On the clinical pharmacokinetics and pharmacodynamics and drug level informed optimization of SGLT2 inhibitors in patients with Type 2 Diabetes Mellitus
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as cornerstone therapies for Type 2 Diabetes Mellitus (T2DM). They provide therapeutic benefits beyond glycemic control, including cardiovascular and renal protection, body weight reduction, and blood pressure regulation. Despite this, the clinical adoption of this class remains suboptimal, partly due to variability in patient responses. Substantial variability in pharmacokinetics (PK) and pharmacodynamics (PD) challenges efficacy and safety of current dose regimens and minimizing this variability through therapeutic drug monitoring (TDM) might improve clinical outcome. We reviewed the literature to describe the existing data on the PK and PD of the SGLT2 inhibitors and explore the potential for individualizing therapy by integrating PK/PD models with patient-specific covariates, drug concentrations, and pharmacodynamic endpoints. This review highlights the PK/PD characteristics of several SGLT2 inhibitors, emphasizing exposure-response relationships, the role of drug-metabolizing enzymes, variabilities in urinary glucose excretion (UGE) and plasma glucose, and the impact of renal and hepatic impairment. Our review evaluates whether the current literature provides sufficient data on systemic exposure, exposure-response relationships, and patient variability to start developing strategies for trough level-based TDM and drug- and biomarker-supported model informed precision dosing (MIPD) of SGLT2 inhibitors.…
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