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.
