A Phase III, Randomized, Double-Blind Clinical Trial of a Novel Triple Fixed-Dose Combination (Glimepiride/Vildagliptin/Metformin) in Mexican Adults with Uncontrolled Type 2 Diabetes After Dual Oral Therapy Failure

Background/Objectives: Achieving glycaemic control remains challenging in patients with type 2 diabetes mellitus (T2DM). Fixed-dose combinations with complementary mechanisms may facilitate treatment intensification and improve adherence. This study evaluated the efficacy and safety of a dose-titrated fixed-dose combination (FDC) of glimepiride, vildagliptin, and metformin in this population. Methods: This phase III, randomized, double-blind, multicentre clinical trial enrolled adults with inadequate glycaemic control after dual oral therapy. Participants were randomly assigned to Sequence A (escalation to intermediate-dose FDC) or Sequence B (escalation to high-dose FDC), with all participants administered the low-dose FDC once daily. On days 45 and 90, participants meeting escalation criteria were up-titrated to their assigned target dose. The primary endpoint was HbA1c on day 180, expressed as the difference between sequences. Results: On day 180, mean HbA1c was 7.57% in Sequence A and 7.89% in Sequence B (p = 0.068). At the end of follow-up, 52.4% of participants achieved HbA1c <7.0%: 24.1% with the low-dose FDC, 12.0% after escalation to the intermediate-dose FDC, and 16.3% with the high-dose FDC. A total of 133 adverse events were reported in 62 participants: 54.9% were mild, and none were severe. Hypoglycaemia was the most frequent event (13.5%; n = 18 episodes). Conclusions: The FDC was associated with glycaemic improvements after dual-therapy failure and was well tolerated across all dose levels. These findings suggest that a response-guided triple oral FDC strategy represents a potentially effective and accessible intensification option for patients with T2DM who remain inadequately controlled on dual oral therapy. Trial Registration: ClinicalTrials.gov, NCT04841096.