A model-based meta analysis study of sodium glucose co-transporter-2 inhibitors

Type 2 diabetes mellitus (T2DM) agent sodium-glucose co-transporter 2 (SGLT2) inhibitors show special benefits in reducing body weight and heart failure risks. To accelerate clinical development for novel SGLT2 inhibitors, a quantitative relationship among pharmacokinetics, pharmacodynamics, and disease end points (PK/PD/end points) in healthy subjects and patients with T2DM was developed. PK/PD/end point data in published clinical studies for three globally marketed SGLT2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) were collected according to pre-set criteria. Overall, 80 papers with 880 PK, 27 PD, 848 fasting plasma glucose (FPG), and 1219 hemoglobin A1c (HbA1c) data were collected. A two-compartmental model with Hill's equation was utilized to capture PK/PD profiles. A novel translational biomarker, the change of urine glucose excretion (UGE) from baseline normalized by FPG (delta UGE(c)) was identified to bridge healthy subjects and patients with T2DM with different disease statuses. delta UGE(c) was found to have a similar maximum increase with different half-maximal effective concentration values of 56.6, 2310, and 841 mg/mL center dot h for dapagliflozin, canagliflozin, and empagliflozin respectively. delta UGE(c) will change FPG based on linear function. HbA1c profiles were captured by indirect response model. Additional placebo effect was also considered for both end points. The PK/delta UGE(c)/FPG/HbA1c relationship was validated internally using diagnostic plots and visual assessment and further validated externally using the fourth globally approved same-in-class drug (ertugliflozin). This validated quantitative PK/PD/end point relationship offers novel insight into long-term efficacy prediction for SGLT2 inhibitors. The novelty identified delta UGE(c) could make the comparison of different SGLT2 inhibitors' efficacy characteristics easier, and achieve early prediction from healthy subjects to patients.

Automated summary

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as dapagliflozin, canagliflozin, and empagliflozin, show special benefits in reducing weight and heart failure risks for patients with type 2 diabetes mellitus (T2DM). A quantitative relationship between pharmacokinetics, pharmacodynamics, and disease end points (PK/PD/end points) was developed using data from clinical studies. A novel biomarker, the change of urine glucose excretion (UGE) from baseline normalized by fasting plasma glucose (delta UGE(c)), was identified to bridge healthy subjects and T2DM patients. This relationship offers insight into long-term efficacy prediction for SGLT2 inhibitors.