Introduction & Objective: Type 2 diabetes (T2D) is considerably heterogeneous due to different pathogenetic mechanisms that may affect response to treatment. We aimed to assess the efficacy of GLP-1RA according to the phenotypes described by Ahlqvist et al. (Diabetes, 2000).
Methods: In this retrospective monocentric study, every individual attending our outpatient clinic since 2013 was evaluated for eligibility. Main inclusion criteria were age at T2D diagnosis ≥50 years, T2D duration ≤5 years, BMI ≥25 kg/m2, first users of a GLP-1RA with at least one follow-up visit at 6-12 months. Main exclusion criteria were type 1 diabetes, LADA, ketoacidosis. The assignment to T2D phenotypes (MARD, mild age-related diabetes; MOD, mild obesity-related diabetes; SIDD, severe insulin deficient diabetes; SIRD, severe insulin resistant diabetes) was performed via the algorithm developed by Bello-Chavolla et al. (BMJ, 2020). The primary outcome was difference in HbA1c change from baseline, evaluated with ANOVA. SHapley Additive exPlanations (SHAP) allowed to rank predictors of HbA1c reduction. Kaplan-Meier analysis and log-rank test were used to estimate differences in time to treatment failure, defined as time to HbA1c ≥7.0%.
Results: We enrolled 128 patients. The SIDD phenotype was associated with a significantly greater HbA1c reduction (-1.9% vs. -0.67% [MARD], -0.75% [MOD], -0.56% [SIRD]; p<0.001) following GLP-1RA initiation after a median follow-up of 8 months. However, SHAP analysis identified baseline HbA1c, rather than SIDD phenotype, as the most relevant predictor of HbA1c change, accounting for ~0.5% HbA1c reduction. Yet, belonging to the SIDD phenotype was associated to earlier treatment failure (p<0.01).
Conclusion: Easily available clinical variables such as baseline HbA1c might be more useful to predict response to GLP-1RA than T2D subclassification. However, the diverse pathogenesis of T2D phenotypes might account for differences in treatment durability.
I. Caruso: Other Relationship; Eli Lilly and Company, Novo Nordisk, Laboratori Guidotti SpA. F. Giordano: None. L. Di Gioia: Consultant; Roche Diabetes Care, Eli Lilly and Company, Novo Nordisk, Sanofi. I.I. Matichecchia: None. A. Cignarelli: None. G. Sorice: None. S. Perrini: None. A. Natalicchio: Speaker's Bureau; AstraZeneca, Novo Nordisk, Sanofi, Eli Lilly and Company. L. Laviola: Speaker's Bureau; A. Menarini Diagnostics, Abbott, AlfaSigma. Advisory Panel; Boehringer-Ingelheim, Eli Lilly and Company, Medtronic, Novo Nordisk. Speaker's Bureau; AstraZeneca. Advisory Panel; Roche Diabetes Care, Sanofi. Speaker's Bureau; Terumo Corporation. F. Giorgino: Consultant; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, LifeScan Diabetes Institute, Merck Sharp & Dohme Corp., Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi. Research Support; Eli Lilly and Company, Roche Diabetes Care.
