Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial

Abstract

Aims/hypothesisTraditional blood glucose lowering agents do not prevent the progressive loss of beta cell function in patients with type 2 diabetes. The dipeptidylpeptidase (DPP)-4 inhibitor vildagliptin improves beta cell function both acutely and chronically (up to 2 years). Whether this effect persists after cessation of treatment remains unknown. Here, we assessed the insulin secretory capacity in drug-naive patients with type 2 diabetes after a 52 week treatment period with vildagliptin or placebo, and again after a 12 week washout period.MethodsThis study was conducted at a single university medical centre, and was a double-blind, randomised clinical trial in 59 drug-naive patients with type 2 diabetes and mild hyperglycaemia to either vildagliptin 100 mg (n = 29) or placebo (n = 30). Randomisation was performed by a validated 1:1 system. Neither patient, nor caregiver, was informed about the assigned treatment. Inclusion criteria were drug-naive patients ≥30 years, with HbA1c ≤7.5% and BMI of 22–45 kg/m2. The mildly hyperglycaemic patient population was chosen to minimise glucose toxicity as a confounding variable. Beta-cell function was measured during an arginine-stimulated hyperglycaemic clamp at week 0, week 52 and after a 12 week washout period. All patients with at least one post-randomisation measure were analysed (intent-to-treat).ResultsFifty-two week vildagliptin 100 mg (n = 26) treatment increased the primary efficacy variable, combined hyperglycaemia and arginine-stimulated C-peptide secretion (AIRarg), by 5.0 ± 1.8 nmol/l × min, while it decreased by 0.8 ± 1.8 nmol/l × min with placebo (n = 25) (between-group difference p = 0.030). No significant between-group difference in AIRarg was seen after the 12 week washout period. The between-group difference adjusted mean 52 week changes from baseline was −0.19 ± 0.11, p = 0.098 and −0.22 ± 0.23%, p = 0.343 for HbA1c and fasting plasma glucose, respectively. There were no suspected drug treatment-related serious adverse events.Conclusions/interpretationOne year treatment with vildagliptin significantly increased beta cell secretory capacity. This effect was not maintained after the washout, indicating that this increased capacity was not a disease modifying effect on beta cell mass and/or function.Trial registration:ClinicalTrials.gov NCT00260156Funding:This study was sponsored by the Novartis Pharmaceutical Cooperation.

Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism

“…Support comes from human data on the capacity of beta cells to stimulate insulin secretion as studied after combined glucose and arginine-stimulated C-peptide secretion rate. Thus, whereas there indeed was an increase in the capacity for insulin secretion after 3 or 12 months of treatment with vildagliptin [5,32] or sitagliptin [34] as long as treatment was ongoing, such an effect was not maintained after a 3 month washout period. Similarly, a pilot study failed to show any evidence that sitagliptin preserved beta cell function after intensive insulin therapy [51].…”

“…Sitagliptin and vildagliptin also increased glucose utilisation in clamps where glucose utilisation in muscle was predicted to be the rate-limiting step [46, [98][99][100]. In contrast, vildagliptin did not increase glucose utilisation in two other clamp studies where glucose utilisation in muscle was predicted to be the rate-limiting step [5,75]. Participants in both of these studies had lower baseline FPG values than the participants in any of the other studies, suggesting that the degree of glucotoxicity is a confounding variable in the response to a DPP-4 inhibitor [75].…”

“…The inadequate insulin secretion is caused by reduced sensitivity of the beta cells to glucose and a progressive decrease in insulin secretion capacity [2][3][4][5]; the augmented glucagon secretion is caused by its impaired suppression by glucose [6]. The reduced sensitivity of beta cells to glucose appears mainly to manifest itself in susceptible individuals with an inherently lower capacity for insulin secretion subsequent to increased demand for insulin because of greater triacylglycerol storage in non-fat tissues, termed lipotoxicity [4].…”

Persons with latent autoimmune diabetes in adults express higher dipeptidyl peptidase-4 activity compared to persons with type 2 and type 1 diabetes

“…Existing studies indicate that DPP-4 inhibitors have the potential to protect β-cell function [11,12] in persons with T2DM as well as in a mouse model of AI diabetes [15] which indicates the possible role of DPP-4 activity in the disease pathogenesis . Our present results are consistent with that hypothesis especially because LADA might represent the combination of underlying risk factors of both types of diabetes.…”

“…Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a new class of oral antidiabetic agents that have shown the potential to preserve β-cell function in mouse models of type 2 diabetes [9,10], in persons with T2DM [11], and even in persons with impaired fasting glucose tolerance [12]. DPP-4 inhibition reduces insulitis as well, and stimulates β -cell function in a non-obese diabetic mouse model of AI diabetes, a classic model of T1DM [13,14].…”