Model-based Meta-analysis of the Effect on Body Weight of PF-04971729, a Sodium Glucose Co-transporter-2 Inhibitor (SGLT2i), in Comparison to Other SGLT2i and Anti-diabetic Agents (ADA)

Author(s): Jaap Mandema, Kevin Sweeney, Steven Terra, Vaishali Sahasrabudhe

PF-04971729 is a potent, selective SGLT2i in development for treatment of type 2 diabetes mellitus (T2DM). Since there is growing recognition of the need for comparative effectiveness of various ADA, a model was developed to quantify the time course of dose vs body weight change for PF-04971729 relative to other ADA including SGLT2i, DPP4 inhibitors (DPP4i), GLP-1 agonists (GLP1), sulfonylureas (SU), thiazolidinediones (TZD), and metformin. A systematic literature review yielded 120 randomized controlled trials representing >52000 T2DM patients and 21 drugs. Data for PF-04971729 were obtained from a 12-week, randomized, placebo-controlled study in T2DM patients on metformin background. A dose response was observed for weight effect of SGLT2i, TZD, DPP4i and GLP-1 whereas a dose-independent treatment effect was estimated for metformin and SU. The treatment effect was significantly dependent on baseline weight. The model predicted a statistically significant weight loss for SGLT2i (1.5 to 2 kg), GLP1 (0.7 to 1.5 kg) and metformin (0.4 kg), and a statistically significant weight gain for DPP4i (0.5 to 1.1 kg), TZD (3.1 to 3.3 kg) and SU (2.8 to 4.3 kg) at 24 weeks. Figure 2 illustrates model-estimated and observed dose response for various SGLT2i. Estimated differences in weight loss between PF-04971729-25 mg and top doses of other SGLT2i were small (-0.20 to -0.34 kg). This analysis offers a quantitative framework to leverage external data and thus enables an indirect comparison of novel drugs with existing treatments.