus −0.83/−0.60 percentage points; bodyweight: −5.72/−4.18 versus −5.50/−3.49 kg). Early discontinuers showed attenuated treatment effects and higher gastrointestinal event rates than those remaining on-treatment (23.5–26.1 versus 10.6–13.8 per 100 person-years). Interpretation New users of semaglutide achieved greater reductions in HbA1c and bodyweight than new users of dulaglutide with comparable safety, with benefits preserved across SUSTAIN-7 trial-eligible and non-eligible individuals, supporting preferential use of semaglutide in UK clinical practice. Funding Swiss National Science Foundation.