Rethinking diabetes as a modifier of the weight-loss response to incretin-based therapies. A twin trial...

Incretin-based therapies are effective for body weight (BW) management, but an attenuation in their weight loss efficacy has been consistently reported in the treatment of type 2 diabetes (T2D) versus obesity. However, no trial has directly compared BW outcomes between populations with T2D and those with obesity but without T2D. We aimed to determine whether T2D independently modifies the weight-loss response to incretin therapies using a twin-trial approach.

We performed a meta-regression of "twin" incretin-based RCTs, each pair consisting of a trial in adults with obesity without T2D and a corresponding T2D trial evaluating the same molecule, dose, and treatment duration. The outcome of interest was placebo-adjusted percent BW change, and ratios within each trial couple were pooled using inverse-variance weighting. Two sets of meta-regressions assessed associations between BW loss and study-level covariates.

Twenty-one RCTs forming 11 twin pairs were included. T2D trials had fewer female participants, but higher prevalence of hypertension and dyslipidaemia. Placebo-adjusted weight loss was significantly lower in T2D versus obesity trials (pooled ratio: 0.61, 95% C.I. 0.56; 0.67). Study-level diabetes status, age, BMI, sex distribution, ethnicity, and cardiometabolic comorbidities significantly correlated with BW loss at univariate analysis. Adjustment for covariates differing between trial type and associated with BW reduction nullified the association between T2D status and weight loss (p = 0.93).

Reduced weight loss with incretin-based therapies observed in T2D versus obesity trials appears primarily driven by demographic and cardiometabolic features rather than diabetes-specific biological resistance.