Comparative In Vitro Antifungal Analysis Of Selected Oral Anti-Diabetic Drugs Against Candida Species Commonly Encountered In Clinical Practice

Abstract

Type 2 diabetes mellitus (T2DM) is associated with an increased susceptibility to opportunistic fungal infections, particularly those caused by Candida species. Recent pharmacological evidence suggests that certain oral antidiabetic drugs (OADs) may exhibit intrinsic antimicrobial activity beyond their glycemic control. This study aimed to evaluate and quantify the in vitro antifungal effects of five commonly prescribed OADs (metformin, pioglitazone, gliclazide, vildagliptin, and dapagliflozin) against two isolates of Candida albicans and Candida glabrata. Antifungal activity was initially assessed using a 96-well microdilution assay across clinically relevant concentrations (0.125–8.0 mg/L), with fungal growth quantified via relative optical density. Subsequently, a dynamic in vitro pharmacokinetic/pharmacodynamic model was employed to simulate human plasma clearance and drug exposure (fAUC_0-24). Key pharmacodynamic parameters, including half-maximal inhibitory concentration (IC₅₀), maximum effect (E_max), and Area Under the Curve (AUC), were estimated using a nonlinear sigmoidal E_max model. Metformin demonstrated the highest intrinsic antifungal efficacy, achieving E_max values of 72% for C. albicans (IC₅₀: 1.0 mg/L) and 68% for C. glabrata (IC₅₀: 2.0 mg/L). Pioglitazone and gliclazide exhibited moderate, clinically relevant fungistatic activity. Conversely, vildagliptin and dapagliflozin displayed the weakest effects, requiring high concentrations to achieve minimal inhibition. These findings highlight that specific OADs, particularly metformin and pioglitazone, possess intrinsic antifungal properties that may offer secondary clinical advantages in opportunistic fungal infections among immunocompromised patients with T2DM patients.