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PubMed2005

Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.

OBJECTIVE: This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses. RESEARCH DESIGN AND METHODS: A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 +/- 10 years with BMI of 34.2 +/- 5.9 kg/m(2) and HbA(1c) of 8.2 +/- 1.1%. After 4 weeks of placebo, subjects self-administered 5 microg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 microg exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy. RESULTS: At week 30, HbA(1c) changes from baseline +/- SE for each group were -0.78 +/- 0.10% (10 microg), -0.40 +/- 0.11% (5 microg), and +0.08 +/- 0.10% (placebo; intent to treat; adjusted P < 0.002). Of evaluable subjects, 46% (10 microg), 32% (5 microg), and 13% (placebo) achieved HbA(1c) < or =7% (P < 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (-2.8 +/- 0.5 kg [10 microg], -1.6 +/- 0.4 kg [5 microg]; P < 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia. CONCLUSIONS: Exenatide was generally well tolerated and reduced HbA(1c) with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.

Adult↗
PubMed2004

Exenatide: NMR/CD evaluation of the medium dependence of conformation and aggregation state.

Exenatide, synthetic exendin-4, is the first member of the incretin mimetic class of potential therapeutic agents. It has been the subject of extensive clinical trials in people with Type 2 diabetes. Results to date indicate that exenatide decreases postmeal blood glucose concentrations and that this effect is associated with weight loss. Prior NMR studies of exendin-4 utilized 30% trifluoroethanol because this medium affords sharp, high-resolution NMR spectra. These studies defined its three-dimensional structure in this medium. The NMR-derived ensemble included a novel tertiary structure motif that has subsequently been optimized, yielding water-soluble Trp-cage miniproteins. Prior to the present study, the structuring propensities (and aggregation/association state) of exendin-4 in strictly aqueous media had not been established. Studies of exendin-4 and N-terminally truncated analogs of exendin have established that the structuring propensities of these species are highly medium dependent. This study extends knowledge of the medium dependence of exendin structure to DMSO-water mixtures and to aqueous media mimicking the formulation conditions for this investigational drug. Exenatide retains a substantial helical propensity from residues 9-27 even in 98% DMSO. The addition of water leads to the appearance of NMR diagnostics of the Trp-cage formation. In strictly aqueous media (pH 4-4.4), exenatide is monomeric only at <10 microM peptide concentrations. Under these conditions the Trp cage is partially formed. NMR and CD data indicate that higher concentrations lead to helix bundle formation and that the helix/helix interactions involve residues 11-26. Both the N- and C-termini of the helix bundle state display rapid segmental motion.

Amino Acid Sequence↗
PubMed2006

Effect of exenatide on the pharmacokinetics and pharmacodynamics of warfarin in healthy Asian men.

Exenatide, a treatment for type 2 diabetes, slows gastric emptying as part of its pharmacologic action and may alter the absorption of concomitant oral drugs. This open-label, 2-period, fixed-sequence study evaluated the influence of exenatide coadministration on the pharmacokinetics and pharmacodynamics of warfarin, a narrow therapeutic index drug, in healthy men (N = 16). A single, 25-mg oral dose of warfarin, with a standardized breakfast, was administered alone in period 1 and concomitantly with 10 microg exenatide subcutaneous twice daily in period 2. Exenatide did not produce significant changes in R- or S-warfarin pharmacokinetics. Although there were minor reductions in warfarin anticoagulant effect, the ratios of geometric means for the area under the international normalized ratio (INR)-time curve from dosing until the time of the last measurable INR value or maximum-observed INR response being 0.94 (0.93-0.96) and 0.88 (0.84-0.92), respectively, the magnitude and direction of these changes do not suggest a safety concern from this interaction.

Administration, Oral↗
PubMed2004

Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight.

The effects of the incretin mimetic exenatide (exendin-4) on metabolic parameters, insulin sensitivity, and beta-cell mass were examined in nondiabetic, insulin-resistant obese fa/fa Zucker rats. After 6 wk of treatment, ad libitum-fed exenatide-treated (EX) and pair-fed vehicle control (PF) rats had comparable food intake, body weight, hemoglobin A(1c) (HbA(1c)), and fasting plasma concentrations of glucose, insulin, and lipids. Concurrent decreases in food intake and weight gain were observed in EX and PF rats, compared with ad libitum-fed vehicle control (CON) rats (P < 0.001). The increases in HbA(1c) and fasting plasma insulin concentrations that occur during the normal progression of this disease model were significantly reduced in EX and PF rats, compared with CON rats (P < 0.001). The insulin sensitivity index (ISI; glucose infusion rate to plasma insulin concentration) measured during a hyperinsulinemic euglycemic clamp was 224% higher in EX rats than CON rats (P < 0.001) and 61% higher in EX rats than PF rats (P < 0.004). The latter difference was despite comparable HbA(1c), fasting glucose, fasting insulin, total cholesterol, high-density lipoprotein, and daily food consumption between EX and PF animals. In the absence of exenatide, beta-cell mass was hyperbolically related to ISI (beta-cell mass * ISI was constant). Analogous to the disposition index, the beta-cell mass * ISI product was 63% greater in EX than PF rats (P < 0.05). Thus, exenatide increased beta-cell mass to a greater extent than would be expected in animals of comparable insulin resistance, suggesting a direct trophic effect on islet neogenesis in obese fa/fa rats independent of body weight and glycemia.

Animals↗
PubMed2003

Exenatide. Amylin/Eli Lilly.

Amylin Pharmaceuticals Inc and Eli Lilly & Co are co-developing exenatide (AC-2993; synthetic exendin-4), a 39-amino acid, glucagon-like peptide-1 agonist derived from the venom of the Gila monster lizard (Heloderma suspectum) as a potential injectable treatment for type 2 diabetes. The first phase III trial (exenatide as a monotherapy) was initiated in December 2001. In January 2002 the second phase III trial, of exenatide in conjunction with sulfonylureas, was initiated and in March 2002, Amylin initiated the third phase III trial, of exenatide in combination with metformin and sulfonylureas.

Animals↗
PubMed2003

Ex vivo human placental transfer of the peptides pramlintide and exenatide (synthetic exendin-4).

Two peptides, pramlintide (37 amino acids), an analog of human amylin, and exenatide, synthetic exendin-4 (39 amino acids), are both in late-stage clinical development as potential new treatments for people with diabetes. Both are potential long-term treatments, and there is the likelihood that some women will become pregnant while using one of these peptide therapies. Therefore, it was important to evaluate the potential for each peptide to cross the placental barrier and thereby result in exposure to the fetus. This was examined using ex vivo perfusions of human placentas. The fetal and maternal side of a cotyledon were cannulated and perfused first with buffer, and then with radioactive antipyrine in order to establish the integrity of the system and the perfusion constants. Either pramlintide or exenatide was then added to each acceptable cotyledon perfusate on the maternal side. Each peptide was evaluated at an initial concentration near the therapeutic plasma concentration and at approximately 10-50 times that concentration in each of the three cotyledons. Maternal and fetal perfusate samples were assayed for peptide concentrations using an immunoassay. The ratio of fetal-to-maternal peptide concentrations during equilibrium perfusion were extremely low (pramlintide < or = 0.006, exenatide < or = 0.017). These data demonstrate negligible passage of either peptide across the placental barrier. It is, therefore, likely that maternal use of either peptide during gestation will result in negligible exposure to the fetus.

Amyloid↗
PubMed2006

Is exenatide advancing the treatment of type 2 diabetes?

Glucagon-like peptide 1 is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the glucagon-like peptide 1 receptor. Synthetic exendin-4 (exenatide) has recently been trialled in patients with Type 2 diabetes taking either metformin alone or a combination of metformin and a sulfonylurea. In both trials, exenatide 5 and 10 microg s.c. was shown to improve glycaemic control, with few adverse events. Exenatide represents a new and useful addition to the medicines used to treat Type 2 diabetes.

Diabetes Mellitus, Type 2↗
PubMed2006

Exenatide: a GLP-1 receptor agonist as novel therapy for Type 2 diabetes mellitus.

Exenatide is a glucagon-like peptide 1 receptor agonist, which has recently received FDA approval in the US for the treatment of Type 2 diabetes. Exenatide is an incretin mimetic that improves glycaemic control in patients with diabetes through acute mechanisms, such as glucose-dependent stimulation of insulin secretion, suppression of inappropriate glucagon secretion and slowing of gastric emptying, as well as chronic mechanisms that include enhancement of beta-cell mass in rodent studies and weight loss and inhibition of food intake in humans. This article reviews the mechanisms of exenatide action, as well as its efficacy in the treatment of Type 2 diabetes.

Animals↗
PubMed2005

Exenatide for the treatment of type 2 diabetes mellitus.

Exenatide is a glucagon-like peptide-1 agonist. It is being investigated as an add-on therapy for patients with type 2 diabetes mellitus who are taking oral antidiabetic drugs. Evidence indicates that exenatide reduces glycosylated hemoglobin and plasma glucose levels when compared with placebo. Limitations of the therapy include the need for twice daily injections and potentially dose-limiting nausea and vomiting. Long-term studies are required to determine the effects of exenatide on disease-related morbidity and mortality.

Blood Glucose↗
PubMed2003

Pharmacology of exenatide (synthetic exendin-4) for the treatment of type 2 diabetes.

New therapies for the long-term treatment of type 2 diabetes are needed to ameliorate declining pancreatic beta-cell function. Ideally, these therapies should lower fasting and post-prandial blood glucose, produce no hypoglycemia or weight gain, cause no other limiting side effects, and reduce cardiovascular complications. Exenatide (synthetic exendin-4) is a potential therapeutic which may fulfill these criteria. Dose-ranging studies have identified an optimal dose of 0.05 to 0.2 microgram/kg administered subcutaneously twice daily. Pharmacokinetic data support a pivotal study design which mitigates the transient nausea observed in early studies by including a dose initiation period of 1 month at 5 micrograms twice daily, followed by maintenance therapy at 10 micrograms twice daily. Ongoing studies suggest exenatide improves glycemic control through a combination of mechanisms discussed in this review.

Animals↗
PubMedDate not supplied

[Exenatide: use in humans].

Exenatide is the first synthetic agonist of the GLP-1 (glucagon-like peptide 1) receptor approved for clinical use in patients with type 2 diabetes. The multiplicity of its effects over glucose metabolism, appetite, body weight and its potential capacity to preserve the ?cell mass, makes it an attractive therapeutic alternative. This article attempts to review the current literature on pharmacokinetics, pharmacodynamics, efficacy, and safety of exenatide in humans, derived from the early phase I and II studies, and from the clinical controlled trials that led to its approval for clinical use as a combination therapy with sulphonylureas and metformin.

Clinical Trials as Topic↗
PubMed2006

Exenatide inhibits beta-cell apoptosis by decreasing thioredoxin-interacting protein.

Exenatide (Ex-4) is a novel anti-diabetic drug that stimulates insulin secretion and enhances beta-cell mass, but the mechanisms involved are not fully understood. We found that Ex-4 protects INS-1 beta-cells against oxidative stress-induced apoptosis (TUNEL) and also reduces expression (mRNA and protein) of thioredoxin-interacting protein (TXNIP), a pro-apoptotic factor involved in beta-cell glucose toxicity and oxidative stress. This reduction was observed in INS-1 cells, mouse, and human islets as well as in wild-type mice receiving Ex-4 and was accompanied by decreased expression of the apoptotic factors caspase-3 and Bax. To determine whether Ex-4-mediated TXNIP reduction is critical for this inhibition of apoptosis, we stably overexpressed TXNIP in INS-1 cells, which completely blunted the anti-apoptotic Ex-4 effects. Thus, Ex-4 inhibits apoptosis by reducing TXNIP expression and early initiation of Ex-4 treatment may help preserve endogenous beta-cell mass, protect against oxidative stress, and delay type 2 diabetes progression.

Animals↗
PubMed2004

Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes.

Exenatide (synthetic exendin-4), glucagon-like peptide-1 (GLP-1), and GLP-1 analogues have actions with the potential to significantly improve glycemic control in patients with diabetes. Evidence suggests that these agents use a combination of mechanisms which may include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, enhancement of beta-cell mass, slowing of gastric emptying, inhibition of food intake, and modulation of glucose trafficking in peripheral tissues. The short in vivo half-life of GLP-1 has proven a significant barrier to continued clinical development, and the focus of current clinical studies has shifted to agents with longer and more potent in vivo activity. This review examines recent exendin-4 pharmacology in the context of several known mechanisms of action, and contrasts exendin-4 actions with those of GLP-1 and a GLP-1 analogue. One of the most provocative areas of recent research is the finding that exendin-4 enhances beta-cell mass, thereby impeding or even reversing disease progression. Therefore, a major focus of this is article an examination of the data supporting the concept that exendin-4 and GLP-1 may increase beta-cell mass via stimulation of beta-cell neogenesis, stimulation of beta-cell proliferation, and suppression of beta-cell apoptosis.

Amino Acid Sequence↗
PubMed2003

Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes.

Despite the advent of new treatments, glucose control in the type 2 diabetes population is unsatisfactory. AC2993 (synthetic exendin-4; exenatide), a novel glucose-dependent insulinotropic agent, exhibited notable antidiabetic potential in two clinical studies in patients with type 2 diabetes. In study A, 24 subjects received sc injections of study medication (0.1 micro g/kg AC2993 or placebo) twice daily with meals for 5 d. Statistically significant reductions in mean postprandial circulating concentrations of glucose, insulin, and glucagon occurred following treatment with AC2993. In study B, 13 subjects receiving a single dose of study medication (0.05, 0.1, or 0.2 micro g/kg AC2993 or placebo) following an overnight fast had reduced fasting plasma glucose concentrations during the subsequent 8-h period. The relative glucose and insulin concentration profiles were consistent with glucose-dependent insulinotropism. AC2993 was well tolerated. Mild transient headache, nausea, and vomiting were the main adverse events. In conclusion, AC2993 acutely and markedly reduces fasting and postprandial glucose concentrations in patients with type 2 diabetes. During fasting, glucose-dependent enhancement of insulin secretion and suppression of glucagon secretion are the predominant mechanisms, and postprandially, slowing of gastric emptying is additionally operative. This robust antidiabetic effect warrants further evaluation of AC2993.

Acetaminophen↗
PubMed2006

Investigational treatments for Type 2 diabetes mellitus: exenatide and liraglutide.

Although a number of compounds are currently used to treat Type 2 diabetes mellitus, achieving a sustained glycaemic control over time is often not possible using oral antidiabetics. Endogenous incretins exhibit beneficial effects that could be useful for Type 2 diabetes mellitus treatment, such as stimulating insulin secretion during hyperglycaemia, improving beta-cell mass and function, reducing glucagon secretion, delaying gastric emptying, reducing postprandial hyperglycaemia and diminishing body weight; however, their short half-life makes them unsuitable for treatment. Incretin mimetics such as liraglutide and exenatide were developed to overcome this limitation. This review discusses the effects of these compounds and their potential as a new class of antidiabetic agents.

Animals↗
PubMed2003

Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes.

OBJECTIVE: AC2993 (synthetic exendin-4; exenatide) is a peptide that enhances glucose-dependent insulin secretion, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. AC2993 also promotes beta-cell proliferation and neogenesis in vitro and in animal models. This study examines the activity and safety of subcutaneously injected AC2993 in patients with type 2 diabetes currently treated with diet and/or oral antidiabetic agents (OAAs). RESEARCH DESIGN AND METHODS: A total of 109 patients treated with diet and a sulfonylurea and/or metformin were enrolled in a blinded study. Patients were randomly assigned to one of three subcutaneously (SC) injected regimens of AC2993 (0.08 micro g/kg) or placebo for 28 days. RESULTS: All three AC2993 regimens led to significant reductions in serum fructosamine relative to placebo (P <or= 0.004). Mean reductions ranged from 39 to 46 micro mol/l. All AC2993 groups had reductions in HbA(1c) ranging from 0.7 to 1.1% (P <or= 0.006). An end-of-study HbA(1c) <7% was achieved by 15% of AC2993 patients versus 4% of placebo patients, confirming AC2993 effects on fasting and postprandial glycemia. On days 14 and 28, the beta-cell index (homeostasis model assessment) for patients treated with AC2993 was 50-100% higher than baseline, contrasting with unchanged levels for placebo. The most common adverse event was transient mild-to-moderate nausea. CONCLUSIONS: AC2993 is a promising therapeutic for patients with type 2 diabetes. In this study, it had significant effects on HbA(1c) levels in patients not currently achieving optimal glucose control with diet and/or OAAs.

Blood Glucose↗
PubMed2005

Exenatide.

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Diabetes Mellitus, Type 2↗