original article
original article
Diabetes, Obesity and Metabolism 16: 812–818, 2014. © 2014 John Wiley & Sons Ltd
Glucagon dynamics during hypoglycaemia and food-re-challenge following treatment with vildagliptin in insulin-treated patients with type 2 diabetes ´ 1 J. Farngren1 , M. Persson2 , A. Schweizer3 , J. E. Foley4 & B. Ahren 1 Department of Clinical Sciences Lund, Lund University, Lund, Sweden 2 Department of Clinical Sciences Malmo, ¨ Lund University, Lund, Sweden 3 Novartis Pharma AG, Basel, Switzerland 4 Novartis Pharmaceuticals, East Hanover, NJ, USA
Aims: To determine the effects of dipeptidyl peptidase-4 (DPP-4) inhibition on glucagon dynamics in patients with insulin-treated type 2 diabetes (T2D).
Methods: The study was a single-centre, double-blind, randomized, placebo controlled crossover study in patients with T2D, mean age 59 ± 6 (s.d.) years and mean haemoglobin A1c 7.7 ± 0.8%, treated with exogenous insulin with or without oral antihyperglycaemic agents. Patients received vildagliptin (50 mg BID) or placebo as add-on to insulin for 4 weeks in random order with a 4-week washout in-between. On day 28 of the respective treatment, patients were served a standard meal (500 kcal) followed by a hyperinsulinaemic hypoglycaemic clamp (target 2.5 mmol/l) and a subsequent food re-challenge (700 kcal). The completers population (n = 29) was analysed. Results: Glucose levels were lower with vildagliptin than with placebo during the meal [areas under the curve (AUC) 1.23 ± 0.07 vs. 1.46 ± 0.05 mol/l min, P < 0.001] and similar between the groups during the clamp. During the meal, glucagon levels were lower with vildagliptin (AUC 1.98 ± 0.15 vs. 2.15 ± 0.17 nmol/l min, P = 0.016). In contrast, the glucagon counter-regulation to the insulin-induced hypoglycaemia was sustained by vildagliptin (6.05 ± 1.20 pmol/l during vildagliptin vs.6.94 ± 1.09 pmol/l during placebo, NS). During the food re-challenge after hypoglycaemia, glucagon levels were, again, significantly lower after vildagliptin (AUC 1.30 ± 0.11 vs. 1.52 ± 0.12 nmol/l min, P < 0.039). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels were significantly elevated by vildagliptin compared to placebo during meal, hypoglycaemia and food re-challenge. Conclusions: Vildagliptin action to block GLP-1 and GIP inactivation by DPP-4 improves glucagon dynamics during hypoglycaemia, hyperglycaemia and food re-challenge. Keywords: DPP-4 inhibition, glucagon, hypoglycaemia, insulin-treated, type 2 diabetes, vildagliptin Date submitted 8 December 2013; date of first decision 19 January 2014; date of final acceptance 20 February 2014
Introduction Glucose-sensing of islet α-cells is impaired in type 2 diabetes (T2D), which leads to inappropriate glucagon hypersecretion at normal and elevated glucose levels, which causes a detrimental increase in hepatic glucose production [1]. This glucagon hypersecretion is therefore an important target for glucoselowering therapy of T2D. The first glucose-lowering therapy of T2D that targets the α –cell defect is incretin therapy, which is based on the action of glucagon-like peptide-1 (GLP-1) to inhibit glucagon secretion at elevated glucose levels together with stimulation of β-cell function [1,2]. This therapy is today widely used in the form of GLP-1 receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors; the therapy improves glycaemia with low risk of hypoglycaemia and weight reduction or weight neutrality [3–5]. ´ Department of Clinical Sciences, Lund University, B11 Correspondence to: Dr Bo Ahren, BMC, 22184 Lund, Sweden. E-mail: [email protected]
What is equally important as the hyperglucagonaemia at elevated glucose levels in T2D, however, is that people with T2D also often experience an impaired glucagon response to hypoglycaemia [6]. This inappropriately low glucagon at low glucose increases the risk of hypoglycaemia, since glucagon is an important mediator of the glucose counter-regulation [7]. This impaired counter-regulation needs therefore to be targeted by glucose-lowering therapy in order not only to reduce hyperglycaemia but also to prevent hypoglycaemia. We previously reported that the DPP4 inhibitor vildagliptin augmented the glucagon response to hypoglycaemia during a hypoglycaemic clamp at 2.5 mmol/l when given as monotherapy in drug-na¨ıve patients with T2D [8]. This is consistent with the low risk of hypoglycaemia when vildagliptin is used as glucose-lowering treatment in monotherapy [9]. This low risk of hypoglycaemia in spite of a lower haemoglobin A1c (HbA1c) has also been observed when vildagliptin has been given to patients with T2D in combination with other oral agents [10–13].
original article
DIABETES, OBESITY AND METABOLISM
In contrast to the documented sustained glucagon response to hypoglycaemia by vildagliptin when administered to drugna¨ıve patients, there is no study on the influences on counterregulation to hypoglycaemia when incretin therapy has been added to insulin therapy. This is an important question because insulin therapy is associated with impaired glucagon counterregulation [6,14] and since incretin therapy, both DPP-4 inhibitors and GLP-1 receptor agonists, is used in combination with insulin [15,16]. For example, in a recent study, vildagliptin was demonstrated to reduce HbA1c by 0.8% (7 mmol/mol) from the baseline of 8.8% (69 mmol/mol) without increased risk of hypoglycaemia and no weight gain when added to insulin with or without metformin in patients with T2D [17]. Whether the low risk of hypoglycaemia is associated with sustained glucagon counter-regulation to hypoglycaemia is, however, not known. We have therefore performed an interventional physiological study [trial registry number: NCT012191400 (vildagliptin and the glucagon response to hypoglycaemia in insulin-treated patients with T2D)] examining the glucagon dynamics during hyper- and hypoglycaemia in patients treated with combination of DPP-4 inhibition and insulin.
Methods Study Population and Study Design The study was a single-centre (Lund University), double-blind, randomized, placebo-controlled crossover study in patients with T2D who were treated with a stable dose of insulin (long-acting insulin with or without short-acting insulin) with or without oral hypoglycaemic agents. It was performed during 2011–2013. Eligible patients were 18 years or older with a diagnosed antibody-negative T2D and a HbA1c value between 6.5–8.5% (48–68 mmol/mol) and fasting plasma glucose levels (FPG)
original article
Diabetes, Obesity and Metabolism 16: 812–818, 2014. © 2014 John Wiley & Sons Ltd
Glucagon dynamics during hypoglycaemia and food-re-challenge following treatment with vildagliptin in insulin-treated patients with type 2 diabetes ´ 1 J. Farngren1 , M. Persson2 , A. Schweizer3 , J. E. Foley4 & B. Ahren 1 Department of Clinical Sciences Lund, Lund University, Lund, Sweden 2 Department of Clinical Sciences Malmo, ¨ Lund University, Lund, Sweden 3 Novartis Pharma AG, Basel, Switzerland 4 Novartis Pharmaceuticals, East Hanover, NJ, USA
Aims: To determine the effects of dipeptidyl peptidase-4 (DPP-4) inhibition on glucagon dynamics in patients with insulin-treated type 2 diabetes (T2D).
Methods: The study was a single-centre, double-blind, randomized, placebo controlled crossover study in patients with T2D, mean age 59 ± 6 (s.d.) years and mean haemoglobin A1c 7.7 ± 0.8%, treated with exogenous insulin with or without oral antihyperglycaemic agents. Patients received vildagliptin (50 mg BID) or placebo as add-on to insulin for 4 weeks in random order with a 4-week washout in-between. On day 28 of the respective treatment, patients were served a standard meal (500 kcal) followed by a hyperinsulinaemic hypoglycaemic clamp (target 2.5 mmol/l) and a subsequent food re-challenge (700 kcal). The completers population (n = 29) was analysed. Results: Glucose levels were lower with vildagliptin than with placebo during the meal [areas under the curve (AUC) 1.23 ± 0.07 vs. 1.46 ± 0.05 mol/l min, P < 0.001] and similar between the groups during the clamp. During the meal, glucagon levels were lower with vildagliptin (AUC 1.98 ± 0.15 vs. 2.15 ± 0.17 nmol/l min, P = 0.016). In contrast, the glucagon counter-regulation to the insulin-induced hypoglycaemia was sustained by vildagliptin (6.05 ± 1.20 pmol/l during vildagliptin vs.6.94 ± 1.09 pmol/l during placebo, NS). During the food re-challenge after hypoglycaemia, glucagon levels were, again, significantly lower after vildagliptin (AUC 1.30 ± 0.11 vs. 1.52 ± 0.12 nmol/l min, P < 0.039). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels were significantly elevated by vildagliptin compared to placebo during meal, hypoglycaemia and food re-challenge. Conclusions: Vildagliptin action to block GLP-1 and GIP inactivation by DPP-4 improves glucagon dynamics during hypoglycaemia, hyperglycaemia and food re-challenge. Keywords: DPP-4 inhibition, glucagon, hypoglycaemia, insulin-treated, type 2 diabetes, vildagliptin Date submitted 8 December 2013; date of first decision 19 January 2014; date of final acceptance 20 February 2014
Introduction Glucose-sensing of islet α-cells is impaired in type 2 diabetes (T2D), which leads to inappropriate glucagon hypersecretion at normal and elevated glucose levels, which causes a detrimental increase in hepatic glucose production [1]. This glucagon hypersecretion is therefore an important target for glucoselowering therapy of T2D. The first glucose-lowering therapy of T2D that targets the α –cell defect is incretin therapy, which is based on the action of glucagon-like peptide-1 (GLP-1) to inhibit glucagon secretion at elevated glucose levels together with stimulation of β-cell function [1,2]. This therapy is today widely used in the form of GLP-1 receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors; the therapy improves glycaemia with low risk of hypoglycaemia and weight reduction or weight neutrality [3–5]. ´ Department of Clinical Sciences, Lund University, B11 Correspondence to: Dr Bo Ahren, BMC, 22184 Lund, Sweden. E-mail: [email protected]
What is equally important as the hyperglucagonaemia at elevated glucose levels in T2D, however, is that people with T2D also often experience an impaired glucagon response to hypoglycaemia [6]. This inappropriately low glucagon at low glucose increases the risk of hypoglycaemia, since glucagon is an important mediator of the glucose counter-regulation [7]. This impaired counter-regulation needs therefore to be targeted by glucose-lowering therapy in order not only to reduce hyperglycaemia but also to prevent hypoglycaemia. We previously reported that the DPP4 inhibitor vildagliptin augmented the glucagon response to hypoglycaemia during a hypoglycaemic clamp at 2.5 mmol/l when given as monotherapy in drug-na¨ıve patients with T2D [8]. This is consistent with the low risk of hypoglycaemia when vildagliptin is used as glucose-lowering treatment in monotherapy [9]. This low risk of hypoglycaemia in spite of a lower haemoglobin A1c (HbA1c) has also been observed when vildagliptin has been given to patients with T2D in combination with other oral agents [10–13].
original article
DIABETES, OBESITY AND METABOLISM
In contrast to the documented sustained glucagon response to hypoglycaemia by vildagliptin when administered to drugna¨ıve patients, there is no study on the influences on counterregulation to hypoglycaemia when incretin therapy has been added to insulin therapy. This is an important question because insulin therapy is associated with impaired glucagon counterregulation [6,14] and since incretin therapy, both DPP-4 inhibitors and GLP-1 receptor agonists, is used in combination with insulin [15,16]. For example, in a recent study, vildagliptin was demonstrated to reduce HbA1c by 0.8% (7 mmol/mol) from the baseline of 8.8% (69 mmol/mol) without increased risk of hypoglycaemia and no weight gain when added to insulin with or without metformin in patients with T2D [17]. Whether the low risk of hypoglycaemia is associated with sustained glucagon counter-regulation to hypoglycaemia is, however, not known. We have therefore performed an interventional physiological study [trial registry number: NCT012191400 (vildagliptin and the glucagon response to hypoglycaemia in insulin-treated patients with T2D)] examining the glucagon dynamics during hyper- and hypoglycaemia in patients treated with combination of DPP-4 inhibition and insulin.
Methods Study Population and Study Design The study was a single-centre (Lund University), double-blind, randomized, placebo-controlled crossover study in patients with T2D who were treated with a stable dose of insulin (long-acting insulin with or without short-acting insulin) with or without oral hypoglycaemic agents. It was performed during 2011–2013. Eligible patients were 18 years or older with a diagnosed antibody-negative T2D and a HbA1c value between 6.5–8.5% (48–68 mmol/mol) and fasting plasma glucose levels (FPG)
