Lifetime cost-effectiveness simulation of once-weekly exenatide in type 2 diabetes: A cost-utility analysis based on the EXSCEL trial.

Aims: The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial assessed once-weekly exenatide (EQW) vs. placebo, added to usual care in 14,752 patients with type 2 diabetes mellitus (Clinicaltrials.gov: NCT01144338).

Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes.

Background: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective.

Confirming the Bidirectional Nature of the Association Between Severe Hypoglycemic and Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL.

Objective: We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk.

Research Design And Methods: In a post hoc analysis of 14,752 Exenatide Study of Cardiovascular Event Lowering (EXSCEL) participants, we examined time-dependent associations between SHEs and subsequent major adverse cardiac events (CV death, nonfatal myocardial infarction [MI] or stroke), fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for acute coronary syndrome (hACS), hospitalization for heart failure (hHF), and all-cause mortality (ACM), as well as time-dependent associations between nonfatal CV events and subsequent SHEs.

Results: SHEs were uncommon and not associated with once-weekly exenatide therapy (hazard ratio 1.

Within-Trial Evaluation of Medical Resources, Costs, and Quality of Life Among Patients With Type 2 Diabetes Participating in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

Objective: To compare medical resource use, costs, and health utilities for 14,752 patients with type 2 diabetes who were randomized to once-weekly exenatide (EQW) or placebo in addition to usual diabetes care in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

Research Design And Methods: Medical resource use data and responses to the EuroQol 5-Dimension (EQ-5D) instrument were collected at baseline and throughout the trial. Medical resources and medications were assigned values by using U.

Changes in Serum Calcitonin Concentrations, Incidence of Medullary Thyroid Carcinoma, and Impact of Routine Calcitonin Concentration Monitoring in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL).

Objective: Increases in serum calcitonin, a tumor marker for medullary thyroid carcinoma (MTC), have been associated with glucagon-like peptide 1 receptor agonist use in some preclinical studies. We report calcitonin changes in exenatide-treated and placebo-administered participants and MTC incidence in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) and consider the impact of within-trial calcitonin monitoring.

Research Design And Methods: EXSCEL participants were randomized 1:1 to once-weekly exenatide 2 mg or placebo.

Effect of Once-Weekly Exenatide on Clinical Outcomes According to Baseline Risk in Patients With Type 2 Diabetes Mellitus: Insights From the EXSCEL Trial.

Background In the EXSCEL (Exenatide Study of Cardiovascular Event Lowering), exenatide once-weekly resulted in a nonsignificant reduction in major adverse cardiovascular events ( MACEs ) and a nominal 14% reduction in all-cause mortality in 14 752 patients with type 2 diabetes mellitus (T2 DM ) with and without cardiovascular disease. Whether patients at increased risk for events experienced a comparatively greater treatment benefit with exenatide is unknown. Methods and Results In the EXSCEL population, we created risk scores for MACEs and all-cause mortality using step-wise selection of baseline characteristics.

Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis.

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs. Findings from cardiovascular outcome trials showed cardiovascular safety of GLP-1 receptor agonists, but results for cardiovascular efficacy were varied. We aimed to examine overall cardiovascular efficacy for lixisenatide, liraglutide, semaglutide, and extended-release exenatide.

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Background: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.

Methods: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

Comparison of the circulating metabolite profile of PF-04991532, a hepatoselective glucokinase activator, across preclinical species and humans: potential implications in metabolites in safety testing assessment.

A previous report from our laboratory disclosed the identification of PF-04991532 [(S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid] as a hepatoselective glucokinase activator for the treatment of type 2 diabetes mellitus. Lack of in vitro metabolic turnover in microsomes and hepatocytes from preclinical species and humans suggested that metabolism would be inconsequential as a clearance mechanism of PF-04991532 in vivo. Qualitative examination of human circulating metabolites using plasma samples from a 14-day multiple ascending dose clinical study, however, revealed a glucuronide (M1) and monohydroxylation products (M2a and M2b/M2c) whose abundances (based on UV integration) were greater than 10% of the total drug-related material.

Effects of multiple doses of the DPP-IV inhibitor PF-734200 on the relationship between GLP-1 and glucose in subjects with type 2 diabetes mellitus.

A randomized, placebo-controlled study evaluated the effects multiple-doses (28 days) dipeptidyl peptidase-IV (DPP-IV) inhibitor PF-734200 on DPP-IV activity, glucose, glucagon-like peptide-1 (GLP-1), glucagon and insulin levels in 72 subjects with type 2 diabetes. The relationship between changes in active GLP-1 and glucose during a meal test appeared non-linear.

Non-linear increase in GLP-1 levels in response to DPP-IV inhibition in healthy adult subjects.

Aim: Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a new promising therapeutic intervention for the treatment of type 2 diabetes mellitus. The aim of this study was to investigate the effects of DPP-IV inhibition by PF-00734200, a potent competitive DPP-IV inhibitor, on the dynamics of DPP-IV activity and glucagon-like peptide-1 (GLP-1) kinetics in healthy adult subjects.

Methods: This was a prospective randomized, crossover, placebo-controlled, ascending, single, oral dose study conducted at a clinical research centre.

Intraportal administration of neuropeptide Y and hepatic glucose metabolism.

We examined whether intraportal delivery of neuropeptide Y (NPY) affects glucose metabolism in 42-h-fasted conscious dogs using arteriovenous difference methodology. The experimental period was divided into three subperiods (P1, P2, and P3). During all subperiods, the dogs received infusions of somatostatin, intraportal insulin (threefold basal), intraportal glucagon (basal), and peripheral intravenous glucose to increase the hepatic glucose load twofold basal.

Stimulation of both type I and type II corticosteroid receptors blunts counterregulatory responses to subsequent hypoglycemia in healthy man.

Antecedent increases of corticosteroids can blunt counterregulatory responses to subsequent stress. Our aim was to determine whether prior activation of type I corticosteroid (mineralocorticoid) or type II corticosteroid (glucocorticoid) receptors blunts counterregulatory responses to subsequent hypoglycemia. Healthy volunteers participated in five randomized 2-day protocols.

Islet auto-transplantation into an omental or splenic site results in a normal beta cell but abnormal alpha cell response to mild non-insulin-induced hypoglycemia.

The present studies were designed to determine if totally pancreatectomized dogs that underwent islet auto-transplantation retained a functional pancreatic counterregulatory response to mild non-insulin-induced hypoglycemia. Six dogs underwent total pancreatectomy followed by islet auto-transplantation to spleen or omentum. The animals recovered and fasting plasma glucose and insulin levels were normal.

Effects of hyperglycemia, glucagon, and epinephrine on renal glucose release in the conscious dog.

The role of renal glucose production after an overnight fast and in response to different hormonal conditions has been debated. The aim of this study was to determine whether hyperglycemia, glucagon, or epinephrine can affect renal glucose production. In 18-hour fasted conscious dogs a pancreatic clamp initially fixed insulin and glucagon at basal levels, following which 1 of 4 protocols was instituted.

A fall in portal vein insulin does not cause the alpha-cell response to mild, non-insulin-induced hypoglycemia in conscious dogs.

The aim of the present study was to determine whether a decrease in the portal vein insulin level during non-insulin-induced hypoglycemia is sensed and is responsible for the normal increase in glucagon release from the alpha cell. To address this aim, a glycogen phosphorylase inhibitor was used to create mild, non-insulin-induced hypoglycemia in 2 groups of 18-hour fasted conscious dogs. Arterial insulin was clamped at a basal level in both groups, but in one group (PE) the portal vein insulin level was permitted to fall by approximately 65% while in the other group (POR) it was clamped at a basal level.

Glucagon's actions are modified by the combination of epinephrine and gluconeogenic precursor infusion.

It was previously shown that glucagon and epinephrine have additive effects on both gluconeogenic and glycogenolytic flux. However, the changes in gluconeogenic substrates may have been limiting and thus may have prevented a synergistic effect on gluconeogenesis and a reciprocal inhibitory effect on glycogenolysis. Thus the aim of the present study was to determine if glucagon has a greater gluconeogenic and a smaller glycogenolytic effect in the presence of both epinephrine and clamped gluconeogenic precursors.

Interaction of glucagon and epinephrine in the control of hepatic glucose production in the conscious dog.

Epinephrine increases net hepatic glucose output (NHGO) mainly via increased gluconeogenesis, whereas glucagon increases NHGO mainly via increased glycogenolysis. The aim of the present study was to determine how the two hormones interact in controlling glucose production. In 18-h-fasted conscious dogs, a pancreatic clamp initially fixed insulin and glucagon at basal levels, following which one of four protocols was instituted.

Effect of intraportal glucagon-like peptide-1 on glucose metabolism in conscious dogs.

Arteriovenous difference and tracer ([3-(3)H]glucose) techniques were used in 42-h-fasted conscious dogs to identify any insulin-like effects of intraportally administered glucagon-like peptide 1-(7-36)amide (GLP-1). Each study consisted of an equilibration, a basal, and three 90-min test periods (P1, P2, and P3) during which somatostatin, intraportal insulin (3-fold basal) and glucagon (basal), and peripheral glucose were infused. Saline was infused intraportally in P1.