Comparative Weight-Loss Outcomes Following Initiation of GLP-1 Receptor Agonists versus SGLT2 Inhibitors: A Real-World Active Comparator Study.

OBJECTIVE

To compare 12-month weight loss between GLP-1 receptor agonist (GLP-1RA) and SGLT2 inhibitor (SGLT2i) initiators and assess effect modification by diabetes status, sex, and race/ethnicity in a diverse US cohort.

METHODS

Retrospective active comparator new-user cohort study using the NIH All of Us Research Program (2018-2023). We identified 2,932 SGLT2i-naïve GLP-1RA initiators and 941 GLP-1RA-naïve SGLT2i initiators aged 18-80 with BMI ≥27 kg/m2 and available weight measurements. Inverse probability of treatment weighting (IPTW) with a 17-covariate propensity score model - including heart failure and CKD - achieved balance on all 28 diagnostics (maximum SMD 0.077). The primary outcome was percent body weight change at 12 months; secondary outcomes included ≥10% weight loss, HbA1c, and blood pressure change.

RESULTS

After IPTW, GLP-1RA initiators lost more weight than SGLT2i initiators (difference -1.20 pp [95% CI, -1.91 to -0.48]; P = .001; OR 1.75 [95% CI, 1.40-2.19]; RR 1.61 [95% CI, 1.19-2.03]; NNT 14), concentrated in obesity-only patients (-1.96 pp; P <.001) but absent in type 2 diabetes (+0.08 pp; interaction P = .006). Sex modified the effect (P = .017): -1.71 pp in women vs +0.12 pp in men. HbA1c decreased more with GLP-1RA (-0.261%; P = .032); blood pressure did not differ significantly.

CONCLUSION

GLP-1RA initiators achieved greater weight loss than SGLT2i initiators, concentrated in women and patients without type 2 diabetes, supporting individualized treatment selection. Interaction findings are hypothesis-generating and require prospective confirmation.