Glucagon Counter-Regulation to Hypoglycemia During Incretin-Based Therapy

Abstract: AbstractIncretin-based therapy is associated with low risk of hypoglycemia in type 2 diabetes mellitus (T2DM) possibly due to its glucose-dependency in stimulating insulin secretion and a sustained glucagon response during hypoglycemia. This is of special relevance when it is combined with insulin or given to elderly patients since both insulin therapy and high age are associated with impaired glucagon counter-regulation. Incretin-based therapy may also be used as add-on to insulin therapy in type 1 diabetes mellitus (T1DM), where there is also an impaired glucagon counter-regulation. The studies in this thesis evaluated the glucagon and the other hormonal counter-regulations to insulin induced hypoglycemia during incretin therapy in four different patient populations. These populations were all particularly vulnerable patients with increased risk for hypoglycemia: T1DM, insulin-treated T2DM and elderly subjects with T2DM. Both dipeptidyl peptidase-4 (DPP-4) inhibition and glucagon-like peptide-1 receptor agonism (GLP-1 RA) were examined. In all, the four studies examined vildagliptin (DPP-4 inhibition) + insulin in T1DM (study 1), vildagliptin + insulin (±oral medication) in T2DM (study 2), lixisenatide (GLP-1 RA) + basal insulin + metformin in T2DM (study 3) and sitagliptin (DPP-4 inhibition) + metformin in elderly subjects with T2DM (study 4). All studies were single-center, double-blind, randomized, placebo (PBO)-controlled crossover studies involving 18-29 subjects. Mean age was 30 (T1DM), 55, 59, and 74 (T2DM) years, respectively, in the four studies, and diabetes duration 9-14 years, mean baseline hemoglobin A1c (HbA1c) 52-61 mmol/mol and mean body mass index (BMI) 25-33 kg/m2. Subjects received the active study medication or PBO as add-on therapy for 4 weeks (6 weeks in study 3) in random order with a four-week washout in-between. After each treatment period, the subjects underwent a hyperinsulinemic hypoglycemic clamp with glucose at 2.5 mmol/l (study 1), 2.6 mmol/l (study 2), 3.5 and 2.8 mmol/l (study 3) and 3.5 and 3.1 mmol/l (study 4); clamped glucose levels were preserved for 30 min during which the samples for counter-regulatory hormones including glucagon were collected for analysis.Results showed that at 3.1 mmol/l and below, the glucagon and the other hormonal responses were similar during incretin therapy as during PBO, whereas at 3.5 mmol/l (study 3 and 4), the glucagon and some of the other hormonal responses were lower during incretin therapy than during PBO.We conclude that the glucagon and the other hormonal counter-regulatory responses to hypoglycemia are preserved when incretin therapy is used in these particularly vulnerable patients. Furthermore, the results suggest that at glucose levels between 3.5 and 3.1 mmol/l inhibition of glucagon secretion vanishes during incretin therapy in these patient groups. It is suggested that this is a mechanism behind the low risk of hypoglycemia associated with incretin therapy.