Abstract
Aims/hypothesisIn rodent models of diabetes, treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors improves beta cell function. This analysis assessed the effects of the SGLT2 inhibitor, canagliflozin, on model-based measures of beta cell function in patients with type 2 diabetes.MethodsData from three Phase 3 studies were analysed, in which: (Study 1) canagliflozin 100 and 300 mg were compared with placebo as monotherapy for 26 weeks; (Study 2) canagliflozin 100 and 300 mg were compared with placebo as add-on to metformin + sulfonylurea for 26 weeks; or (Study 3) canagliflozin 300 mg was compared with sitagliptin 100 mg as add-on to metformin + sulfonylurea for 52 weeks. In each study, a subset of patients was given mixed-meal tolerance tests at baseline and study endpoint, and model-based beta cell function parameters were calculated from plasma glucose and C-peptide.ResultsIn Studies 1 and 2, both canagliflozin doses increased beta cell glucose sensitivity compared with placebo. Placebo-subtracted least squares mean (LSM) (SEM) changes were 23 (9) and 18 (9) pmol min−1 m−2 (mmol/l)−1 with canagliflozin 100 and 300 mg, respectively (p < 0.002, Study 1), and 16 (8) and 10 (9) pmol min−1 m−2 (mmol/l)−1 (p < 0.02, Study 2). In Study 3, beta cell glucose sensitivity was minimally affected, but the insulin secretion rate at 9 mmol/l glucose increased to similar degrees from baseline with canagliflozin and sitagliptin [LSM (SEM) changes 38 (8) and 28 (9) pmol min−1 m−2, respectively; p < 0.05 for both].Conclusions/interpretationTreatment with canagliflozin for 6 to 12 months improved model-based measures of beta cell function in three separate Phase 3 studies. Trial registration: Clinicaltrials.gov NCT01081834 (Study 1); NCT01106625 (Study 2); NCT01137812 (Study 3)Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3196-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
MethodsDefects in beta cell function, including reduced insulin secretion and reduced efficiency of proinsulin conversion to insulin, are key pathophysiological factors underlying the hyperglycaemia of patients with type 2 diabetes mellitus [1, 2]
In Study 3, beta cell glucose sensitivity was minimally affected, but the insulin secretion rate at 9 mmol/l glucose increased to similar degrees from baseline with canagliflozin and sitagliptin [least squares mean (LSM) (SEM) changes 38 (8) and 28 (9) pmol min−1 m−2, respectively; p
Patient disposition and baseline characteristics Baseline demographic and disease characteristics for patients in the Measures of beta cell function and insulin sensitivity In Study 1, both doses of canagliflozin led to an upward shift in the relationship between insulin secretion rate (ISR) and plasma glucose, as well as an increased slope (Fig. 2j–l), whereas a slight downward shift was observed with placebo
Summary
MethodsDefects in beta cell function, including reduced insulin secretion and reduced efficiency of proinsulin conversion to insulin, are key pathophysiological factors underlying the hyperglycaemia of patients with type 2 diabetes mellitus [1, 2]. Declining beta cell function is a major contributing factor to the progressive nature of type 2 diabetes, with many patients eventually requiring insulin therapy to achieve and maintain glycaemic control [3, 4]. Glucose-lowering agents, which in addition to lowering plasma glucose levels, can improve beta cell function or slow the progression of beta cell dysfunction, may be useful for the long-term management of type 2 diabetes [1]. Studies in animals have shown that beta cell function is restored when normoglycaemia is achieved by treatment with SGLT2 inhibitors [7–10]. The improvements in beta cell function observed in animal models are believed to be secondary to the improved glucose control, rather than due to direct effects of SGLT2 inhibitors on beta cells
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