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.
Highlights
Type 1 diabetes (T1D) is an autoimmune disorder causing serious metabolic dysregulation characterized by insulin deficiency and substantial reduction in life expectancy [1,2].Inhibitors of sodium-glucose co-transporters 1 (SGLT1) and 2 (SGLT2) have been shown to improve glycemic control and result in weight loss in patients with T1D [3,4,5,6,7]
Empagliflozin is a highly selective SGLT2 inhibitor that has been approved for use in adults with type 2 diabetes (T2D)
Was evaluated in the Empagliflozin as Adjunctive to Insulin Therapy (EASE) clinical program, which included two international, multicenter, phase III, randomized, doubleblind, placebo-controlled, parallel-group sister trials of once-daily oral empagliflozin doses conducted over 52 weeks (EASE-2) and 26 weeks (EASE-3) [8,9,10]
Summary
Inhibitors of sodium-glucose co-transporters 1 (SGLT1) and 2 (SGLT2) have been shown to improve glycemic control and result in weight loss in patients with T1D [3,4,5,6,7]. These agents have been shown to improve glucometabolic outcomes in the context of clinical trials, their use is associated with an increased risk of diabetic ketoacidosis [6,7,8]. In phase III trials, empagliflozin significantly improved glycemic control and resulted in significant reductions in weight, daily insulin dose, and blood pressure; severe hypoglycemic episodes
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