Treatment intensification strategies and metabolic outcomes in individuals with type 2 diabetes on GLP-1 RA therapy

Aims: Despite the efficacy of glucagon like peptide 1 receptor agonists (GLP-1 RAs), many patients with type 2 diabetes (T2D) require additional therapy to achieve HbA1c targets. Few studies have explored real-world outcomes following GLP-1 RA failure. This analysis evaluates different intensification approaches, timing, and outcomes in T2D patients on GLP-1 RAs. Methods: This retrospective cohort study was based on AMD Annals database. From 191,041 patients on GLP-1 RAs between 2010 and 2022, individuals receiving a first therapeutic intensification were selected. Patients were stratified by intensification strategy; baseline characteristics were compared alongside glycated hemoglobin (HbA1c) and weight changes at 6 and 12 months. Results: Among the 37,198 patients intensified, the majority received oral antihyperglycemic drugs (OADs), particularly those with higher BMI, lower HbA1c, and shorter disease duration. Basal insulin (BI) was mainly added in those with higher HbA1c (8.9%) and longer diabetes. Intensification with BI or switch to fixed ratio combinations (FRCs) yielded the greatest HbA1c reduction (-0.92 and -0.85%; p<0.001) and weight neutrality, whereas OADs led to a higher target achievement rate (36% with HbA1c <7%) and persistent weight loss. Switching to basal-bolus was reserved for more complicated patients and it was associated with weight gain (+2.9 kg; p<0.001) and lower target achievement rate (16.8% HbA1c <7%). Suboptimal insulin titration was observed across all strategies. Conclusion: Adding OADs or BI/FRCs to GLP-1 RAs are optimal intensification strategies to provide glycemic control while avoiding weight gain. Target achievement rates are poor in individuals switched to insulin therapy. Therapeutic inertia remains a critical issue in clinical practice.