**Background:** Type 2 diabetes (T2D) is a chronic condition requiring optimal glycemic control to reduce complications. Key barriers include poor treatment persistence, reduced adherence, and therapeutic inertia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended for T2D patients with obesity due to glycemic benefits and weight loss, but real-world data on persistence, adherence, and inertia for these agents are limited.
**Methods:** This retrospective cohort study used electronic medical records from the Valencia Clínico-Malvarrosa Health Department (Spain) from January 2014 to December 2019. Among 26,944 adults with T2D, four groups were established: GLP-1RA users, SGLT2 inhibitor users, insulin users, and a miscellany group (other glucose-lowering agents). Propensity score matching (PSM) was performed using age, gender, and pre-existing cardiovascular disease, yielding 7392 individuals (1848 per group). Persistence was defined as continued treatment without gaps >30 days (non-insulin) or >3 months (insulin). Adherence was measured as proportion of days covered (PDC ≥80%). Therapeutic inertia was defined as non-intensification despite HbA1c ≥7.5% during follow-up. Chi-square tests and competing risk analysis were used.
**Key Results:** At 1 year, overall persistence was 85.6% (6048/7068). GLP-1RA users had lower 1-year persistence than non-users (81.5% vs 86.9%, p<0.0001). At 2 years, this gap widened: 48.4% of GLP-1RA users persisted vs 72.7% of non-users (p<0.0001). However, GLP-1RA users showed higher adherence than non-users (73.8% vs 68.9%, p<0.0001). Among GLP-1RA users with HbA1c measurements (n=985), 66.2% were persistent at 2 years. Persistent users had significantly greater HbA1c reduction (40.6% vs 18.6%, p<0.0001) and a trend toward more achieving HbA1c ≤7.0% (54.5% vs 47.8%, p=0.054). No significant differences in death, acute myocardial infarction, stroke, or heart failure hospitalization were found between persistent and non-persistent GLP-1RA users. Weekly GLP-1RA users had higher adherence than daily users (79.9% vs 66.6%, p<0.0001) but lower 1-year persistence (77.0% vs 87.0%, p<0.0001). Long-acting GLP-1RA users had higher adherence than short-acting users (75.6% vs 55.0%, p<0.0001). Therapeutic inertia was observed in 38.0% (519/1364) of the overall population with HbA1c ≥7.5%. Among GLP-1RA users with suboptimal control, only 11.1% experienced inertia (45/407), compared to 49.5% (474/957) of non-users. Inertia rates were 33.3% in SGLT2i, 47.7% in insulin, and 100% in the miscellany group. Mean time to intensification was 4.17 months for GLP-1RA users, 3.48 months for SGLT2i, and 7.62 months for insulin.
**Clinical Implications:** This study demonstrates that while GLP-1RA users show better adherence and receive more timely treatment intensification than non-users, persistence at 2 years remains poor—less than half of patients continue therapy. Persistent users derive clear glycemic benefits, yet the high discontinuation rate and substantial therapeutic inertia (especially in non-GLP-1RA groups) represent major barriers to optimal diabetes management. Strategies to improve medication persistence and reduce therapeutic inertia are urgently needed. Limitations include the retrospective design, limited PSM variables (excluding diabetes duration, BMI, socioeconomic status), short follow-up (mean 2.01 years for GLP-1RA group) potentially insufficient to detect cardiovascular outcome differences, and reliance on prescription data rather than actual medication consumption.