Exenatide Group Research Articles

Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction

Exenatide, a glucagon-like-peptide-1 analogue, increases myocardial salvage in experimental settings with coronary occlusion and subsequent reperfusion. We evaluated the cardioprotective effect of exenatide at the time of reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). A total of 172 patients with STEMI and Thrombolysis in Myocardial Infarction flow 0/1 were randomly assigned to exenatide or placebo (saline) intravenously. Study treatment was commenced 15 min before intervention and maintained for 6 h after the procedure. The primary endpoint was salvage index calculated from myocardial area at risk (AAR), measured in the acute phase, and final infarct size measured 90 ± 21 days after pPCI by cardiac magnetic resonance (CMR). In 105 patients evaluated with CMR, a significantly larger salvage index was found in the exenatide group than in the placebo group (0.71 ± 0.13 vs. 0.62 ± 0.16; P= 0.003). Infarct size in relation to AAR was also smaller in the exenatide group (0.30 ± 0.15 vs. 0.39 ± 0.15; P= 0.003). In a regression analysis, there was a significant correlation between the infarct size and the AAR for both treatment groups and an analysis of covariance showed that datapoints in the exenatide group lay significantly lower than for the placebo group (P= 0.011). There was a trend towards smaller absolute infarct size in the exenatide group (13 ± 9 vs. 17 ± 14 g; P= 0.11). No difference was observed in left ventricular function or 30-day clinical events. No adverse effects of exenatide were observed. In patients with STEMI undergoing pPCI, administration of exenatide at the time of reperfusion increases myocardial salvage.

Effect of Exenatide on Inflammatory and Oxidative Stress Markers in Patients with Type 2 Diabetes Mellitus

This study was designed to determine the effect of exenatide on inflammatory and oxidative stress markers in type 2 diabetes mellitus (T2DM) patients who were suboptimally controlled with metformin and/or sulfonylurea. Twenty-three patients with T2DM with inadequate glucose control were randomly divided into two groups: exenatide group (E group) (12 patients, 5 μg b.d. × 4 weeks followed by 10 μg b.d. × 12 weeks) and placebo group (P group) (11 patients). Glycosylated hemoglobin (HbA1c), the seven-point glucose profile, daily mean glucose, and glycemic excursion were determined. The effects of exenatide on 8-iso-prostaglandin F2α (PGF2α), monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity C-reactive protein (hs-CRP) were investigated. Exenatide treatment reduced body weight and body mass index (BMI) and improved HbA1c, the seven-point glucose profile, and daily mean glucose compared with placebo (P < 0.05). Limited glycemic excursion was found in the E group compared with the P group (P < 0.05), including a smaller SD and postprandial glucose excursion. In addition, the oxidative stress maker PGF2α was significantly reduced by exenatide treatment (P < 0.05). The inflammatory markers hs-CRP and MCP-1 were also significantly reduced in the E group compared with the P group (P < 0.05). PGF2α was significantly correlated with glycemic excursion (P < 0.05), whereas MCP-1 was significantly correlated with body weight, BMI, glycemic excursion, and HbA1c (P < 0.05 for all). Exenatide treatment reduced patient body weight and BMI, improved HbA1c and the seven-point glucose profile, reduced daily mean glucose, limited glycemic excursion, and reduced oxidative stress and inflammatory markers in patients of T2DM having inadequate glucose control.

Exenatide improves glucocorticoid-induced glucose intolerance in mice.

Exenatide is an incretin mimetic that is recently available in the US for the treatment of diabetes. There is a paucity of information on the effects of exenatide in glucocorticoid (GC)-induced diabetes. Although the effect of continuous intravenous infusion of exenatide on GC-induced glucose intolerance has been investigated before in healthy human males receiving oral prednisolone, we investigated the efficacy of a single subcutaneous dose of exenatide (3 μg/kg) in lowering blood glucose in GC-induced glucose intolerance in C57BL/6 mice. In a longitudinal experiment, the area under the curve (AUC) of oral glucose tolerance tests (OGTT) significantly increased after dexamethasone (P = 0.004), which was subsequently decreased by exenatide (P < 0.001). A cross-sectional experiment showed that exenatide improved glucose tolerance compared with placebo in a mouse model of dexamethasone-induced glucose intolerance. AUC of OGTT in the exenatide group were significantly (P < 0.001) lower than in the placebo group. Insulin tolerance tests (ITT) demonstrated that exenatide decreased the ability of the mice to tolerate insulin compared with placebo. The AUC of ITT in the exenatide group were also significantly (P = 0.006) lower than in the placebo group. In conclusion, a single dose of exenatide was able to decrease glucose intolerance and insulin resistance in these placebo-controlled experiments. Future clinical trials are justified to investigate the role of exenatide in the treatment of GC-induced glucose intolerance/diabetes.

Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin

OBJECTIVECases of acute pancreatitis have been reported in association with exenatide, sitagliptin, and type 2 diabetes without use of these medications. It remains unknown whether exenatide or sitagliptin increase the risk of acute pancreatitis.RESEARCH DESIGN AND METHODSA retrospective cohort study of a large medical and pharmacy claims database was performed. Data for 786,656 patients were analyzed. Cox proportional hazard models were built to compare the risk of acute pancreatitis between diabetic and nondiabetic subjects and between exenatide, sitagliptin, and control diabetes medication use.RESULTSIncidence of acute pancreatitis in the nondiabetic control group, diabetic control group, exenatide group, and sitagliptin group was 1.9, 5.6, 5.7, and 5.6 cases per 1,000 patient years, respectively. The risk of acute pancreatitis was significantly higher in the combined diabetic groups than in the nondiabetic control group (adjusted hazard ratio 2.1 [95% CI 1.7–2.5]). Risk of acute pancreatitis was similar in the exenatide versus diabetic control group (0.9 [0.6–1.5]) and sitagliptin versus diabetic control group (1.0 [0.7–1.3]).CONCLUSIONSOur study demonstrated increased incidence of acute pancreatitis in diabetic versus nondiabetic patients but did not find an association between the use of exenatide or sitagliptin and acute pancreatitis. The limitations of this observational claims-based analysis cannot exclude the possibility of an increased risk.

The synthetic GLP-I receptor agonist, exenatide, reduces intimal hyperplasia in insulin resistant rats

We studied the effect of a synthetic GLP-1 receptor agonist, exenatide, a drug approved for the treatment of type 2 diabetes, on the recovery from vascular injury in Zucker (non-diabetic) fatty rats. Exenatide 5.0 microg/kg per day or saline was administered for seven days before, and 21 days after balloon catheter mediated carotid injury. A pair feeding experiment helped differentiate between the drug itself and the known effects of the drug on decreased food intake. Body weight and glucose (weekly), carotid artery I/M ratio, aortic protein eNOS and NFkappaB-p65 were measured. Body weight gain in exenatide rats was significantly lower (53+/-5 vs. 89+/-8 g) than controls. Blood glucose did not change significantly. The I/M ratio in the exenatide group was 0.2+/-0.1 vs. 0.9+/-0.1 in controls (p<0.05). The expression of aortic eNOS was unchanged in exenatide treated rats and a small decrease seen in NFkappaB-p65 expression was not statistically significant. We conclude that exenatide attenuates intimal hyperplasia following balloon catheter induced vascular injury independently of glucose regulation and food intake. Our findings provide additional support for cardiovascular benefits of exenatide, especially in obese and pre-diabetic patients. Further research is needed to elucidate the mechanism underlying these effects.

The use of exenatide in severely burned pediatric patients

IntroductionIntensive insulin treatment (IIT) has been shown to improve outcomes post-burn in severely burnt patients. However, it increases the incidence of hypoglycemia and is associated with risks and complications. We hypothesized that exenatide would decrease plasma glucose levels post-burn to levels similar to those achieved with IIT, and reduce the amount of exogenous insulin administered.MethodsThis open-label study included 24 severely burned pediatric patients. Six were randomized to receive exenatide, and 18 received IIT during acute hospitalization (block randomization). Exenatide and insulin were administered to maintain glucose levels between 80 and 140 mg/dl. We determined 6 AM, daily average, maximum and minimum glucose levels. Variability was determined using mean amplitude of glucose excursions (MAGE) and percentage of coefficient of variability. The amount of administered insulin was compared in both groups.ResultsGlucose values and variability were similar in both groups: Daily average was 130 ± 28 mg/dl in the intervention group and 138 ± 25 mg/dl in the control group (P = 0.31), MAGE 41 ± 6 vs. 45 ± 12 (respectively). However, administered insulin was significantly lower in the exenatide group than in the IIT group: 22 ± 14 IU patients/day in the intervention group and 76 ± 11 IU patients/day in the control group (P = 0.01). The incidence rate of hypoglycemia was similar in both groups (0.38 events/patient-month).ConclusionsPatients receiving exenatide received significantly lower amounts of exogenous insulin to control plasma glucose levels. Exenatide was well tolerated and potentially represents a novel agent to attenuate hyperglycemia in the critical care setting.Trial registrationNCT00673309.

Clinical application of Exenatide for type 2 diabetes

Exenatide is the first in a new class of compounds, which possess similar activity to the naturally-occurring hormone glucagon-like peptide-1 (GLP-1. In three phase Ⅲ trials in patients with type 2 diabetes mellitus (T2DM). who have Inadequate glycaemic control despite receiving treatment with metformin and/ or sulfonylurea, the addition of exenatide twice daily significantly reduced glycated haemoglobin ( ≤ 1 %), and fasting and postprandial plasma glucose and was associated with progressive and significant bodyweight reduction from baseline for up to 2 years, Nausea (about 40%) was the most commonly reported adverse event in the combined exenatide groups. The addition of exenatide also improved glycemic control in a small population with T2DM receiving thiazolidinedione. The glycaemic control with exenatide was similar to that achieved with insulin glargine or biphasic insulin aspart. However， the insulin doses were well below doses used in recent studies. In a head-to-head clinical trial， exenatide once-weekly caused greater improvements in glycemic control and was better tolerated than exenatide twice daily. On the basis of the data, adjunctive therapy with exenatide is a valuable therapeutic option in obese patients with T2DM requiring moderate improvements in glycaemic control despite treatment with metformin and/or a sulfonylurea, In addition, exenatide once-weekly is a promising development candidate for the treatment of T2DM.

Persistence with injectable antidiabetic agents in members with type 2 diabetes in a commercial managed care organization

Objective:While many patients with type 2 diabetes require insulin to achieve glycemic goals, little is known about patients’ persistence with insulin or other injectable antidiabetic therapies. The objective of this study was to evaluate persistence with injectable antidiabetic agents in patients with type 2 diabetes who were naïve to these treatments.Methods:The study cohort was obtained using administrative and pharmacy claims data from a commercial managed care organization of approximately 1.2 million members with pharmacy benefits. The inclusion criteria were members with type 2 diabetes who had at least one pharmacy claim for insulin glargine, insulin detemir, exenatide, or isophane insulin human (NPH insulin) from January 1, 2006 through June 30, 2006. The first claim for any of these injectable therapies was considered the index prescription. Members were excluded if they filled a prescription (a) for any injectable antidiabetic medication from July 2005 through December 2005; or (b) for short/rapid-acting or mixed insulins during 2006, either prior to the index date or within 30 days following the index date. The primary outcome was persistence with the index drug, defined as number of months between the initiation of therapy (i.e., index date) and either the end of therapy (date of last fill plus days supply) or study period of 12 months. The secondary outcome was the percentage of patients with claims for new antidiabetic agents added after index date. Multivariate regression with life data (survival analysis) was performed with number of months of persistence as the dependent variable.Results:The cohort consisted of 1769 members with a mean (SD) age of 53.2 (12.5) years and 47.4% were men. Mean (SD) months of persistence for members on insulin glargine, insulin detemir and exenatide were similar at 7.8 (4.1), 7.8 (4.4), and 7.6 (4.4), respectively. Members taking NPH insulin had statistically lower persistence at 5.6 (4.5) months (P < 0.001). Overall persistence was 28.7% for injectable antidiabetics at 1 year among treatment-naïve patients. In a multivariate regression model, patients who were younger (P = 0.025) and who initially received NPH insulin (P < 0.001) were less likely to persist. There was no association between persistence and sex, initial copayment, or number of oral antidiabetic medications at time of index prescription. Members in the exenatide and NPH insulin groups were less likely to receive new antidiabetic agents compared with the insulin glargine group (P < 0.001). Limitations include the use of pharmacy claims to proxy the type of diabetes and patients with gestational diabetes may have been included. Missing or inaccurate claims data, the use of samples and hospitalizations may have occurred and would result in an underestimation of persistence.Conclusions:Persistence was low for injectable antidiabetics at 1 year among treatment-naïve patients. Patients who received insulin glargine, insulin detemir, or exenatide were more likely to persist than patients receiving NPH insulin. Older patients were more likely to persist, but sex, copayment and number of oral antidiabetic medications at initiation of the injectable antidiabetic were not associated with persistence.

Exenatide compared with long‐acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long‐Acting insulin (HEELA) study

Aim: The Helping Evaluate Exenatide in overweight patients with diabetes compared with Long-Acting insulin (HEELA) study was designed to examine whether the glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide, could improve HbA1c (≤7.4%) with minimal weight gain (≤1 kg) compared with insulin glargine.Methods: Patients [body mass index (BMI) >27 kg/m2] with elevated cardiovascular risk and type 2 diabetes inadequately controlled on two or three oral antidiabetes drugs (OADs) were randomized to add-on exenatide 5–10 μg b.i.d. (n = 118) or insulin glargine o.d. (titrated to target fasting plasma glucose ≤5.6 mmol/l; n = 117) for 26 weeks.Results: The study population had baseline mean (s.d.) age of 56.5 (9.1) years and BMI of 34.1 (5.3) kg/m2, and 58.5% of patients were taking two OADs. Mean baseline HbA1c was 8.65 (0.68)% in the exenatide group and 8.48 (0.66)% in the insulin glargine group. The proportions of patients achieving the composite endpoint of HbA1c ≤7.4% with weight gain ≤1 kg were 53.4% for the exenatide group and 19.8% for the insulin glargine group (p < 0.001 for exenatide vs. insulin glargine). Exenatide and insulin glargine did not demonstrate a significant difference in HbA1c improvements [least square (LS) mean [s.e.m.]: −1.25 [0.09]% and −1.26 [0.09]% respectively; p = 0.924], but had divergent effects on body weight (−2.73 [0.31] vs. +2.98 [0.31] kg respectively, p < 0.001) after 26 weeks. There were more treatment-related adverse events with exenatide but a lower incidence of nocturnal hypoglycaemia, with no differences in overall or severe hypoglycaemia.Conclusions: Additional treatment with exenatide resulted in significantly more overweight and obese patients with an elevated cardiovascular risk and type 2 diabetes achieving better glycaemic control with minimal weight gain compared with insulin glargine.

A review of exenatide as adjunctive therapy in patients with type 2 diabetes

Incretin glucagon-like peptide-1 (GLP-1) is a hormone released from cells in the gastrointestinal tract (GI), leading to glucose-dependent insulin release from the pancreas. It also suppresses postprandial hyperglycemia, glucagon secretion and slows gastric emptying. Exenatide (EXE), a functional analog of human GLP-1, was approved by the US FDA in April 2005. This article reviews current primary literature on the clinical efficacy and safety of EXE in the treatment of type 2 diabetes mellitus (DM) and describes the pharmacokinetics, pharmacodynamics, dosing and administration of EXE. English-language articles were identified through a search of MEDLINE (1966 to March 2009), International Pharmaceutical Abstracts (1970 to present), and Cochrane Database of Systemic Reviews (1995 to March 2009). Search terms included EXE, diabetes mellitus, postprandial hyperglycemia, gastric emptying, glucagon, pharmacokinetics and pharmacodynamics. Articles were selected for review if their designs were randomized, blinded and of controlled design that focused on clinical outcomes of patients with type 2 DM. EXE is administered subcutaneously in the thigh, abdomen or upper arm within the 60-minute period before the morning and evening meals. Its C(max) is reached within 2.1 hours, and its T(1/2) in 2.4 hours. EXE's metabolism is primarily through the kidneys. For the patients who received EXE 10 microg SC BID in three, 30-week, placebo-controlled studies with background sulfonylureas (SUs), metformin (MET), or SU + MET, there were significant reductions in HbA(1c) (0.77 to 0.86%), fasting plasma glucose (0.6 mmol/L) and body weight (1.6 to 2.8 kg) (P < or = 0.05 vs PCB) that were sustained in patients who completed two open-label phase trials with an additional 52 weeks of therapy. The use of thiazolidinediones was associated with a slight advantage over EXE in improving HbA(1c) along with increased weight gain; those who received EXE lost weight, but experienced more GI adverse effects. Patients who received EXE lost significant body weight while patients who received insulin gained weight. Patients receiving insulin had lower fasting, prelunch and predinner glucose excursions while patients in the EXE groups had lower postprandial glucose levels. Nausea was most frequently (>20%) reported in patients receiving the highest dose of EXE (10 microg SC BID vs 5 microg SC BID). EXE at the dose of 10 microg SC BID has been proven to decrease HbA(lc) by 1.3% +/- 0.1% and decrease body weight by up to 5.3 +/- 0.8 kg at week 82. Nausea was the most frequently reported adverse event (>20%) especially in patients being treated with EXE 10 microg SC BID. EXE can be safely added to MET therapy, SU therapy or MET + SU combination to effectively target glycemic goals in patients with type 2 DM. Long-term, head-to-head studies assessing the effect of the EXE +/- oral agents/insulins in patients with HbA(lc) > or = 10% are still needed to fully clarify the role of EXE in poorly controlled patients with type 2 DM.

Exenatide efficacy and safety: a systematic review

To examine the efficacy, effectiveness and side effects of exenatide when compared with oral glucose-lowering agents or insulin therapy. Relevant citations were identified from searches of multiple bibliographic databases supplemented with searches of the US Food and Drug Administration website and other sources. A qualitative synthesis was performed, with a random effects meta-analysis when appropriate. We identified 17 studies. In placebo-controlled trials of subjects with poorly controlled diabetes (with both groups receiving various oral glucose-lowering agents), exenatide 10 microg twice daily improved glycated haemoglobin (HbA(1c)) by approximately 1.0% over 30 weeks [pooled estimate -0.97%, 95% confidence interval (CI), -1.16 to -0.79%, P < 0.0001] and exenatide treatment over 16-30 weeks was associated with weight loss of 1.0-2.5 kg. Exenatide appeared to confer a similar benefit to various insulin regimes for glycaemic control at follow-up between 16 and 52 weeks (pooled estimate HbA(1c)-0.04%, 95% CI, -0.14 to 0.06%, P = 0.41), but was advantageous over insulin with respect to weight loss (3-6 kg loss at up to 52 weeks of follow-up). Nausea was the most common adverse event in placebo- and active-controlled trials. Rates of hypoglycaemia were similar in exenatide and insulin groups, but were higher with exenatide 10 microg twice daily compared with placebo and hypoglycaemia was most frequent when a sulphonylurea was administered. In subjects with poorly controlled diabetes, exenatide was associated with a reduction in HbA(1c) that was similar to introducing another oral agent or insulin. Weight loss may be an advantage with exenatide. Long-term studies in diverse and unselected populations are needed to clarify the benefit vs. harm profile of this drug.

Efficacy and safety of biphasic insulin aspart 70/30 versus exenatide in subjects with type 2 diabetes failing to achieve glycemic control with metformin and a sulfonylurea

ABSTRACTObjective: To compare safety and efficacy of biphasic insulin aspart 70/30 (BIAsp 30) with exenatide in subjects with type 2 diabetes mellitus (T2DM) not achieving glycemic targets with metformin and sulfonylurea in a randomized, open-label, 24-week trial.Research design and methods: Subjects (N = 372, T2DM > 6 months, age ≥ 18 and ≤ 80 years, HbA1c ≥ 8%, insulin naive not achieving glycaemic targets, receiving metformin and sulfonylurea) were randomized 1: 1: 1 to receive either BIAsp 30 QD (12 U before supper); BIAsp 30 BID (12 U divided equally between pre-breakfast and pre-supper); or exenatide (5 µg BID for 4 weeks and 10 µg BID thereafter). Efficacy (HbA1c, fasting plasma glucose [FPG]) and safety (adverse events and hypoglycemic episodes) were assessed.Results: Glycemic control achieved with both BIAsp 30 BID and BIAsp 30 QD was superior to that with exenatide (BIAsp 30 BID-exenatide: HbA1c difference −0.91% [95% CI: −1.23 to −0.59%] and BIAsp 30 QD-exenatide: difference: −0.67% [95% CI: −0.99 to −0.34%]). At the end of the study, more subjects achieved HbA1c < 7% and ≤ 6.5% in the BIAsp 30 BID group than in the exenatide group (HbA1c < 7%: 37% vs. 20%, p = 0.0060; HbA1c ≤ 6.5%: 25% vs. 8%, p = 0.0004, respectively). Combined hypoglycemic episodes (major, minor, symptoms only) were reported by 56%, 61%, and 29% of the subjects in the BIAsp 30 QD, BIAsp 30 BID, and exenatide groups, respectively. Weight gain was observed in the BIAsp 30 group (BIAsp 30 QD: 2.85 kg, BIAsp 30 BID: 4.08 kg) and weight loss was observed in the exenatide group (−1.96 kg). Nausea or vomiting was responsible for discontinuation of seven subjects in the exenatide group and one subject in the BIAsp 30 BID group.Conclusions: Significantly more T2DM patients (poorly controlled with combination metformin/sulfonylurea) achieved glycemic goals when treated with BIAsp 30 than with exenatide. The high baseline HbA1c values (∼10.2%) and the long duration of diabetes (∼9 years) suggests that some subjects may have been in an advanced stage of their diabetes and may not have had sufficient β-cell function for a GLP-1 mimetic to be effective. The insulin-treated groups had more minor hypoglycemic events and weight gain but less gastrointestinal side-effects. In summary, BIAsp 30 was more efficacious in helping patients with high baseline HbA1c achieve glycemic goals.Clinical trial registration: www.clinicaltrials.gov, NCT00097877

Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug—naive patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, parallel-group study

Background: Evaluation of exenatide monotherapy in patients with type 2 diabetes may be of clinical interest based on improvements in glycemic control and weight that have been reported with the use of exenatide in combination with oral antidiabetic agents. Objective: The aim of this study was to evaluate the efficacy and tolerability of exenatide monotherapy in patients with type 2 diabetes naive to antidiabetic agents and whose disease was inadequately controlled with diet and exercise alone. Methods: This 24-week, double-blind, placebo-controlled, parallel-group study was conducted at 23 centers across the United States, Puerto Rico, Romania, Russia, and India. Patients aged ≥18 years with type 2 diabetes were randomly assigned to receive exenatide 5 µg, exenatide 10 µg, or placebo administered SC BID. Patients were instructed by investigators to maintain their individualized prestudy diet and exercise regimens throughout the study. Efficacy measures included: glycosylated hemoglobin (HbA 1c); fasting serum glucose (FSG); 6-point self-monitored blood glucose; percentages of patients achieving HbA 1c values ≤6.5% and ≤7.0%; weight; and homeostasis model of β-cell function (HOMA-B, a clinical measure of pancreatic β-cell function). Tolerability measures included patient-reported adverse events, hypoglycemia, and blood pressure. Results: A total of 232 patients were included in the intent-to-treat population (130 men, 102 women; 68% white; mean [SD] age, 54 [10] years; duration of type 2 diabetes, 2 [3] years; weight, 86 [16] kg; body mass index, 31 [5] kg/m 2; HbA 1c, 7.8% [0.9%]). At end point, least-squares mean (SE) HbA 1c reductions (%) from baseline were significantly greater with exenatide 5 and 10 µg than placebo (-0.7 [0.1] and -0.9 [0.1] vs -0.2 [0.1]; P = 0.003 and P < 0.001, respectively), as were FSG reductions (mg/dL) (-17.5 [4.0] and -18.7 [4.0] vs -5.2 [4.0]; P = 0.029 and P = 0.016, respectively). Changes in daily mean postprandial glucose excursions (mg/dL) from baseline to end point were significantly greater with exenatide 5 and 10 µg than placebo (-21.3 [2.7] and -24.7 [2.7] vs -8.3 [2.5]; both, P < 0.001). With exenatide 5 and 10 µg, 31% and 35% of patients achieved HbA 1c ≤6.5% at end point versus 19% with placebo ( P = NS and P = 0.026, respectively), while 48% and 46% versus 29% achieved HbA 1c ≤7.0% ( P = 0.024 and P = 0.036, respectively). Changes in weight (kg) at 24 weeks were greater with exenatide 5 and 10 ²g than placebo (-2.8 [0.3] and -3.1 [0.3] vs -1.4 [0.3]; P = 0.004 and P < 0.001, respectively). HOMA-B values increased from baseline to end point by 32% and 28% in the exenatide 5- and 10-µg groups, respectively, versus 6% for placebo. Improvements from baseline to end point in HOMA-B were significantly greater with exenatide 5 and 10 µg than placebo ( P = 0.002 and P = 0.010, respectively). Significant improvements in mean systolic and diastolic blood pressure (mm Hg) from baseline to end point were also observed with exenatide (systolic, both 5 and 10 µg, -3.7 [1.2] [ P = 0.037]; diastolic, 10 µg, -2.3 [0.7] [ P = 0.046]) versus placebo (systolic, -0.3 [1.2]; diastolic, -0.3 [0.7]). Overall, 25% of patients reported ≥1 treatment-emergent adverse event. Nausea was reported with the greatest incidence (5 µg, 3%; 10 µg, 13%; placebo, 0%; P = 0.010 for the combined exenatide group vs placebo). Most (88%) treatment-emergent adverse events were mild or moderate in intensity. Hypoglycemia was reported in 5%, 4%, and 1% of patients in the exenatide 5- and 10-µg and placebo groups, respectively ( P = NS), with no incidents of severe hypoglycemia reported. Conclusions: In these patients with type 2 diabetes naive to treatment with antidiabetic agents, exenatide monotherapy was associated with improved HbA 1c, improved fasting and postprandial glucose control, reduced weight, improved β-cell function (HOMA-B), and improved blood pressure, and was well tolerated. These results suggest that exenatide monotherapy may provide a viable treatment option beyond diet and exercise and support further study of exenatide monotherapy in antidiabetic drug-naive patients with type 2 diabetes.

Effect of exenatide on 24-hour blood glucose profile compared with placebo in patients with type 2 diabetes: A randomized, double-blind, two-arm, parallel-group, placebo-controlled, 2-week study

Objective: The aim of this study was to examine the glucose-lowering effect of exenatide over 24 hours in patients with type 2 diabetes with inadequate glycemic control using metformin, with or without a thiazolidinedione (TZD). Methods: This randomized, double-blind, 2-arm, parallel-group, placebo-controlled, 2-week study was conducted in patients with type 2 diabetes with inadequate glycemic control, despite metformin with or without a TZD. Patients underwent a baseline and a week-2 (study end) 24-hour admission during which serial serum glucose measurements were taken. Preprandial and postprandial concentrations of triglycerides and free fatty acids were also measured. Meals provided for each patient were identical at the baseline and week-2 assessments. Following the baseline admission, patients were randomized to receive SC injections of either exenatide (5 μg BID for 1 week, then 10 μg BID for the next week) or placebo (volume equivalent) for 14 days. Results: A total of 30 patients (19 women [63%], 11 men [37%]; mean [SD] age, 52.6 [11.2] years; weight, 94.3 [23.0] kg; body mass index, 34.2 [6.1] kg/m 2; glycosylated hemoglobin value, 8.0% [0.9%]; diabetes duration, 8.7 [5.6] years; race, Hispanic 18 [60%], white 10 [33%], black 2 [7%]) were eligible. Seventeen patients (57%) were randomized to treatment with exenatide and 13 patients (43%) received placebo. Concurrent antidiabetic medications were metformin only (n = 19 [63%]) and metformin plus a TZD (n = 11 [37%]). All postbaseline values were least squares mean (SE). After 2 weeks (study end), the 24-hour time-average glucose values were 7.0 (0.2) and 8.8 (0.3) mmol/L for exenatide-treated and placeboadministered patients, respectively ( P < 0.001). The glucose values for patients treated with exenatide were lower compared with those in patients who received placebo 2 hours after the morning meal (6.6 [0.4] vs 12.0 [0.5] mmol/L; P < 0.001), the midday meal (8.8 [0.5] vs 11.8 [0.6] mmol/L; P = 0.001), and the evening meal (6.8 [0.4] vs 11.3 [0.4] mmol/L; P < 0.001). The mean durations of patient exposure to glucose concentrations >7.8 and >11.1 mmol/L were significantly shorter for the exenatide group compared with the placebo group (>7.8 mmol/L: 6.8 [0.9] vs 14.1 [1.1] hours; >11.1 mmol/L: 1.0 [0.7] vs 4.7 [0.8] hours; both, P < 0.001). After 2 weeks, the postprandial triglyceride excursions after the morning and evening meals for patients treated with exenatide were significantly lower compared with those treated with placebo. There was no apparent effect on free fatty acid concentrations. Conclusions: In these patients with type 2 diabetes, exenatide was associated with significantly reduced glucose concentrations at multiple time points during 24 hours, with the greatest effect seen on postprandial glucose concentrations. In addition, exenatide was associated with decreased overall hyperglycemic exposure and significantly decreased postprandial triglyceride excursions. These results are consistent with those seen in other studies that reported the effectiveness of exenatide in controlling hyperglycemia in patients with type 2 diabetes.

Exploring the Substitution of Exenatide for Insulin in Patients With Type 2 Diabetes Treated With Insulin in Combination With Oral Antidiabetes Agents

This 16-week study explored the safety of substituting exenatide for insulin in patients with type 2 diabetes using insulin in combination with oral antidiabetes agents. Successful maintenance of glycemic control was predefined as an A1C increase of < 0.5%. A total of 49 patients (aged 53 +/- 8 years, with BMI 34 +/- 4 kg/m2, A1C 8.1 +/- 1.1%, and duration of diabetes 11 +/- 7 years) were randomized to either substitute exenatide for insulin or remain on their current insulin regimen. Patients who either completed > or = 8 weeks of study or discontinued because of loss of glycemic control were included in primary efficacy analysis. A total of 62% (18 of 29) of the exenatide-treated patients maintained glycemic control compared with 81% (13 of 16) of the insulin-treated patients. Of the 11 exenatide-treated patients who did not maintain control, 5 discontinued before week 16 because of loss of glucose control. The overall safety profile was generally consistent with previous exenatide trials. The mean overall hypoglycemia rates were 1.72 and 0.97 events/patient-year for the exenatide and insulin reference groups, respectively. This pilot study suggests that it is feasible to sustain glycemic control when substituting exenatide for insulin. Although it is not possible to characterize clear predictors of outcome given the size and exploratory nature of the study, the data suggest that patients with longer disease duration, who are taking higher doses of insulin and have less endogenous beta-cell function, may experience deterioration in glucose control if exenatide is substituted for insulin therapy.

The Effect of Adding Exenatide to a Thiazolidinedione in Suboptimally Controlled Type 2 Diabetes

Exenatide therapy is effective in combination with metformin or sulfonylureas for treating type 2 diabetes. Thiazolidinediones (TZDs) also are commonly used, but the efficacy of exenatide with a TZD has not been reported. To compare the effects of exenatide versus placebo on glycemic control. Placebo run-in, randomized, double-blind, placebo-controlled trial conducted from May 2004 to August 2005. 49 sites in Canada, Spain, and the United States. 233 (exenatide group, n = 121; placebo group, n = 112) patients with type 2 diabetes that was suboptimally controlled with TZD treatment (with or without metformin). Mean (+/-SE) baseline glycated hemoglobin A1c level was 7.9% +/- 0.1%. Subcutaneous abdominal injections of 10 microg of exenatide or placebo twice daily, added to a TZD (with or without metformin) for 16 weeks. The primary outcome was change from baseline in hemoglobin A1c level. Other outcomes were fasting serum glucose level, body weight, self-monitored blood glucose level, and any adverse events. Exenatide treatment reduced hemoglobin A(1c) level (mean difference, -0.98% [95% CI, -1.21% to -0.74%]), serum fasting glucose level (mean difference, -1.69 mmol/L [-30.5 mg/dL] [CI, -2.22 to -1.17 mmol/L {-40.0 to -21.1 mg/dL}]), and body weight (mean difference, -1.51 kg [CI, -2.15 to -0.88 kg]). Sixteen percent of patients in the exenatide group and 2% of patients in the placebo group discontinued treatment because of adverse events. In the exenatide group, 40% (n = 48) of patients experienced nausea (mostly mild [n = 21] or moderate [n = 19]), 13% experienced vomiting, and 11% experienced hypoglycemia. In the placebo group, 15% of patients experienced nausea, 1% experienced vomiting, and 7% experienced hypoglycemia. Combinations with TZDs and sulfonylureas were not tested. Trial duration was relatively short. Only 71% and 86% of patients in the exenatide and placebo groups, respectively, completed the study. Exenatide therapy improved glycemic control, reduced body weight, and caused gastrointestinal symptoms more than placebo in patients with type 2 diabetes that was suboptimally controlled with TZD therapy. ClinicalTrials.gov registration number: NCT00099320. For more information on exenatide click here.

Exenatide effects on statin pharmacokinetics and lipid response

Exenatide is an adjunctive treatment for type 2 diabetes. Many patients with type 2 diabetes have dyslipidemia, which requires treatment with three hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase inhibitors (statins), hence, concurrent use of exenatide and statins is likely. Exenatide slows gastric emptying, which may alter the absorption rate of co-administered oral medications. Thus, the potential interaction between exenatide and statins was evaluated in two study settings. In an open-label, fixed-sequence, clinical pharmacology study, the plasma pharmacokinetics of lovastatin (40 mg after breakfast) in the presence and absence of exenatide (10 microg before breakfast and dinner) was evaluated in 21 healthy subjects. In a second clinical setting, changes in lipid profiles and statin dosage over 30 weeks in patients with type 2 diabetes were retrospectively compared (n = 180 exenatide 10 microg twice daily (BID), n = 168 placebo BID) in a combined analysis of three placebo-controlled, randomized exenatide Phase 3 trials. In healthy subjects, exenatide decreased mean lovastatin area under the plasma concentration time curve from zero to infinity (AUC0-infinity) and maximum plasma concentration (Cmax) by 40 and 28%, respectively, and increased median time to maximum plasma concentration (tmax) by 4 hours. In the exenatide Phase 3 trials, 30-week changes from baseline for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides and statin dosage were not significantly different between the exenatide and placebo groups treated with statins. Despite observed changes in lovastatin bioavailability in the pharmacokinetic drug interaction study, exenatide did not negatively affect long-term lipid profiles or statin dosage in patients with concurrent statin therapy. Thus, co-administration of exenatide does not require adjustment in statin dosage.

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

BackgroundPatient-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.MethodsPatients 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.ResultsA 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.ConclusionThis 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.

Exenatide: An incretin mimetic for the treatment of type 2 diabetes mellitus

Background: Exenatide is a subcutaneously injected incretin mimetic. It is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) who are already receiving therapy with metformin, a sulfonylurea, or both but continue to have suboptimal glycemic control. Objective: This article reviews available information on the clinical pharmacology, comparative efficacy, tolerability, drug interactions, contraindications and precautions, dosage and administration, availability and storage, and cost of exenatide. Methods: MEDLINE (1966–April 2006) and Web of Science (1995–April 2006) were searched for original research and review articles published in the English language. The search terms used were exenatide, exendin-4, glucagon-Like peptide-1, GLP-1, and incretin mimetic. The reference lists of identified articles were also consulted, as was selected information from the package insert for exenatide. All relevant comparative efficacy studies that were available in published form were included in the review. Results: Naturally occurring incretins, such as glucagon-like peptide-1 (GLP-1), exhibit insulinotropic properties after release into the circulation from the gut. As a GLP-1 agonist, exenatide improves glucose homeostasis by mimicking the actions of naturally occurring GLP-1. It improves glycemic control by reducing fasting and postprandial glucose concentrations through a combination of known mechanisms, including glucose-dependent insulin secretion, restoration of first-phase insulin response, regulation of glucagon secretion, delaying gastric emptying, and decreasing food intake. Three Phase III comparative efficacy trials were identified that enrolled a total of 1446 patients who received exenatide 5 pg SC BID, exenatide 10 μg SC BID, or placebo for 30 weeks in addition to their existing therapy with metformin, sulfonylurea, or both. In these trials, the addition of exenatide was associated with significant reductions in glycosylated hemoglobin (HbA 1c) values ( P < 0.001– P < 0.002), greater proportions of patients achieving an HbA 1c ≤7%, significant decreases in fasting plasma glucose concentrations ( P < 0.001– P < 0.005), and a dose-dependent progressive weight loss compared with placebo. Nausea (43.5%) was the most commonly reported adverse event in the combined exenatide groups. Other adverse events occurring in >10% of patients receiving exenatide were hypoglycemia (19.6%), diarrhea (12.8%), and vomiting (12.8%). Conclusions: During clinical trials, exenatide added to existing metformin and/or sulfonylurea therapy in patients with T2DM reduced fasting and postprandial glucose concentrations, with improvements in HbA 1c and modest weight loss. The main adverse effect associated with exenatide therapy was nausea.

Exenatide versus Insulin Glargine in Patients with Suboptimally Controlled Type 2 Diabetes

Physicians may use either insulin or exenatide injections for patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs. To compare effects of exenatide and insulin glargine on glycemic control in patients with type 2 diabetes mellitus that is suboptimally controlled with metformin and a sulfonylurea. 26-week multicenter, open-label, randomized, controlled trial. 82 outpatient study centers in 13 countries. 551 patients with type 2 diabetes and inadequate glycemic control (defined as hemoglobin A1c level ranging from 7.0% to 10.0%) despite combination metformin and sulfonylurea therapy. Exenatide, 10 microg twice daily, or insulin glargine, 1 daily dose titrated to maintain fasting blood glucose levels of less than 5.6 mmol/L (<100 mg/dL). Hemoglobin A1c level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability. Baseline mean hemoglobin A1c level was 8.2% for patients receiving exenatide and 8.3% for those receiving insulin glargine. At week 26, both exenatide and insulin glargine reduced hemoglobin A1c levels by 1.11% (difference, 0.017 percentage point [95% CI, -0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than exenatide. Body weight decreased 2.3 kg with exenatide and increased 1.8 kg with insulin glargine (difference, -4.1 kg [CI, -4.6 to -3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenatide (0.9 event/patient-year versus 2.4 events/patient-year; difference, -1.6 events/patient-year [CI, -2.3 to -0.9 event/patient year]). Gastrointestinal symptoms were more common in the exenatide group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%). The trial was open-label and did not assess clinical complications related to diabetes. Of the 551 participants, 19.4% of those receiving exenatide and 9.7% of those receiving insulin glargine withdrew from the study. Only 21.6% of the insulin glargine group and 8.6% of the exenatide group achieved the target level for fasting plasma glucose of less than 5.6 mmol/L (<100 mg/dL). Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine.