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

Diabetes Obes Metab. 2012 Dec;14(12):1137-44. doi: 10.1111/dom.12003. Epub 2012 Sep 25.

Abstract

Aims: In this randomized, single blind, cross-over study 2.5 mg and 5 mg of the modified-release terbutaline formulation (SKP-1052) were compared with conventional immediate-release terbutaline (IRT, 5 mg) and placebo on overnight blood glucose (BG) and hypoglycaemia in 30 subjects with type 1 diabetes mellitus.

Methods: Subjects received subcutaneous injections of insulin glargine (individualized doses) before dinner. SKP-1052, IRT or placebo was administered around 21:00 hours. BG and terbutaline concentrations were monitored overnight for 10 h post-dosing. Endpoints comprised of the nadir BG (BGn 0-10 h, primary endpoint), mean overnight BG (BGmean), morning BG (BGmorning) and hypoglycaemia rates as well as pharmacokinetic (PK) endpoints.

Results: SKP-1052 delayed release of terbutaline by 2 h [PK-tmax (mean ± SD) 5.0 ± 2.1 h (2.5 mg) and 4.7 ± 1.7 h (5 mg) vs. 2.6 ± 1.3 h with IRT, p < 0.01, respectively]. Compared with placebo, no significant differences were observed for BGn 0-10 h across treatments, but both 5 mg formulations showed less hypoglycaemic events [10 (IRT), 16 (SKP-1052) vs. 33], higher BGmean (120, 114 and 95 mg/dl) and BGmorning (126, 126 and 101 mg/dl, all comparisons p < 0.05 vs. placebo). Numerically higher BG-levels between 3 and 8 h post-dosing were observed with 2.5 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-dose without fasting hyperglycaemia while 5 mg SKP-1052 resulted in fasting hyperglycaemia vs. placebo. Future studies will investigate optimized doses of SKP-1052 for nocturnal hypoglycaemia prevention.

Keywords: adverse drug reactions; diabetes complications; experimental pharmacology; glucose metabolism; insulin therapy; phase III study.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Blood Glucose / drug effects*
  • Cross-Over Studies
  • Delayed-Action Preparations
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Drug Administration Schedule
  • Fasting
  • Female
  • Humans
  • Hyperglycemia / prevention & control*
  • Hypoglycemia / chemically induced
  • Hypoglycemia / prevention & control*
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects*
  • Injections, Subcutaneous
  • Insulin / metabolism*
  • Insulin Glargine
  • Insulin, Long-Acting / administration & dosage
  • Insulin, Long-Acting / adverse effects
  • Male
  • Middle Aged
  • Single-Blind Method
  • Terbutaline / administration & dosage*
  • Terbutaline / pharmacokinetics

Substances

  • Blood Glucose
  • Delayed-Action Preparations
  • Hypoglycemic Agents
  • Insulin
  • Insulin, Long-Acting
  • Insulin Glargine
  • Terbutaline