Metabolic Signatures of Antidiabetic Drug Combinations: Dissecting Additive and Interaction Effects in a Real-World Cohort

Abstract

Although combination therapy is widely used for for type 2 diabetes (T2D), few studies have identified them at the metabolite level in real clinical settings. Using targeted metabolomics based on liquid chromatography-tandem mass spectrometry, this study attempted to precisely identify the metabolic patterns and interactions induced by the single and combination therapy of major 6 oral hypoglycemic agents. In a cohort of patients with T2D, we stratified them into drug-naive controls, monotherapy groups, and two combination therapy groups based on their 6 month prescription history. Using age and sex adjusted linear regression and interaction models, we evaluated the effectiveness and statistical significance of each drug on more than 300 core metabolites related to T2D. Each monotherapy showed its own metabolic signature. In particular, distinct differences were observed in the interaction analysis of the combination therapy. The addition of a DPP-4 inhibitor to metformin exhibited signigicant alterations related to uremic toxins. In contrast, the addition of a SGLT2 inhibitor antagonized metformin’s effects on key amino acid metabolic pathways. This approach demonstrated that the metabolic effects of antidiabetic drug combinations are not just a sum of individual durg actions, guiding personalized treatment strategies in T2D.