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PubMed2004

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

OBJECTIVE: This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy. RESEARCH DESIGN AND METHODS: This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 +/- 11 years, BMI 33 +/- 6 kg/m(2), HbA(1c) 8.6 +/- 1.2% [+/-SD]) and began 4 weeks at 5 microg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 microg b.i.d. exenatide. All subjects continued sulfonylurea therapy. RESULTS: At week 30, HbA(1c) changes from baseline were -0.86 +/- 0.11, -0.46 +/- 0.12, and 0.12 +/- 0.09% (+/-SE) in the 10-microg, 5-microg, and placebo arms, respectively (adjusted P < 0.001). Of evaluable subjects with baseline HbA(1c) > 7% (n = 237), 41% (10 microg), 33% (5 microg), and 9% (placebo) achieved HbA(1c) <or= 7% (P < 0.001). Fasting plasma glucose concentrations decreased in the 10-microg arm compared with placebo (P < 0.05). Subjects in the exenatide arms had dose-dependent progressive weight loss, with an end-of-study loss in the 10-microg exenatide arm of -1.6 +/- 0.3 kg from baseline (P < 0.05 vs. placebo). The most frequent adverse events were generally mild or moderate and gastrointestinal in nature. No severe hypoglycemia was observed. CONCLUSIONS: Exenatide significantly reduced HbA(1c) in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea. Exenatide was generally well tolerated and was associated with weight loss.

Adult↗
PubMedDate not supplied

Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin.

BACKGROUND: In two placebo-controlled 30-week trials, treatment with exenatide reduced HbA(1c) and body weight in patients with type 2 diabetes in the context of sulphonylurea (SU) or SU plus metformin (MET) as background treatment. This analysis examines the effects of 82 weeks of exenatide treatment for participants in these earlier 30-week trials. METHODS: Data were pooled from the two pivotal trials of exenatide added to SU or SU plus MET. Both 30-week, placebo-controlled trials of 5 microg or 10 microg exenatide b.i.d. were followed by 52-week open-label, uncontrolled extension studies in which all participants received 10 microg exenatide b.i.d. and continued prior oral therapies. This interim analysis includes data for 222 patients who completed 82 weeks of exenatide treatment (61% M, age 57 +/- 10 y, weight 99 +/- 21 kg, BMI 34 +/- 6 kg/m(2), HbA(1c)8.4 +/- 1.0% [mean +/- SD]). RESULTS: Reduction in HbA(1c) from baseline to week 30 (-0.8 +/- 0.1% and -1.0 +/- 0.1% for 5 microg b.i.d. and 10 microg b.i.d., respectively [mean +/- SE]) was sustained up to week 82 (-1.0 +/- 0.1%). Of 207 patients with baseline HbA(1c) > 7%, 44% achieved HbA(1c) < or = 7% at week 82. Reduction of body weight from baseline to week 30 (-1.4 +/- 0.3 kg and -2.1 +/- 0.3 kg for 5 microg b.i.d. and 10 microg b.i.d., respectively) was progressive up to week 82 (-4.0 +/- 0.3 kg). The most frequent adverse events were nausea and hypoglycaemia, both generally mild to moderate in intensity. CONCLUSIONS: Exenatide added to maximally effective doses of SU or SU plus MET resulted in a sustained reduction in HbA(1c) and a progressive reduction in weight over 1 1/2 years.

Adolescent↗
PubMed2006

Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes.

AIM: Exenatide, an incretin mimetic for the adjunct treatment of type 2 diabetes (DM2), reduced A1C and weight in 30-week placebo-controlled trials. This analysis examined the effects of exenatide on glycaemic control and weight over an 82-week period in patients with DM2 unable to achieve adequate glycaemic control with sulphonylurea (SU) and/or metformin (MET). METHODS: This interim analysis is of 314 patients who received exenatide in the 30-week placebo-controlled trials and subsequently in 52 weeks of open-label uncontrolled extension studies for 82 weeks of exenatide in total. Patients continued their SU and/or MET regimens throughout. RESULTS: Patients completed 82 weeks of exenatide treatment [n = 314, 63% M, age 56 +/- 10 years, weight 99 +/- 21 kg, body mass index 34 +/- 6 kg/m2, A1C 8.3 +/- 1.0% (mean +/- SD)]. Reduction in A1C from baseline to week 30 [-0.9 +/- 0.1% (mean +/- SE)] was sustained to week 82 (-1.1 +/- 0.1%), with 48% of patients achieving A1C < or = 7% at week 82. At week 30, exenatide reduced body weight (a secondary endpoint) from baseline (-2.1 +/- 0.2 kg), with progressive reduction at week 82 (-4.4 +/- 0.3 kg). Similar results were observed for the intent-to-treat population (n = 551), with reductions in A1C and weight at week 82 of -0.8 +/- 0.1% and -3.5 +/- 0.2 kg respectively. The 82-week completer cohort showed statistically significant improvement in some cardiovascular risk factors. The most frequent adverse events were generally mild-to-moderate nausea and hypoglycaemia. CONCLUSION: In summary, 82 weeks of adjunctive exenatide treatment in patients with DM2 treated with SU and/or MET resulted in sustained reduction in A1C and progressive reduction in weight, as well as improvement in some cardiovascular risk factors.

Adolescent↗
PubMed2006

Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data.

The therapeutic options for treating type 2 diabetes have been widened by the introduction of exenatide as the first incretin mimetic. Incretins are gut hormones that contribute to the stimulation of insulin secretion after a carbohydrate rich meal. The incretin hormone glucagon-like peptide-1 (GLP-1) not only stimulates insulin secretion under hyperglycaemic conditions, but also suppresses glucagon secretion, slows gastric emptying, induces satiety and improves beta cell function in type 2 diabetes. These beneficial effects have awakened the interest to use GLP-1 for the treatment of type 2 diabetes. Because of its short biological half-life, GLP-1 itself is not practical for type 2 diabetes therapy. Exenatide is a peptide found in the lizard Heloderma suspectum and has a high similarity to GLP-1. Exenatide belongs to the novel class of incretin mimetics because of its incretin-like action. It has a much longer biological half life than GLP-1 and is a GLP-1 receptor agonist that can be used for therapeutic purposes by twice daily injection. Clinical studies and clinical experience with exenatide have shown a significant reduction in HbA1c, fasting- and postprandial glucose and a marked reduction in body weight in type 2 diabetic patients. Animal studies reveal an improvement of beta cell function and an increase in beta cell mass after exenatide treatment. This review gives an overview on exenatide, its pharmacological profile and its role and potential in the therapeutic setting of type 2 diabetes. Furthermore, future developments concerning exenatide application are highlighted.

Animals↗
PubMedDate not supplied

Exenatide: from the Gila monster to the pharmacy.

OBJECTIVE: To explain the incretin concept and review the pharmacology and clinical utility of exenatide (Byetta-Amylin; Lilly), a new agent for the treatment of patients with type 2 diabetes mellitus, and provide pharmacists with information necessary for counseling patients in the use of exenatide. DATA SOURCES: Review articles, clinical trials, and data on file with the manufacturers. STUDY SELECTION: By the authors. DATA EXTRACTION: By the authors. DATA SYNTHESIS: Exenatide is a synthetic form of a protein found in the saliva of the Gila monster that mimics the action of glucagon-like peptide-1, an incretin important in glucose homeostasis and deficient in patients with diabetes mellitus. Three pivotal clinical trials of exenatide as an add-on therapy in patients with type 2 diabetes mellitus who were unable to achieve glycemic control with maximum doses of metformin, sulfonylurea, or these drugs in combination demonstrated significant reductions in glycosylated hemoglobin (A1C) levels following twice-daily self-injection of exenatide compared with placebo. Weight loss was observed in patients in conjunction with A1C improvement, which occurred without additional patient instruction, intentional caloric deficit, or exercise. Mild-to-moderate nausea was the most common adverse event with exenatide treatment, occurring at the beginning of therapy, lessening over time, and reduced by titration of the dose. CONCLUSION: Exenatide offers a wide range of beneficial glucoregulatory effects, including enhancement of glucose-dependent insulin secretion, restoration of first-phase insulin response, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. These positive effects depend on the patient's understanding of the proper administration technique and timing, the need for continued adherence, and what to do if adverse effects occur, all elements that can be conveyed by pharmacists in their counseling and education of patients with type 2 diabetes mellitus.

Animals↗
PubMed2005

Exenatide.

Exenatide is the first in a new class of compounds that exhibit activity similar to the naturally occurring hormone glucagon-like peptide-1 (GLP-1). Released from cells in the gut in response to food, GLP-1 binds to pancreatic beta-cell receptors to stimulate the release of insulin. Exenatide mirrors many of the effects of GLP-1, improving glycemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, reduced appetite and enhanced beta-cell function. As stimulation of insulin secretion occurs only in the presence of elevated blood glucose concentrations, the risk of hypoglycemia should be greatly reduced with exenatide. In addition to positive therapeutic effects on fasting and postprandial glucose levels, exenatide treatment is associated with significant, dose-dependent reductions in glycated hemoglobin (HbA1c) from baseline and progressive reductions in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but it can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Exenatide may enable patients with type 2 diabetes to achieve glycemic control while reducing or eliminating the risk of hypoglycemia and weight gain. These would represent significant therapeutic gains.

Adolescent↗
PubMed2005

A randomized, open-label, crossover study examining the effect of injection site on bioavailability of exenatide (synthetic exendin-4).

BACKGROUND: Exenatide (synthetic exendin-4;AC2993) is a 39-amino acid peptide in the new class of antidiabetic agents known as incretin mimetics. In clinical trials, exenatide exhibited glucoregulatory effects (glucose-dependent stimulation of insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying) in patients with type 2 diabetes mellitus (DM). OBJECTIVE: The goal of this study was to determine the relative bioavailability of exenatide injected subcutaneously into the abdomen, arm, or thigh. METHODS: Patients with type 2 DM were randomized in an open-label, crossover study to assess relative bioavailability of exenatide (10 microg) injected into the arm and thigh versus injection into the abdomen. Serial plasma exenatide concentrations were measured for 10 hours after injection. A sample size of >24 patients provided approximately 80% power to ensure that 90% CIs were within the 80% to 125% interval for the ratios (geometric least squares [LS] means) of AUC(0-infinity). RESULTS: Twenty-eight patients were randomized into the study (mean age, 56 [8] years; glycosylated hemoglobin, 8.0 [1.7]%; body mass index, 33 [5] kg/m2; all values given as mean [SD]). AUC(0-infinity) values (geometric LS mean SE for SC injections into the abdomen arm and thigh were 63,935 (6608), 59,573 (6157), and 62,148 (6424) pg./mL, respectively. The AUC (geometric LS mean ratio for relative bioavailability) for arm versus abdomen was 0.93 (geometric 90% CI, 0.82-1.05); for thigh versus abdomen it was 0.97 (geometric 90% CI, 0.86-1.10). Consistent with the observed data, intrasubject variability of AUC(0-infinity) was low among the 3 treatments (coefficient of variation, 26%). C(max) values (geometric LS mean [SE]) were 220 (24) pg/mL, abdomen; 218 (23) pg/mL, arm; and 193 (21) pg/mL, thigh. The C(max) (geometric LS mean ratio) for arm versus abdomen was 0.99 (geometric 90% CI, 0.85-1.15), and for thigh versus abdomen it was 0.88 (geometric 90% CI, 0.75-1.02). The most common treatment-emergent adverse events were mild to moderate nausea (36%), headache (25%), vomiting (21%), and dizziness (18%). Three patients received an inadvertent 10-fold overdose and were withdrawn from the study immediately. All experienced severe nausea and vomiting, and 1 patient experienced severe hypoglycemia requiring aid. All recovered without mishap and were excluded from statistical and tolerability results. There were no adverse events related to the injection or the injection site. CONCLUSION: In this study of patients with type 2DM, SC administration of exenatide into the abdomen, arm, or thigh resulted in comparable bioavailability.

Abdomen↗
PubMed2005

Pharmacokinetics of an oral drug (acetaminophen) administered at various times in relation to subcutaneous injection of exenatide (exendin-4) in healthy subjects.

Exenatide is an incretin mimetic with potential glucoregulatory activity in type 2 diabetes. This randomized, single-blind, placebo-controlled 6-way crossover study assessed exenatide's effect on acetaminophen pharmacokinetics. Of 40 randomized healthy subjects, 39 completed the study. On the placebo day, acetaminophen (1000 mg) was ingested and placebo injected subcutaneously at 0 hours. On exenatide days, acetaminophen was ingested at -1, 0, +1, +2, and +4 hours, relative to the 10 mug exenatide injected subcutaneously at 0 hours. With exenatide injection, mean plasma acetaminophen AUC(0-12 h) values were reduced by 11% to 24% (vs placebo). Peak plasma acetaminophen concentrations were similar for the -1-hour and placebo groups and reduced by 37% to 56% at other times. The most frequent adverse events were generally mild to moderate nausea and vomiting. Exenatide treatment concurrent with or preceding acetaminophen ingestion slowed acetaminophen absorption but had minimal effect on the extent of absorption.

Acetaminophen↗
PubMed2006

Patient-reported outcomes in a trial of exenatide and insulin glargine for the treatment of type 2 diabetes.

BACKGROUND: Patient-reported measures can be used to examine whether drug differences other than clinical efficacy have an impact on outcomes that may be important to patients. Although exenatide and insulin glargine appear to have similar efficacy for treatment of type 2 diabetes, there are several differences between the two treatments that could influence outcomes from the patient's perspective. The purpose of the current study was to examine whether the two drugs were comparable as assessed by patient-reported outcomes using data from a clinical trial in which these injectable medications were added to pre-existing oral treatment regimens. METHODS: Patients were randomized to either twice daily exenatide or once daily insulin glargine during a 26-week international trial. At baseline and endpoint, five patient-reported outcome measures were administered: the Vitality Scale of the SF-36, The Diabetes Symptom Checklist - Revised (DSC-R), the EuroQol EQ-5D, the Treatment Flexibility Scale (TFS), and the Diabetes Treatment Satisfaction Questionnaire (DTSQ). Change from baseline to endpoint was analyzed within each treatment group. Group differences were examined with General linear models (GLMs), controlling for country and baseline scores. RESULTS: A total of 549 patients with type 2 diabetes were enrolled in the trial, and current analyses were conducted with data from the 455 per protocol patients (228 exenatide and 227 insulin glargine). The sample was primarily Caucasian (79.6%), with slightly more men (55.2%) than women, and with a mean age of 58.5 years. Paired t-tests found that both treatment groups demonstrated statistically significant baseline to endpoint change on several of the health outcomes instruments including the DSC-R, DTSQ, and the SF-36 Vitality subscale. GLMs found no statistically significant differences between groups in change on the health outcomes instruments. CONCLUSION: This analysis found that both exenatide and insulin glargine were associated with significant improvements in patient-reported outcomes when added to oral medications among patients with type 2 diabetes. Despite an additional daily injection and a higher rate of gastrointestinal adverse events, treatment satisfaction in the exenatide group was comparable to that of the glargine group, possibly because of weight reduction observed in patients treated with exenatide.

Adult↗
PubMed2006

Exenatide.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of exenatide are discussed. SUMMARY: Exenatide, derived from a compound found in the saliva of the Gila monster, is an incretin mimetic agent that enhances glucose-dependent insulin secretion and has several other antihyperglycemic actions. The drug is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or both but who have not achieved adequate glycemic control. Peak plasma concentration following subcutaneous administration of exenatide is attained in 2.1 hours. The mean apparent volume of distribution after administration of a single subcutaneous dose is 28.3 L. The terminal half-life of the drug is 2.4 hours. Based on animal studies, the bioavailability of exenatide after subcutaneous injection has been estimated to be between 65% and 75%. The drug is predominantly eliminated by glomerular filtration followed by proteolytic degradation. Clinical trials have shown that exenatide given subcutaneously twice daily significantly reduced glycosylated hemoglobin values when maximum doses of a sulfonylurea, metformin, or both were ineffective. The most common adverse effects are nausea, vomiting, diarrhea, jitteriness, dizziness, headache, and dyspepsia. Drug-drug interactions with digoxin, lovastatin, lisinopril, and acetaminophen have been documented. The recommended starting dosage is 5 microg subcutaneously twice daily within one hour before the morning and evening meals. CONCLUSION: Exenatide offers a novel treatment option for patients with type 2 diabetes mellitus who are refractory to metformin or sulfonylurea therapy or both.

Animals↗
PubMed2004

Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia.

This study assessed whether glucose-dependent insulin secretion and overall counterregulatory response are preserved during hypoglycemia in the presence of exenatide. Twelve healthy fasted volunteers were randomized in a triple-blind crossover study to receive either intravenous exenatide (0.066 pmol. kg(-1). min(-1)) or placebo during a 270-min stepwise hyperinsulinemic-hypoglycemic clamp (insulin infusion 0.8 mU. kg(-1). min(-1)). Plasma glucose was clamped sequentially at 5.0 (0-120 min), 4.0 (120-180 min), 3.2 (180-240 min), and 2.7 mmol/l (240-270 min). At 270 min, insulin infusion was terminated and plasma glucose increased to approximately 3.2 mmol/l. The time to achieve plasma glucose >/=4 mmol/l thereafter was recorded. Insulin secretory rates (ISRs) and counterregulatory hormones were measured throughout. Glucose profiles were superimposable between the exenatide and placebo arms. In the presence of euglycemic hyperinsulinemia, ISRs in the exenatide arm were approximately 3.5-fold higher than in the placebo arm (353 +/- 29 vs. 100 +/- 29 pmol/min [least-square means +/- SE]). However, ISRs declined similarly and rapidly at all hypoglycemic steps (</=4 mmol/l) in both groups. Glucagon was suppressed in the exenatide arm during euglycemia and higher than placebo during hypoglycemia. Plasma glucose recovery time was equivalent for both treatments. The areas under the concentration-time curve from 270 to 360 min for cortisol, epinephrine, norepinephrine, and growth hormone were similar between treatment arms. There were no differences in adverse events. In the presence of exenatide, there was a preserved, glucose-dependent insulin secretory response and counterregulatory response during hypoglycemia.

Adult↗
PubMed2005

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

OBJECTIVE: This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metformin-sulfonylurea combination therapy. RESEARCH DESIGN AND METHODS: A 30-week, double-blind, placebo-controlled study was performed in 733 subjects (aged 55 +/- 10 years, BMI 33.6 +/- 5.7 kg/m(2), A1C 8.5 +/- 1.0%; means +/- SD) randomized to 5 microg subcutaneous exenatide b.i.d. (arms A and B) or placebo for 4 weeks. Thereafter, arm A remained at 5 microg b.i.d. and arm B escalated to 10 microg b.i.d. Subjects continued taking their dose of metformin and were randomized to either maximally effective (MAX) or minimum recommended (MIN) doses of sulfonylurea. RESULTS: Week 30 A1C changes from baseline (+/-SE) were -0.8 +/- 0.1% (10 microg), -0.6 +/- 0.1% (5 microg), and +0.2 +/- 0.1% (placebo; adjusted P < 0.0001 vs. placebo), yielding placebo-adjusted reductions of -1.0% (10 microg) and -0.8% (5 microg). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C < or =7% than placebo-treated subjects (34% [10 microg], 27% [5 microg], and 9% [placebo]; P < 0.0001). Both exenatide arms demonstrated significant weight loss (-1.6 +/- 0.2 kg from baseline each exenatide arm, -0.9 +/- 0.2 kg placebo; P < or = 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 microg), 19% (5 microg), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment. CONCLUSIONS: Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.

Adult↗
PubMedDate not supplied

Is exenatide a useful addition to diabetes therapy?

OBJECTIVE: To present an evidence-based evaluation of the antidiabetic drug exenatide. METHODS: The English literature from 1965 to January 2006 was reviewed by using data sources from MED-LINE, endocrinology textbooks, and manual searching of cross-references from original articles and reviews. RESULTS: Glucagon-like peptide-1 (GLP-1) is the major physiologic incretin, a gut-derived hormone that enhances glucose-induced insulin secretion. Moreover, GLP-1 inhibits glucagon secretion, delays gastric emptying, and may promote satiety, leading to reduction of postprandial glucose levels. Exenatide (AC-2993, synthetic exendin-4) is a GLP-1 analogue that was recently approved as adjunctive therapy in patients with diabetes in whom sulfonylureas, metformin, or both have failed. Exenatide is administered by subcutaneous injections twice daily. The use of exenatide has been associated with a mean reduction in hemoglobin A1c levels of approximately 0.8% and a mean weight loss of approximately 2 kg after 30 weeks of therapy in comparison with baseline. Treatment-related hypoglycemia was generally mild and occurred more commonly in association with the use of sulfonylureas. In 5% to 10% of patients, however, exenatide could not be tolerated, mainly because of nausea and vomiting. CONCLUSION: Exenatide is a moderately effective antidiabetic agent. Mild degrees of weight loss and hypoglycemia are its main advantages, whereas the frequent occurrence of nausea and vomiting and the requirement of subcutaneous administration are its strongest limitations. Nevertheless, this new drug may be a useful add-on therapy in obese patients with diabetes who have suboptimal control of their disease as a result of continuing weight gain, severe postprandial hyperglycemia, or both.

Animals↗
PubMed2006

Mathematical modeling shows exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin or metformin and a sulfonylurea.

The incretin mimetic exenatide improved glycemic control and reduced body weight in patients with type 2 diabetes inadequately controlled with metformin+/-a sulfonylurea. We assessed postprandial beta-cell function by mathematical modeling, independent of confounding effects from differing ambient glucose levels among treatments. Subjects were 63% males, 55+/-10 years, BMI 33+/-6 kg/m2, HbA1C 8.1+/-1.1% (+/- SD) randomized to 5 microg exenatide or placebo twice daily for 4 weeks. Subsequently, one arm remained at 5 microg twice daily, one arm escalated to 10 microg twice daily, and one treatment arm remained on placebo for 26 weeks. Subjects continued metformin+/-a sulfonylurea. A subset with meal tests at baseline and week 30 were analyzed (n=73). Outcome measures were the model-based beta-cell function parameters dose-response relating insulin secretion to glucose concentration, rate sensitivity, and potentiation. Exenatide reduced postprandial glucose excursions. Modeling predicted an upward shift of the beta-cell dose-response. Model-predicted insulin secretion rate at a reference glucose concentration increased 72% (10 microg), increased 40% (5 microg), or decreased 21% (placebo) at week 30 [ p=0.015 (10 microg); p=0.045 (5 microg); vs. placebo]. At week 30, the 2-hour post-meal to basal potentiation factor ratio was increased to 1.53+/-0.10 (10 microg; p=0.0142 vs. placebo) or 1.40+/-0.08 (5 microg; p=0.0402 vs. placebo) compared with 1.15+/-0.06 (placebo). Exenatide caused an upward shift of the beta-cell dose-response and enhanced potentiation of insulin secretion. This model suggests exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin+/-a sulfonylurea.

Adult↗
PubMedDate not supplied

Exenatide: a novel incretin mimetic agent for treating type 2 diabetes mellitus.

Maintaining glycemic control is the primary goal for preventing macrovascular and microvascular complications associated with type 2 diabetes. Currently available antidiabetic drugs work in different ways to lower blood glucose levels; unfortunately, each of them has its tolerability and safety concerns. Exenatide is the first drug in a new class known as the incretin mimetic agents. It improves glucose control by mimicking the effects of glucagon-like peptide-1, a natural mammalian incretin hormone secreted during food intake. Exenatide was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in conjunction with metformin and/or sulfonylurea. The recommended dosage is 5 mug to 10 mug twice daily subcutaneously before breakfast and dinner. In randomized, placebo-controlled, 30-week clinical studies, exenatide improved glycemic control and promoted weight loss of up to 2.8 kg. The most common adverse effects were nausea (44%), vomiting (13%), diarrhea (13%), and hypoglycemia (5-36%). Hypoglycemia occurred in a dose-dependent fashion. Patients should be closely monitored for hypoglycemia, especially when exenatide is added to sulfonylurea therapy. Overall, exenatide provides a treatment option for patients with type 2 diabetes who fail to obtain glycemic control while on a maximum dose of metformin and/or sulfonylurea therapy. It is also an alternative therapy for those patients who cannot tolerate other antidiabetic drugs.

Amino Acid Sequence↗
PubMed2006

Exenatide: a novel approach for treatment of type 2 diabetes.

Exenatide (synthetic exendin-4) is the analog of glucagon-like peptide 1 (GLP-1), the major physiologic incretin. The latter is an intestinal hormone that enhances glucose-induced insulin secretion after meals. In addition, GLP-1 stimulates insulin synthesis, inhibits glucagon secretion, delays gastric emptying, and may promote satiety. These glucoregulatory actions help control plasma glucose in the postprandial period. However, in diabetes, the GLP-1 response to nutrient intake is impaired, leading to exacerbation of postprandial hyperglycemia. Exenatide was recently approved as adjunctive therapy in diabetic patients failing sulfonylureas and/or metformin. In clinical trials lasting 30 weeks, exenatide therapy was associated with moderate reduction in mean hemoglobin A1c (HbA1c) levels of approximately 0.8%, and an average weight loss of approximately 2 kg compared with baseline. Hypoglycemia was generally mild and occurred more commonly when exenatide was used in conjunction with sulfonylureas. The requirement of subcutaneous injections twice a day, and the frequent occurrence of nausea and vomiting, represent the main limitations of exenatide. Nevertheless, this agent may be a useful add-on therapy in obese diabetic patients with suboptimal control as a result of continuing weight gain and/or severe postprandial hyperglycemia. The introduction of GLP-1-based antidiabetic drugs is a novel and promising strategy to treat diabetes.

Adamantane↗
PubMed2005

Effect of exenatide on the steady-state pharmacokinetics of digoxin.

This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 microg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUCtau,ss) and Cmin,ss but caused a 17% decrease in mean plasma digoxin Cmax,ss (1.40 to 1.16 ng/mL) and an increase in digoxin tmax,ss (median increase, 2.5 hours). Although the decrease in digoxin Cmax,ss was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.

Adult↗
PubMed2006

Recent evidence of sustained benefit with exenatide in Type 2 diabetes.

Exenatide has been shown to improve glycaemic control (over 30 weeks) in subjects with Type 2 diabetes. A recent extension study has shown that, in metformin-treated subjects with Type 2 diabetes, exenatide remained beneficial at 82 weeks. For those subjects who completed the study, in addition to the 1% fall in glycosylated haemoglobin (HbA1c) at 30 weeks, there was another 0.2% fall in HbA1c by 82 weeks. The weight loss achieved was a mean of 3 kg after 30 weeks, and this increased to 5.3 kg after 82 weeks in the completer cohort. In another extension study, continued benefit with exenatide was shown in subjects treated with metformin and/or sulfonylureas. For those subjects who completed the study, in addition to the 0.9% fall in HbA(1c) at 30 weeks, there was another 0.2% fall in HbA(1c) by 82 weeks. The weight loss achieved was a mean of 1.6 kg after 30 weeks, and this increased to 2.1 kg after 82 weeks in the completer cohort. The subjects taking exenatide with metformin had a greater weight loss (5.3 kg), compared with those treated with a sulfonylurea (3.9 kg) and those taking metformin and a sulfonylurea (4.1 kg). In conclusion, extension studies have confirmed that exenatide is an exciting new and useful medicine for Type 2 diabetes.

Diabetes Mellitus, Type 2↗