ObjectiveWe aimed to investigate the effect of Cyclocarya paliurus leaves extracts (CP) on glucose and blood lipid metabolism and its relationship with intestinal flora in type 2 diabetes mellitus (T2DM) patients.MethodsIn this open-label, 84-day randomized controlled trial, a total of 38 T2DM patients were randomly assigned to the CP group or the Glipizide group (G group) in a 2:1 ratio. T2DM-associated metabolic phenotypes, gut microbiota and metabolites including short-chain fatty acids (SCFAs) and bile acids (BAs) were detected.ResultsAt the end of intervention, CP, like Glipizide, significantly improved HbA1c level and other glucose metabolism parameters (fasting plasma glucose (FBG), 2-hour post-meal blood glucose (2hPBG), the area under curve of oral glucose tolerance test glucose (OGTT glucose AUC)). Moreover, CP also resulted in the significant improvement in the levels of blood lipid and blood pressure. Notably, the improvement in blood lipid(triglycerides (TG) and high-density lipoprotein cholesterol (HDL-c)) and blood pressure (diastolic blood pressure (DBP)) was significantly greater in the CP group compared with the G group. Furthermore, the liver and kidney function parameters did not significantly change in both CP group and the G group over the 84-day period. Additionally, the enrichment of potentially beneficial bacteria (Faecalibacterium and Akkermansia), SCFAs and unconjugated BAs and the depletion of potential pathogenic bacteria (Prevotella_9) and conjugated BAs were observed in the CP group, while the abundances of the gut microbial were kept stable in the G group after intervention.ConclusionCP displays a more beneficial effect in the alleviation of T2DM-associated metabolic phenotypes than glipizide by regulating gut microbiota and metabolites in T2DM patients, with no significant effects on liver and kidney function.