Effects of DPP‐4 inhibitor linagliptin and GLP‐1 receptor agonist liraglutide on physiological response to hypoglycaemia in Japanese subjects with type 2 diabetes: A randomized, open‐label, 2‐arm parallel comparative, exploratory trial

Abstract

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors reduce the risk of hypoglycaemia, possibly through augmentation of glucose‐dependent insulinotropic polypeptide (GIP) action, but not that of glucagon‐like peptide‐1 (GLP‐1) on glucagon secretion. To examine this model in Japanese individuals with type 2 diabetes (T2D), the effects of the DPP‐4 inhibitor linagliptin on glucagon and other counter‐regulatory hormone responses to hypoglycaemia were evaluated and compared with those of the GLP‐1 receptor agonist liraglutide in a multi‐centre, randomized, open‐label, 2‐arm parallel comparative, exploratory trial. Three‐step hypoglycaemic clamp glucose tests preceded by meal tolerance tests were performed before and after 2‐week treatment with the drugs. Glucagon levels were increased during the hypoglycaemic clamp test at 2.5 mmol/L. This increase was similar in the linagliptin and liraglutide groups, both before and after the 2‐week treatment. Changes in other counter‐regulatory hormones (ie, growth hormone, cortisol, epinephrine and norepinephrine) were also similar between the groups, but were suppressed substantially after 2‐week treatment compared to baseline. In conclusion, we confirmed that the glucagon response to hypoglycaemia was not affected by linagliptin or liraglutide treatment in Japanese individuals with T2D.

Effects on the glucagon response to hypoglycaemia during DPP‐4 inhibition in elderly subjects with type 2 diabetes: A randomized, placebo‐controlled study

“…Overall, the study suggests a lower counter‐regulatory response to mild hypoglycaemia during DPP‐4 inhibition, whereas the responses, when reducing glucose, to more severe hypoglycaemia are maintained. Previous studies have shown non‐suppressed responses during vildagliptin treatment at a 2.5 mmol/L glucose level, whereas a recent study in type 2 diabetes showed significantly suppressed cortisol, adrenaline and noradrenaline responses to hypoglycaemia at 2.5 mmol/L after treatment with the DPP‐4 inhibitor linagliptin, which is similar to our current finding of suppressed adrenaline and cortisol responses during sitagliptin treatment at a 3.5 mmol/L glucose level. These findings need to be explored in further studies.…”

“…We have demonstrated previously that the glucagon response to hypoglycaemia is maintained during treatment with the DPP‐4 inhibitor vildagliptin in type 2 diabetes, both in monotherapy and in combination with insulin, with results similar to those obtained with linagliptin in Japanese individuals with type 2 diabetes . These studies, however, did not examine elderly subjects.…”

“…This study showed that the glucagon response to hypoglycaemia (3.1 mmol/L) is not adversely affected during treatment with sitagliptin, as compared to placebo, in elderly patients (65‐86 years) with metformin‐treated type 2 diabetes. Previous reports have demonstrated maintenance of the glucagon response to hypoglycaemia by the DPP‐4 inhibitor linagliptin in metformin‐treated patients and by vildagliptin in drug‐naïve patients and insulin‐treated patients with type 2 diabetes . These earlier studies, however, were carried out in younger individuals.…”

Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes patients: The association between remaining β‐cell function and the achievement of the glycated hemoglobin target 1 year after initiation

“…Liraglutide exerts glucose‐lowering effects by enhancing basal and postprandial insulin secretion from pancreatic β‐cells. Therefore, it is conceivable that remaining β‐cell function is one of the critical determinants in the glucose‐lowering effects of liraglutide.…”

Effect of once‐weekly semaglutide on the counterregulatory response to hypoglycaemia in people with type 2 diabetes: A randomized, placebo‐controlled, double‐blind, crossover trial

“…In phase III trials, semaglutide led to improved glycaemic control and decreased body weight, with a safety profile similar to other GLP‐1 receptor agonists (GLP‐1RAs) . Liraglutide, having a similar structure to semaglutide but a different pharmacokinetic profile, was found to have no effect on the counterregulatory responses to hypoglycaemia . These responses have not been evaluated in people treated with semaglutide.…”