Real-World Persistence and Clinical Outcomes with Contemporary Glucose-Lowering Therapies: A Systematic Review

Abstract

 Background: Contemporary glucose-lowering therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) and dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), have transformed the management of type 2 diabetes. However, treatment benefits observed in clinical trials may not be fully realized in routine practice because of premature discontinuation, poor adherence, treatment switching, adverse effects and cost-related barriers. Objective: To systematically review real-world persistence with contemporary glucose-lowering therapies and evaluate the relationship between treatment persistence and glycemic, weight, treatment-utilization and other clinically relevant outcomes. Methods: A systematic review was conducted according to PRISMA 2020 principles. PubMed/MEDLINE, Embase, Scopus, Web of Science, CINAHL and the Cochrane Library were searched for real-world observational studies evaluating treatment persistence, adherence, discontinuation, or switching among adults receiving GLP-1 receptor agonists, dual GIP/GLP-1 receptor agonists, SGLT2 inhibitors, or DPP-4 inhibitors. Studies were eligible when they reported persistence and at least one clinical or treatment outcome, or compared persistence across contemporary glucose-lowering therapies. Randomized trials without real-world treatment-behavior data were excluded. Because persistence definitions, refill-gap thresholds, treatment classes, follow-up duration and clinical outcomes differed substantially, findings were synthesized narratively. Results: A total of 2,314 records were identified. After removal of 604 duplicates, 1,710 records underwent title and abstract screening. Of these, 1,469 were excluded and 241 reports were sought for retrieval. Nine reports were not retrieved, leaving 232 full-text articles for assessment. After exclusion of 180 reports, 52 studies were included. Twenty-four studies evaluated GLP-1 receptor agonists, 14 evaluated SGLT2 inhibitors, seven evaluated DPP-4 inhibitors, three evaluated dual GIP/GLP-1 therapy and four compared multiple contemporary drug classes. Twelve-month persistence varied widely by therapy, population and definition. Once-weekly GLP-1 receptor agonists generally demonstrated greater persistence than daily injectable regimens. Semaglutide and dulaglutide frequently showed comparatively favorable persistence within the GLP-1 class. One-year SGLT2-inhibitor persistence commonly ranged around 50-65%, while DPP-4 inhibitor persistence was similarly suboptimal. Higher persistence or adherence was consistently associated with greater reductions in HbA1c and, for incretin-based therapies, greater weight loss. Gastrointestinal adverse effects, treatment complexity, costs, dose-escalation difficulties and younger age were recurrent correlates of discontinuation. Conclusion: Real-world persistence with contemporary glucose-lowering therapy is substantially lower than the treatment exposure typically achieved in randomized trials. Persistence differs by drug class, formulation and dosing frequency and is clinically important because persistent patients generally achieve greater glycemic and weight benefits. Improving persistence should therefore be considered an integral component of diabetes treatment optimization rather than a secondary medication-use outcome.