Tirzepatide reduces body weight and improves glycemic control, but real-world comparisons between individuals with obesity with and without type 2 diabetes (T2D) remain limited, as well as the potential influence on weight-loss response of baseline characteristics (especially sex and previous treatment exposure). We aimed to compare anthropometric and metabolic outcomes in these populations, as well as treatment persistence, discontinuation, and the influence of prior GLP-1 receptor agonist (GLP-1 RA) exposure.

This retrospective multicenter study included adults with overweight/obesity without T2D (Ob) or with T2D (ObT2D) treated with tirzepatide. Data were collected at baseline and after 2–4 (T1), 5–8 (T2), and 9–15 (T3) months. Longitudinal changes were assessed using linear mixed-effects models, and multivariable analyses identified predictors of weight loss.

Ob participants (n=210, 74.8% female) were younger, had higher BMI, better glycemic control, and less previous GLP-1RA exposure than ObT2D participants (n=378, 49.7% female) (45.7% vs 79.3%; p<0.001). Weight loss was greater in Ob than ObT2D at all follow-ups (−5.0% vs −2.8%, −10.1% vs −3.3%, and −14.2% vs −4.7%; all p≤0.011), with mixed-effects models confirming different trajectories. This difference was attenuated and no longer statistically significant when analyses were restricted to treatment-naïve participants. Prior GLP-1RA exposure was independently associated with lower weight loss, while an interaction between prior GLP-1RA exposure and T2D status emerged at longer follow-up. No effect modification by sex or age was clearly detectable in this cohort. Discontinuation was more frequent in Ob, with adverse events, and financial barriers among the main reported reasons. Adverse events occurred in 16.9%, were mainly mild, transient gastrointestinal events, more frequent in Ob than ObT2D (26.9% vs 11.1%; p<0.001).

Tirzepatide was effective and well tolerated in routine practice. Greater weight loss occurred in obesity without T2D, while prior GLP-1RA exposure was independently associated with a reduced weight response. Previous GLP1-RA exposure may partly account for the different weight-loss trajectories observed between obesity with and without T2D. Residual differences at longer follow-up may reflect additional unmeasured clinical, metabolic, and treatment-related factors.