Dulaglutide versus empagliflozin as add-on therapy to metformin and sulfonylurea in type 2 diabetes: a randomized pilot study with exploratory metabolomic and microbiome analyses.

In patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and sulfonylurea, evidence directly comparing glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors as add-on therapy is limited; therefore, we compared dulaglutide and empagliflozin in this setting. This 12-week, single-center, randomized, open-label, parallel-group pilot study included a 24-week observational extension. Patients with HbA1c≥7.0% receiving stable doses of metformin and glimepiride 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, with follow-up until week 36. The primary endpoint was the change in HbA1c at week 12. Secondary endpoints included changes in glycemic and obesity-related parameters. Exploratory analyses were performed to assess plasma metabolite profiles using liquid chromatography-mass spectrometry, and gut microbiota using 16S rRNA gene sequencing. Twenty-four patients completed the 12-week study (dulaglutide, n=13; empagliflozin, n=11). Both treatments significantly reduced HbA1c at week 12, with no significant between-group difference. Empagliflozin significantly reduced HOMA-IR, whereas dulaglutide significantly increased HOMA-β. At week 12, empagliflozin was associated with greater reductions in body weight and body fat compared with dulaglutide, whereas these differences were attenuated at week 36. Exploratory analyses suggested potential, modest treatment-related differences in plasma metabolite profiles and microbiome-metabolic associations, without marked alterations in overall microbial diversity. As add-on therapy to metformin and sulfonylurea, both dulaglutide and empagliflozin improved glycemic control, with no significant between-group difference observed in this exploratory pilot study. Empagliflozin induced earlier weight loss, whereas dulaglutide showed more gradual weight reduction over time, accompanied by exploratory findings suggesting possible differences in plasma and microbiome-related metabolic signatures.