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Model-Based Meta-Analysis of HbA1c, Weight, and FPG in Type 2 Diabetes: Focus on SGLT2 inhibitors William S. Denney and Gianluca Nucci Pfizer Global R&D, Groton/New London Laboratories, Pfizer Inc, Groton, CT 06340. OBJE CTIVES
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Model-Based Meta-Analysis of HbA1c, Weight, and FPG in Type 2 Diabetes: Focus on SGLT2 inhibitors William S. Denney and Gianluca Nucci Pfizer Global R&D, Groton/New London Laboratories, Pfizer Inc, Groton, CT 06340 OBJE CTIVES Multiple selective inhibitors of the sodium-glucose co-transporter 2 (SGLT2) are currently in development for the treatment of type-2 diabetes mellitus (T2DM), among which dapagliflozin (dapa), canagliflozin (cana), ASP-1941 (ASP), and BI-10773 (BI) are the most advanced. Inhibition of SGLT2 induces urinary glucose excretion (UGE) and thereby reduces plasma glucose concentrations resulting in lowering HbA1c as well as fasting plasma glucose (FPG). UGE results also in loss of calories and fluids leading to weight loss (WT) and favorable blood pressure (BP) lowering. Integrating existing summary level meta-data from competitor drugs sharing the same class is crucial to quantitatively understand the mechanism of action and to simulate the probability of achieving acceptable efficacy targets against the expected competitors’ effects. The objective of this meta-analysis was to describe the dose response relationship for the above mentioned compounds on the major metabolic endpoints and leverage this knowledge to assess comparative effectiveness within the class. MODEL EQUATIONS HbA1c MODEL RESULTS WITH VPC Circle diameter is proportional to N. The blue shaded region is the 90% CI of the mean. WEIGHT MODEL RESULTS WITH VPC Circle diameter is proportional to N. The blue shaded region is the 90% CI of the mean. BI N=326 BI N=326 • ΔHbA1cij, ΔWTij, and ΔFPGij are the change from baseline for the jth treatment arm in the ith trial at the trial endpoint week (only 12 and 24 weeks included). • Dose is the total daily dose (i.e. 100 mg BID treated as 200 mg daily) • ED50 is the dose to achieve 50% of Emax • E0i is the placebo response in the ith trial • For HbA1c, E0 is the placebo effect at week 12. • Emax is the maximal drug effect, reflecting the maximal difference in response between placebo and active treatment • Emax was fit separately for 12 and 24 weeks for weight and indicated ~0.4 kg additional weight loss at week 24. • For all model fitting: • ij is the residual variability with variance 2/Nij. Where Nij is the arm sample size • 95% confidence intervals for the estimated mean dose response are obtained by drawing from the estimated parameters and their estimated variance-covariance matrix assuming asymptotic normality; • Model development and identification used the nlme library in R 2.11.1. cana N=369 cana N=369 METHODS A model based meta-analysis (MBMA) was conducted using data from the above compounds. Data was included in the analyses for placebo-controlled studies with information gathered from Trial Trove, literature sources, ADA, and EASD presentations with a final database update on 12/31/2010. HbA1c, weight, and FPG data were included for trials with results ≥ 12 (HbA1c and WT), and ≥ 4 wk (FPG). Only studies with T2DM patients were included in the analysis (specifically healthy volunteer and obesity studies were excluded). Data from non selective inhibitors were excluded because of the different mechanism of action. (SGLT-1 and -2 inhibition). Models were selected using ANOVA and diagnostic plots. dapa N=2785 dapa N=2785 RESULTS Emax models were developed for the dose/response relationship between HbA1c, weight, and FPG and are reported in the table below. DISCUSSION ASP was not included in the HbA1c or FPG models due to a very high negative placebo effect (worsening not uncharacteristic in the Japanese population but not viewed as homogenous to the other studies). Due to differences in study design (washout, background, stage of disease), the placebo response was estimated as a fixed effect for each study in all models. Emax was estimated to be common to the SGLT2i class for all metabolic parameters. As expected, ED50 was found different across different compounds and more interestingly generally not shared between different endpoints. Baseline FPG was included as covariates of drug effect. Baseline A1c and BW were tested (as deemed physiologic) but not included due to … Dose response models were also attempted for systolic and diastolic BP, but goodness of fit plots and parameter estimation uncertainty were not deemed satisfactory. PARAMETER CFB To the left and below is the raw study results in change from baseline (CFB) for the different compounds and endpoints. Colors within a compound plot indicate different studies. MODEL PARAMETERS CONCLUSIONS Model based meta-analysis permitted a quantitative assessment of the efficacy of the most advanced SGLT2i in development for T2DM. A mechanism-related dose/response Emax relationship between HbA1c, weight, and FPG was established. The maximum effect for HbA1c, WT, and FPG was shared for the mechanism. These models can be used to aid the development of novel SGLT2i allowing for informed Emax priors. In addition permit to put the results of early efficacy studies and biomarkers in context of historical data and later markers of efficacy. Moreover enable the use of comparative effectiveness simulations for the selection of development doses and assessment of the probability of successful development. In conclusion Model Based Meta Analysis allows an effective use of all the available information, contributing to improved design and evaluation of new clinical trials. • STUDIES INCLUDED/EXCLUDED • Endpoints of interest were HbA1c, FPG, Weight, and blood pressure (SBP and DBP). • Information was retrieved from a Trial Trove search, literature sources, ADA, and EASD presentations. • Only studies in T2DM patients were included (obesity studies excluded). • Final database update was on 31 Dec 2010 • HbA1c data was included for trials ≥ 12 wk • Weight data was included for trials ≥ 12 wk • Only placebo-controlled studies/arms were included and positive control arms were excluded. • These criteria excluded 11 studies (2 BI, 5 cana, 2 dapa) and additionally 4 arms Studies Included Note that the fractional individual in the BI study is due to the fact that only total study size was given and N was assumed equally balanced across all study arms. • REFERENCES • Bailey CJ, Gross JL, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Jun 26;375(9733):2223-33. • Ferrannini E, Ramos SJ, et al. Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and Exercise A randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010 Oct;33(10):2217-24. • Ferrannini E, Seman LJ, et al. The potent and highly selective sodium-glucose co-cransporter (SGLT-2) inhibitor BI 10773 is safe and efficacious as monotherapy in patients with type 2 diabetes mellitus. EASD 2010 presentation 877. • List JF, Woo V, et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009 Apr;32(4):650-7. • Rosenstock J, Arbit D, et al. Canagliflozin, an Inhibitor of Sodium Glucose Co-Transporter 2 (SGLT2), Improves Glycemic Control and Lowers Body Weight in Subjects with Type 2 Diabetes (T2D) on Metformin. ADA 2010 abstract 77-OR. • Rosenstock J, Polidori D, et al. Canagliflozin, an inhibitor of sodium glucose co-transporter 2, improves glycaemic control, lowers body weight, and improves beta cell function in subjects with type 2 diabetes on background metformin. EASD 2010 presentation 873. • Strojek K, Hruba V, et al. Efficacy and safety of dapagliflozin in patients with type 2 diabetes mellitus and inadequate glycaemic control on glimepiride monotherapy. EASD 2010 presenation 870. • Wilding JP, Norwood P, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care. 2009 Sep;32(9):1656-62. • Wilding JP, Woo V, et al. Dapagliflozin in Patients with Type 2 Diabetes Poorly Controlled on Insulin Therapy-Efficacy of a Novel Insulin-Independent Treatment. ADA 2010 abstract 78-OR.