Modified release terbutaline (SKP1052) for hypoglycaemia prevention: a proof-of-concept study in people with type 1 diabetes mellitus

摘要

Aims: In this randomized, single blind, cross-over study 2.5 mg and 5mg of the modified-release terbutaline formulation (SKP-1052) werecompared with conventional immediate-release terbutaline (IRT, 5 mg) and placebo on overnight blood glucose (BG) and hypoglycaemia in 30subjects with type 1 diabetes mellitus.Methods: Subjects received subcutaneous injections of insulin glargine (individualized doses) before dinner. SKP-1052, IRT or placebo wasadministered around 21:00 hours. BG and terbutaline concentrations were monitored overnight for 10 h post-dosing. Endpoints comprisedof the nadir BG (BGn o-10h/ primary endpoint), mean overnight BG (BG_(mean)), morning BG (BGmOrning) and hypoglycaemia rates as well aspharmacokinetic (PK) endpoints.Results: SKP-1052 delayed release of terbutaline by 2 h [PK-t_(max) (mean +- SD) 5.0 +- 2.1 h (2.5 mg) and 4.7 +- 1.7 h (5 mg) vs. 2.6 +- 1.3 h withIRT, p < 0.01, respectively]. Compared with placebo, no significant differences were observed for BGn O-ioh across treatments, but both 5mgformulations showed less hypoglycaemic events [10 (IRT), 16 (SKP-1052) vs. 33], higher BG_(mean) (120, 114 and 95mg/dl) and BG_(morning) (126,126 and 101 mg/dl, all comparisons p<0.05 vs. placebo). Numerically higher BG-levels between 3 and 8h post-dosing were observed with2.5 mg SKP-1052 vs. placebo.Conclusions: Compared with IRT SKP-1052 delays release of terbutaline. 2.5 mg SKP-1052 led to numerically higher BG 3 to 8 h post-dosewithout fasting hyperglycaemia while 5mg SKP-1052 resulted in fasting hyperglycaemia vs. placebo. Future studies will investigate optimizeddoses of SKP-1052 for nocturnal hypoglycaemia prevention.