ABSTRACT Aims Glucagon‐like peptide‐1 (GLP‐1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors are widely used for the treatment of type 2 diabetes, yet their downstream consequences in routine clinical practice remain incompletely characterized. We compared downstream treatment burden following initiation of GLP‐1 receptor agonists versus SGLT2 inhibitors among adults with type 2 diabetes. Materials and Methods We conducted a retrospective, propensity score–matched cohort study using a multi‐centre electronic health record network. Adults with type 2 diabetes who newly initiated a GLP‐1 receptor agonist or an SGLT2 inhibitor between 1 January 2017 and 1 June 2025 were included. After 1:1 matching, approximately 164 000 patients were retained in each treatment group. Outcome‐specific baseline‐free cohorts with uniform washout periods were constructed, yielding sample sizes of approximately 124 000–164 000 per outcome. Primary outcomes were initiation of seven downstream medication classes. Secondary outcomes included gastrointestinal and nutritional diagnoses and health‐care utilization. Results Across all seven medication classes, downstream pharmacotherapy initiation occurred more frequently among GLP‐1 initiators. The largest differences were observed for symptom‐driven medications, including antidepressant, an absolute risk difference of 3.38% (95% CI −3.61 to −3.15) and a hazard ratio (HR) of 0.78 (95% CI 0.76–0.80), antiemetic, sedatives/hypnotics. Proton pump inhibitors, laxatives, histamine‐2 receptor antagonists and antidiarrheal were also more frequently initiated, though differences were modest. Differences in secondary diagnoses were smaller. Gastroesophageal reflux disease and esophagitis were more common after GLP‐1 initiation, whereas peptic ulcer disease and endoscopic procedures occurred more frequently among SGLT2 initiators. Nutrient deficiency and unspecified anaemia were more frequent following GLP‐1 therapy. Overall health‐care utilization was similar, except for inpatient acute care, which was more frequent among SGLT2 initiators. Conclusions Initiation of GLP‐1 receptor agonists is associated with a downstream pharmacologic cascade characterized by increased use of symptom‐driven medication without corresponding increases in health‐care utilization. Medication initiation may provide a more sensitive measure of treatment burden than diagnostic codes or utilization metrics in routine diabetes care. To our knowledge, this study represents the largest multicentre real‐world evaluation of downstream pharmacologic cascades following initiation of GLP‐1 receptor agonists and SGLT2 inhibitors.
Alhamdan et al. (Mon,) studied this question.