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Bo Ahrén - One of the best experts on this subject based on the ideXlab platform.

  • Glucose‐lowering action through targeting islet dysfunction in type 2 diabetes: Focus on Dipeptidyl peptidase‐4 inhibition
    'Wiley', 2021
    Co-Authors: Bo Ahrén
    Abstract:

    Abstract Dipeptidyl peptidase‐4 (DPP‐4) inhibition is a glucose‐lowering medication for type 2 diabetes. It works through stimulation of insulin secretion and inhibition of glucagon secretion in a glucose‐dependent manner, resulting in lowered fasting and postprandial glycemia with low risk of hypoglycemia. As impaired insulin secretion and augmented glucagon secretion are key factors underlying hyperglycemia in type 2 diabetes, DPP‐4 inhibition represents a therapy that targets the underlying mechanisms of the disease. If insufficient in monotherapy, it can preferably be used in combination with metformin, which targets insulin resistance, and also in combination with sodium–glucose cotransporter 2 inhibition, thiazolidinediones and insulin, which target other mechanisms. In individuals of East Asian origin, islet dysfunction is of particular importance for the development of type 2 diabetes. Consequently, it has been shown in several studies that DPP‐4 is efficient in these populations. This mini‐review highlights the islet mechanisms of DPP‐4 inhibition, islet dysfunction as a key factor for hyperglycemia in type 2 diabetes and that, consequently, DPP‐4 is of particular value in populations where islet dysfunction is central, such as in individuals of East Asian origin

  • enhanced beta cell function and anti inflammatory effect after chronic treatment with the Dipeptidyl peptidase 4 inhibitor vildagliptin in an advanced aged diet induced obesity mouse model
    Diabetologia, 2013
    Co-Authors: Bilal Omar, James E Foley, Jenny Vikman, Maria Sorhede Winzell, Ulrikke Voss, Eva Ekblad, Bo Ahrén
    Abstract:

    Aims/hypothesis Studies have shown that Dipeptidyl Peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old).

  • Dipeptidyl peptidase 4 inhibitors and cardiovascular risk a meta analysis of randomized clinical trials
    Diabetes Obesity and Metabolism, 2013
    Co-Authors: Matteo Monami, Bo Ahrén, Ilaria Dicembrini, Edoardo Mannucci
    Abstract:

    Aims Preliminary data from randomized trials with metabolic outcomes have shown that treatment with Dipeptidyl Peptidase-4 inhibitors (DPP4i) could be associated with a reduced incidence of major cardiovascular events (MACE). The present meta-analysis is aimed at verifying this protective effect, collecting all available data from randomized trials. Methods A comprehensive search for published and unpublished trials with a duration =24 weeks comparing DPP4i with placebo or other drugs was performed, retrieving all MACE reported as serious adverse events together with death from any cause. MantelHaenzel odds ratio (MHOR) was calculated with random effect models for MACE, myocardial infarction, stroke and mortality. When available, effects on glycated haemoglobin, lipid profile and blood pressure were also assessed and used for the estimation of the modification of risk for myocardial infarction using the UKPDS risk engine. Results A total of 70 trials, enrolling 41?959 patients with a mean follow-up of 44.1 weeks, was collected and included in the analysis. The MHOR (95% Confidence Interval) was 0.71[0.59;0.86], 0.64[0.44;0.94], 0.77[0.48;1.24] and 0.60[0.41;0.88] for MACE, myocardial infarction, stroke and mortality, respectively. Conclusions Treatment with DPP4i reduces the risk of cardiovascular events (particularly myocardial infarction) and all-cause mortality in patients with type 2 diabetes. The reduction in the incidence of myocardial infarction is greater than what predicted on the basis of conventional risk factors, suggesting a role for other mechanisms. (Less)

  • mechanisms of action of the Dipeptidyl peptidase 4 inhibitor vildagliptin in humans
    Diabetes Obesity and Metabolism, 2011
    Co-Authors: Bo Ahrén, Anja Schweizer, B E Dunning, Sylvie Dejager, Edwin Bernard Villhauer, James E Foley
    Abstract:

    Inhibition of Dipeptidyl Peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycemia in type 2 diabetes, with low risk for hypoglycemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and to inhibit glucagon secretion in a glucose-dependent manner. At hypoglycemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycemia with low risk for hypoglycemia. Vildagliptin also suppresses postprandial triglyceride-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced triglyceride stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.

  • vildagliptin an inhibitor of Dipeptidyl peptidase 4 with antidiabetic properties
    Expert Opinion on Investigational Drugs, 2006
    Co-Authors: Bo Ahrén
    Abstract:

    Vildagliptin is a competitive and reversible inhibitor of Dipeptidyl Peptidase-4. Dipeptidyl Peptidase-4 inhibitors act mainly by preventing the rapid degradation of glucagon-like peptide-1. In clinical trials, vildagliptin improves glycaemic control both as monotherapy and in combination with metformin for periods of ≤ 52 weeks in subjects with Type 2 diabetes. This is evident by reduced fasting and prandial glucose levels, and reduced glycosylated haemoglobin levels. Vildagliptin acts by increasing active glucagon-like peptide-1, improving β-cell function and inhibiting glucagon secretion. Furthermore, vildagliptin has proven to be safe and tolerable, with a low occurrence of hypoglycaemia. Further studies are now required to evaluate its long-term durability, effects, safety and tolerability in comparison with other antidiabetic agents and in different patient subgroups.

Masayoshi Soma - One of the best experts on this subject based on the ideXlab platform.

  • the Dipeptidyl peptidase 4 inhibitor alogliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis
    Expert Opinion on Pharmacotherapy, 2013
    Co-Authors: Yuki Fujii, Noriaki Maruyama, Terumi Higuchi, Kazuyoshi Okada, Masanori Abe, Mari Mizuno, Hiroko Suzuki, Shiro Matsumoto, Midori Ito, Masayoshi Soma
    Abstract:

    Objectives: The potent and selective Dipeptidyl Peptidase-4 (DPP-4) inhibitor alogliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and β-cell responsiveness to glucose. In this study, the efficacy and safety of alogliptin in type 2 diabetic patients undergoing hemodialysis (HD) were evaluated. Methods: A prospective, open-label study of 30 patients (male/female: 24/6; mean age: 69.7 ± 1.7 years) with type 2 diabetes who were undergoing HD without insulin injection therapy was conducted. Patients were administered 6.25 mg/day alogliptin and efficacy and safety were determined by monitoring clinical and laboratory parameters during the 48-week study period. Results: After 48 weeks, alogliptin had decreased postprandial plasma glucose levels from 212 ± 8 mg/dL baseline to 156 ± 7 mg/dL, hemoglobin A1c levels from 7.1 ± 0.2% baseline to 6.3 ± 0.2% and glycated albumin (GA) levels from 25.6 ± 0.6% baseline to 20.7 ± 0.4% (all p < 0.0001). ...

  • the Dipeptidyl peptidase 4 dpp 4 inhibitor vildagliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis
    Endocrine Journal, 2011
    Co-Authors: Kazuyoshi Okada, Noriaki Maruyama, Masaaki Tsuchida, Terumi Higuchi, Fumito Kikuchi, Hirokazu Sasaki, Masayoshi Soma
    Abstract:

    The potent and selective Dipeptidyl Peptidase-4 inhibitor vildagliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and β-cell responsiveness to glucose. We conducted a prospective, open-label, parallel group, controlled study of 51 patients with type 2 diabetic patients undergoing hemodialysis (HD) during the 24-week study period. Patients were assigned to two groups: the vildagliptin group (n = 30) and the control group (n = 21). Vildagliptin was administered at 50 mg/day for the first 8 weeks. Then doses were titrated by dose-doubling to a maximum of 100 mg/day if hemoglobin A1c (HbA1c) or glycated albumin (GA) target levels had not been reached. No vildagliptin was administered to the controls. The average final dose of vildagliptin was 80 ± 5 mg daily. After 24 weeks, vildagliptin had decreased average HbA1c levels from 6.7 % baseline to 6.1 %, average GA levels from 24.5 % baseline to 20.5 % and average postprandial plasma glucose levels from 186 mg/dL baseline to 140 mg/dL (all p

James E Foley - One of the best experts on this subject based on the ideXlab platform.

  • enhanced beta cell function and anti inflammatory effect after chronic treatment with the Dipeptidyl peptidase 4 inhibitor vildagliptin in an advanced aged diet induced obesity mouse model
    Diabetologia, 2013
    Co-Authors: Bilal Omar, James E Foley, Jenny Vikman, Maria Sorhede Winzell, Ulrikke Voss, Eva Ekblad, Bo Ahrén
    Abstract:

    Aims/hypothesis Studies have shown that Dipeptidyl Peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old).

  • mechanisms of action of the Dipeptidyl peptidase 4 inhibitor vildagliptin in humans
    Diabetes Obesity and Metabolism, 2011
    Co-Authors: Bo Ahrén, Anja Schweizer, B E Dunning, Sylvie Dejager, Edwin Bernard Villhauer, James E Foley
    Abstract:

    Inhibition of Dipeptidyl Peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycemia in type 2 diabetes, with low risk for hypoglycemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and to inhibit glucagon secretion in a glucose-dependent manner. At hypoglycemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycemia with low risk for hypoglycemia. Vildagliptin also suppresses postprandial triglyceride-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced triglyceride stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.

  • treatment with the Dipeptidyl peptidase 4 inhibitor vildagliptin improves fasting islet cell function in subjects with type 2 diabetes
    The Journal of Clinical Endocrinology and Metabolism, 2009
    Co-Authors: David A Dalessio, B E Dunning, Amanda M Denney, Linda M Hermiller, Ronald L Prigeon, Julie M Martin, William G Tharp, Monica Liqueros Saylan, Yanling He, James E Foley
    Abstract:

    Context: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state. Objective: The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function. Design: We conducted a randomized, double-blind, placebo-controlled trial. Setting: The study was performed in General Clinical Research Centers at two University Hospitals. Subjects: Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin ...

Faiez Zannad - One of the best experts on this subject based on the ideXlab platform.

  • angiotensin converting enzyme inhibitor use and major cardiovascular outcomes in type 2 diabetes mellitus treated with the Dipeptidyl peptidase 4 inhibitor alogliptin
    Hypertension, 2016
    Co-Authors: William B White, George L Bakris, Richard M Bergenstal, Christopher P Cannon, William C Cushman, Cyrus R Mehta, Steven E Nissen, C Wilson, Simon K Heller, Faiez Zannad
    Abstract:

    Activation of the sympathetic nervous system when there is Dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the Dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79–1.19; P =0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73–1.21; P =0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72–1.2; P =0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors.

  • angiotensin converting enzyme inhibitor use and major cardiovascular outcomes in type 2 diabetes mellitus treated with the Dipeptidyl peptidase 4 inhibitor alogliptin
    Hypertension, 2016
    Co-Authors: William B White, George L Bakris, Richard M Bergenstal, Christopher P Cannon, Cyrus R Mehta, Steven E Nissen, C Wilson, Simon K Heller, William Cushman, Faiez Zannad
    Abstract:

    Activation of the sympathetic nervous system when there is Dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the Dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors.

Stacy C Dilzer - One of the best experts on this subject based on the ideXlab platform.

  • metabolism and excretion of the Dipeptidyl peptidase 4 inhibitor 14c sitagliptin in humans
    Drug Metabolism and Disposition, 2007
    Co-Authors: Stella H Vincent, Arthur J Bergman, James R Reed, Charles S Elmore, Bing Zhu, David L Ebel, Patrick J Larson, Wei Zeng, Li Chen, Stacy C Dilzer
    Abstract:

    The metabolism and excretion of [ 14 C]sitagliptin, an orally active, potent and selective Dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 μCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing N -sulfate and N -carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.

  • metabolism and excretion of the Dipeptidyl peptidase 4 inhibitor 14c sitagliptin in humans
    Drug Metabolism and Disposition, 2007
    Co-Authors: Stella H Vincent, Arthur J Bergman, James R Reed, Charles S Elmore, Bing Zhu, David L Ebel, Patrick J Larson, Wei Zeng, Li Chen, Stacy C Dilzer
    Abstract:

    The metabolism and excretion of [(14)C]sitagliptin, an orally active, potent and selective Dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 muCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.