Dulaglutide and empagliflozin similarly improve HbA1c in T2DM, but empagliflozin yields earlier weight loss.

Type 2 Diabetes Mellitus (T2DM) often requires combination therapy for glycemic control. While both GLP-1 receptor agonists and SGLT2 inhibitors are effective add-on options, direct comparative evidence for their use with existing metformin and sulfonylurea regimens is limited. Understanding their distinct metabolic and body composition effects, beyond HbA1c reduction, is crucial for optimizing personalized treatment strategies. This study addresses this gap by comparing dulaglutide and empagliflozin head-to-head.

This 12-week, single-center, randomized, open-label, parallel-group pilot study, with a 24-week observational extension, enrolled 24 patients with HbA1c ≥7.0% on stable metformin and glimepiride. Patients were randomized to dulaglutide 0.75 mg/week or empagliflozin 10 mg/day. Doses were uptitrated at week 4 if tolerated and maintained for 12 weeks. The primary endpoint was change in HbA1c at week 12. Exploratory analyses used liquid chromatography-mass spectrometry for plasma metabolites and 16S rRNA gene sequencing for gut microbiota.

Both dulaglutide (n=13) and empagliflozin (n=11) significantly reduced HbA1c at week 12, with no significant between-group difference.

Empagliflozin significantly reduced HOMA-IR, indicating improved insulin sensitivity, whereas dulaglutide significantly increased HOMA-β, suggesting enhanced beta-cell function. At week 12, empagliflozin was associated with greater reductions in body weight and body fat compared with dulaglutide. However, these differences in body composition were attenuated by week 36. Exploratory analyses revealed potential, modest treatment-related differences in plasma metabolite profiles and microbiome-metabolic associations. Importantly, neither treatment caused marked alterations in overall microbial diversity.