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      A Model-Informed Drug Development (MIDD) Approach for a Low Dose of Empagliflozin in Patients with Type 1 Diabetes

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          Abstract

          In clinical trials, sodium-glucose co-transporter (SGLT) inhibitor use as adjunct to insulin therapy in type 1 diabetes (T1D) provides glucometabolic benefits while diabetic ketoacidosis risk is increased. The SGLT2 inhibitor empagliflozin was evaluated in two phase III trials: EASE-2 and EASE-3. A low, 2.5-mg dose was included in EASE-3 only. As the efficacy of higher empagliflozin doses (i.e., 10 and 25 mg) in T1D has been established in EASE-2 and EASE-3, a modeling and simulation approach was used to generate additional supportive evidence on efficacy for the 2.5-mg dose. We present the methodology behind the development and validation of two modeling and simulation frameworks: M-EASE-1, a semi-mechanistic model integrating information on insulin, glucose, and glycated hemoglobin; and M-EASE-2, a descriptive model informed by prior information. Both models were developed independently of data from EASE-3. Simulations based on these models assessed efficacy in untested clinical trial scenarios. In this manner, the models provide supportive evidence for efficacy of low-dose empagliflozin 2.5 mg in patients with T1D, illustrating how pharmacometric analyses can support efficacy assessments in the context of limited data.

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          Most cited references 26

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          Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial

          Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes.
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            Efficacy and Safety of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes.

            This study assessed the efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in adults with type 1 diabetes.
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              Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes

              OBJECTIVE To assess the safety and efficacy of dual sodium–glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, insulin dose, glycemic control, and other metabolic parameters over 29 days of treatment. RESULTS In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus insulin dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by continuous glucose monitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that showed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage of time in target glucose range 70–180 mg/dL (3.9–10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group. CONCLUSIONS As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with sotagliflozin improved glycemic control and the CGM profile with bolus insulin dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                02 April 2021
                April 2021
                : 13
                : 4
                Affiliations
                [1 ]Metrum Research Group, Tariffville, CT 06081, USA; curtisj@ 123456metrumrg.com (C.K.J.); renae@ 123456metrumrg.com (R.J.E.-B.); ahmede@ 123456metrumrg.com (A.E.); mattr@ 123456metrumrg.com (M.M.R.)
                [2 ]Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany; valerie.nock@ 123456boehringer-ingelheim.com
                [3 ]Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877, USA; jan.marquard@ 123456boehringer-ingelheim.com (J.M.); nima.soleymanlou@ 123456boehringer-ingelheim.com (N.S.)
                Author notes
                Article
                pharmaceutics-13-00485
                10.3390/pharmaceutics13040485
                8066500
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

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