Addition of exenatide BID to insulin glargine: a post-hoc analysis of the effect on glycemia and weight across a range of insulin titration.

BACKGROUND AND OBJECTIVE: In a 30 week, double-blind, randomized, controlled Phase 3 study in patients with type 2 diabetes mellitus, the addition of fixed-dose exenatide twice daily (BID) to titrated insulin glargine resulted in significant glycated hemoglobin (HbA(1c)) lowering and weight loss without increased hypoglycemia risk versus titrated insulin glargine alone. Because individualized insulin titration contributed to these results, this post-hoc analysis examined the results in the context of the degree of insulin titration that occurred. METHODS: Subjects on pre-existing insulin glargine (with or without oral antidiabetes agents) were randomized to placebo (n = 123) or exenatide BID (n = 138; 5 µg for 4 weeks, then 10 µg ongoing). Insulin glargine was titrated in both arms per the Treat-to-Target algorithm. Tertiles (T1, T2, T3) were based on change in insulin dose from baseline to endpoint. Change in HbA(1c), hypoglycemia risk, and weight gain were assessed per insulin dose tertile. RESULTS: The population comprised adult patients (mean age = 59 y) with type 2 diabetes and an HbA(1c) level between 7.0% and 10.5% (mean HbA(1c) = 8.4%). Insulin titration ranged from modest reductions in T1 to substantial increases in T3. Greater improvements in HbA1c were demonstrated with exenatide BID versus placebo in all tertiles (statistically significant in T2 and T3). With exenatide BID, more subjects achieved HbA(1c) <7.0% vs. placebo: T1, 44% vs. 29% (P = not significant); T2, 65% vs. 26%; T3, 54% vs. 29% (P < 0.05 for T2 and T3). Incidence of hypoglycemia was numerically lower with exenatide BID in all tertiles. Adjunctive exenatide BID was associated with statistically significantly greater weight loss (T1, T2) or mitigation of weight gain (T3) compared with placebo. Rates of nausea (42% vs. 8%), diarrhea (18% vs. 7%), and vomiting (18% vs. 4%) were higher with exenatide BID than with placebo and did not vary by tertile. CONCLUSIONS: Addition of fixed-dose exenatide BID to optimized insulin glargine, regardless of the extent of insulin titration, significantly improved glycemia without increasing hypoglycemia risk, while mitigating insulin-induced weight gain in this post-hoc analysis.

Health and economic outcomes for exenatide once weekly, insulin, and pioglitazone therapies in the treatment of type 2 diabetes: a simulation analysis.

BACKGROUND: Patients with type 2 diabetes (T2DM) are at risk of long-term vascular complications. In trials, exenatide once weekly (ExQW), a GLP-1R agonist, improved glycemia, weight, blood pressure (BP), and lipids in patients with T2DM. We simulated potential effects of ExQW on vascular complications, survival, and medical costs over 20 years versus standard therapies. PATIENTS AND METHODS: The Archimedes model was used to assess outcomes for ~25,000 virtual patients with T2DM (NHANES 1999-2006 [metformin ± sulfonylureas, age 57 years, body mass index 33 kg/m(2), weight 94 kg, duration T2DM 9 years, hemoglobin A1c [A1C] 8.1%]). The effects of three treatment strategies were modeled and compared to moderate-adherence insulin therapy: advancement to high-adherence insulin at A1C ≥ 8% (treat to target A1C < 7%) and addition of pioglitazone (PIO) or ExQW from simulation start. ExQW effects on A1C, weight, BP, and lipids were modeled from clinical trial data. Costs, inflated to represent 2010 $US, were derived from Medicare data, Drugstore.com, and publications. As ExQW was investigational, we omitted ExQW, PIO, and insulin pharmacy costs. RESULTS: By year 1, ExQW treatment decreased A1C (~1.5%), weight (~2 kg), and systolic BP (~5 mmHg). PIO and high-adherence insulin decreased A1C by ~1%, increased weight, and did not affect systolic BP. After 20 years, A1C was ~7% with all strategies. ExQW decreased rates of cardiovascular and microvascular complications more than PIO or high-adherence insulin versus moderate-adherence insulin. Over 20 years, ExQW treatment resulted in increased quality-adjusted life-years (QALYs) of ~0.3 years/person and cost savings of $469/life-year versus moderate adherence insulin. For PIO or high-adherence insulin, QALYs were virtually unchanged, and costs/life-year versus moderate-adherence insulin increased by $69 and $87, respectively. CONCLUSIONS: This long-term simulation demonstrated that ExQW treatment may decrease rates of cardiovascular and some microvascular complications of T2DM. Increased QALYs, and decreased costs were also projected.

Exenatide bid observational study (ExOS): baseline population characteristics of a prospective research study to evaluate the clinical effectiveness of exenatide bid use in patients with type 2 diabetes in a real-world setting.

OBJECTIVES: To describe the Exenatide Observational Study (ExOS) and patients initiating exenatide therapy in a real-world clinical practice setting. METHODS: ExOS is a prospective, single-arm, multicenter, observational study to assess the effectiveness of up to 24 months of exenatide therapy in patients with type 2 diabetes (T2D). Patients with T2D ≥18 years of age, who initiated exenatide therapy, were eligible. The primary effectiveness endpoint is achieving or maintaining hemoglobin A1C of ≤7.0%, or an absolute drop of 0.5% from baseline. Secondary objective measures evaluate the absolute and percentage changes from baseline for a variety of clinical measures (lipid markers, weight, BMI, etc.) and quality of life (QOL) is assessed using the Impact of Weight on Quality of Life (IWQOL)-Lite. RESULTS: On average, the baseline population (n = 531) was aged 55 years, predominantly female (62%), white (79%), educated, obese (mean BMI 39 kg/m(2)), with mean HbA(1c), blood pressure, total cholesterol, and triglyceride values of 8.0%, 129/76 mmHg, 174 mg/dL, and 197 mg/dL, respectively. A total of 28% entered the study with HbA(1c) ≤7.0% and 67% were being treated with oral antihyperglycemic drug(s) (OAD) only [1 (28.4%), 2 (28.4%), >2 (10.2%)], or some form of insulin ±OADs (19%), and ≥50% were on a cholesterol-lowering drug(s) ± antihypertensive medication(s). The single-arm design of this study is a limitation; however, the overall objective of the ongoing study is to observe patients on exenatide therapy over time, comparing their status at endpoint to baseline, rather than to make comparisons among different drug therapies. CONCLUSIONS: Patients treated with exenatide tended to be obese, middle-aged women on various combinations of OADs and/or insulin who often had hypertension and/or dyslipidemia. Further planned analyses will provide the largest sample of prospective data on outcomes of exenatide therapy for up to 24 months in this usual-care population.

Patient characteristics, drug adherence patterns, and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine.

OBJECTIVE: Examine real-world effectiveness and hypoglycemia cost burden in patients with type 2 diabetes newly initiated on exenatide or insulin glargine. DESIGN AND METHODS: Retrospective cohort study describing patient characteristics, drug adherence patterns, and 1-year hypoglycemia rates with associated costs using an administrative claims database. Adult subjects with type 2 diabetes had an initial claim for exenatide or insulin glargine between May 1, 2005 and June 30, 2007, and had continuous eligibility for >or= 6 months pre- and >or= 12 months post-initiation. RESULTS: The exenatide cohort (n = 3262) was 53 +/- 10 years (+/-SD); 54% female. The insulin glargine cohort (n = 3038) was 56 +/- 12 years; 41% female. The mean Deyo-Charlson comorbidity index score was 1.45 for exenatide versus 1.82 for insulin glargine (p < 0.001). Baseline OAD use rates for exenatide and insulin glargine, respectively, were 77% versus 69% metformin; 47% versus 65% sulfonylurea; 50% versus 49% thiazolidinedione; 56% versus 60% multiple OAD. For patients with two or more pharmacy claims for exenatide or insulin glargine, the 12-month medication possession ratio (MPR) was 68 +/- 29% for exenatide and 58 +/- 28% for insulin glargine (p < 0.001). MPR >or= 80% was higher for exenatide (p < 0.001) and fewer patients discontinued therapy (p < 0.001). The probability of a hypoglycemic event was significantly lower for exenatide (p < 0.005), resulting in lower associated annual costs. CONCLUSIONS: This study provides the first real-world observational comparison of type 2 diabetes patients newly initiated on exenatide or insulin glargine. Exenatide patients had a lower comorbidity burden, better drug adherence, and a lower rate of hypoglycemic events with associated costs. Retrospective database analyses examine medical care utilization in large populations using a relatively inexpensive and expedient approach. However, data are only representative of a commercial health-care plan with limited information on multiple variables usually collected during clinical trials.

Estimating the long-term cost-effectiveness of exenatide in the United States: an adjunctive treatment for type 2 diabetes mellitus.

OBJECTIVES: This analysis provides an early estimate of the cost-effectiveness of adjunctive exenatide in treating type 2 diabetes mellitus in the United States. Data from pivotal phase III 30-week clinical trials and 52 weeks of their subsequent open-label extension studies (i.e., 82 weeks total) were used to project the effects of 30 years of adjunctive exenatide treatment. METHODS: This analysis utilized a published and validated Markov model incorporating Monte Carlo simulation with tracker variables to estimate the clinical and cost outcomes of adding exenatide to a background of metformin and/or sulfonylurea treatment, with the effects of 30 years of adjunctive exenatide treatment (projected from data from 82 weeks of exenatide treatment) compared with no additional treatment beyond metformin and/or a sulfonylurea. Sensitivity analyses were performed on key clinical assumptions, discount rates, and shorter time horizons. RESULTS: The base-case scenario (30 years of exenatide) yielded an incremental cost-effectiveness ratio (ICER) of $35,571. We found that shortening the time horizons and removing the lipid effects of exenatide had the greatest negative impact on ICERs when performing sensitivity analysis. CONCLUSIONS: Our analysis demonstrated that exenatide used for 20 or 30 years compared with no additional treatment beyond metformin and/or a sulfonylurea is cost-effective in the adjunctive treatment of type 2 diabetes with an ICER less than $50,000 per life-year gained. Sensitivity analyses suggest that, in addition to sustained reduction in HbA(1c), the added clinical effects of improved lipid values, systolic blood pressure, and reduced body mass index all positively contributed to the cost-effectiveness of exenatide.

Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years.

BACKGROUND: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A(1c) (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of > or = 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety. METHODS: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 mug exenatide, or 10 mug exenatide for 30 weeks, followed by 5 mug exenatide BID for 4 weeks, then 10 mug exenatide BID for > or = 3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas. RESULTS: 217 patients (64% male, age 58 +/- 10 years, weight 99 +/- 18 kg, BMI 34 +/- 5 kg/m(2), A1C 8.2 +/- 1.0% [mean +/- SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (-1.1 +/- 0.1% [mean +/- SEM]) were sustained to 3 years (-1.0 +/- 0.1%; p < 0.0001), with 46% achieving A1C < or = 7%. Exenatide progressively reduced body weight from baseline (-5.3 +/- 0.4 kg at 3 years; p < 0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n = 116) had reduced ALT (-10.4 +/- 1.5 IU/L; p < 0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (-6.1 +/- 0.6 kg vs. -4.4 +/- 0.5 kg; p = 0.03), however weight change was minimally correlated with baseline ALT (r = -0.01) or ALT change (r = 0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151). Triglycerides decreased 12% (p = 0.0003), total cholesterol decreased 5% (p = 0.0007), LDL-C decreased 6% (p < 0.0001), and HDL-C increased 24% (p < 0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison. CONCLUSION: Adjunctive exenatide treatment for > or = 3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.

Short-term economic impact of body weight change among patients with type 2 diabetes treated with antidiabetic agents: analysis using claims, laboratory, and medical record data.

BACKGROUND: Obesity is highly prevalent among patients with type 2 diabetes. Unfortunately, weight gain may also be a consequence of some antidiabetic medications. Although clinical benefits of weight loss have been established, the economic consequence of weight change among patients with type 2 diabetes is unclear. OBJECTIVES: The objective was to measure 1-year total and diabetes-related health care costs associated with weight change during the preceding 6-month period among type 2 diabetic patients on antidiabetic therapy. METHODS: Administrative claims, electronic laboratory data and medical chart information were abstracted for continuously enrolled adults with type 2 diabetes from an health maintenance organization (HMO) for the period from July 1, 1997 through October 31, 2005. To assess the economic impact of weight change, three regression models were applied to estimate the following: (1) the effect of weight change in general (one-slope model); (2) the different effects of weight gain and no weight gain (two-slope model); and (3) the different effects of weight gain and no weight gain (i.e., no change or weight loss) among obese and non-obese patients (four-slope model). Patients included in the study had a baseline weight measurement and a second weight measurement approximately 6 months later. They were also required to be on at least one antidiabetic drug therapy within 1 month around the baseline weight measurement date (index date). Based on the measured weight change, patients were classified into two groups--weight gainers and non-weight gainer. Total health care cost and diabetes-related cost were measured during the 1-year period following the second weight measurement and were adjusted to 2004 dollars by the medical component of the Consumer Price Index (CPI). Generalized linear models with log link function and gamma distribution were applied to assess the impacts of weight change on the 1-year total health care cost as well as 1-year diabetes-related cost. All models controlled for patients' baseline demographics, comorbidities, body mass index (BMI), glycosylated hemoglobin (HbA1c), and prior resource utilization. RESULTS: The study included 458 patients, of whom 224 (48.9%) experienced minimum weight gain of 1 pound between the two weight measurements. The average 1-year total health care cost following the second weight measure was $6382 and the diabetes-related cost was $2002. The mean total health care cost was $7260 for the weight-gainers and $5541 for the non-weight gainers (p = 0.046), and the mean diabetes-related cost, respectively, was $2141 and $1869 (p = 0.006). Results from the models showed that one percentage point of weight change was positively associated with a 3.1% ($213, p < 0.01) change in total health care cost. When weight gain and no gain were modeled separately, one percentage point of weight loss was associated with a 3.6% ($256, p < 0.05) decrease in total health care cost and a 5.8% ($131, p < 0.01) decrease in diabetes-related cost. However, one percentage point of weight gain was not associated with significant increase in either total health care or diabetes-related cost. Further, results from the model with interactions between weight change and obesity status revealed that the economic benefit of weight loss was more pronounced in the obese group (BMI > or = 30). Log likelihood ratio tests showed that the one-slope model for total health care cost and the two-slope model for diabetes-related cost are the appropriate models of choice. CONCLUSIONS: Weight loss significantly reduced diabetes-related costs. Controlling for baseline factors in the regression model, the 1-year total health care cost following 1% weight loss (or gain) was $213 cost decrease (or increase). Diabetes-related cost did not appear to be associated with weight gain. Economic benefit of weight loss was evident among type 2 diabetic patients on antidiabetic therapy, especially among obese patients.

The incretin mimetic exenatide as a monotherapy in patients with type 2 diabetes.

BACKGROUND: Exenatide is an adjunctive therapy for type 2 diabetes, and preliminary evidence suggests that its glucoregulatory effects may be similar in the absence of oral therapy. METHODS: Study A was a randomized, double-blind, placebo-controlled study of 99 patients with type 2 diabetes that received either 10 microg twice-daily, 10 microg once-daily, or 20 microg once-daily exenatide or placebo for 28 days in the absence of background pharmacotherapy. Study B was an open-label extension of a short-term study of 127 patients with type 2 diabetes treated with metformin or diet and exercise. Patients received exenatide 5 microg twice-daily for 4 weeks followed by 10 microg for 26 weeks. Subjects treated with metformin continued oral therapy. RESULTS: Monotherapeutic treatment with 10 microg of exenatide twice-daily for 28 days resulted in significant mean reductions in glycosylated hemoglobin (A1C) of -0.4 +/- 0.1% and fasting plasma glucose of -36.1 +/- 11.0 mg/dL compared to increases of +0.2 +/- 0.1% and +11.0 +/- 12.7 mg/dL with placebo. Self-monitored blood glucose profiles showed significant mean reductions in daily blood glucose concentrations in exenatide-treated patients compared to placebo. Exenatide treatment for 30 weeks in an open-label extension study resulted in similar mean reductions from baseline in A1C and body weight in patients treated with diet and exercise alone (-1.0 +/- 0.2% and -4.3 +/- 1.3 kg, respectively) as those treated on a background of metformin (-0.9 +/- 0.1% and -3.7 +/- 0.5 kg, respectively). In both studies, the most frequent adverse events were gastrointestinal and predominantly mild to moderate in intensity. Incidence of mild-to-moderate hypoglycemia was low, with no severe hypoglycemia. CONCLUSIONS: Exenatide twice-daily monotherapy resulted in glycemic improvements and reductions in body weight comparable to that of exenatide combination therapy with metformin in patients with type 2 diabetes.

Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials.

BACKGROUND: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes mellitus (T2DM), reduced glycosylated hemoglobin (HbA(1c)) and weight in 30-week placebo-controlled trials. Some patients were followed up in open-label extensions to provide 'real-world' exenatide clinical experience. OBJECTIVE: The purpose of this study was to examine the metabolic effects of 2 years of exenatide treatment in patients with T2DM. METHODS: For this interim analysis, data were pooled from patients who completed 1 of three 30-week, multicenter, double-blind, placebo-controlled trials and their open-label extensions. In the initial trials, subjects were randomized to BID 5-microg exenatide, 10-microg exenatide, or placebo for 30 weeks. All subjects who enrolled in the extension phase then received 5-pg exenatide BID for 4 weeks, followed by open-label treatment with 10-pg exenatide BID. Subjects continued their existing metformin and/or sulfonylurea regimens. Analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo-controlled trials. RESULTS: A total of 974 patients entered the open-label, extension phase of the trial. Two hundred eighty-three subjects (mean [SD] age, 57 [10] years; mean [SD] weight, 100[19] kg; sex, 63% male; mean [SD] body mass index, 34 [6] kg/m(2); mean [SD] HbA(1c), 8.3% [1.0%]) completed 2 years of exenatide treatment. Reductions in mean (SE) HbA(1c) from baseline to week 30 (-0.9% [0.1%]) were sustained through 2 years (-1.1% [0.1%]; P < 0.05 vs baseline), with 50% of the population achieving HbA(1c) < or = 7%. At week 30, exenatide was associated with a significant reduction in mean (SD) body weight from baseline (-2.1 [0.2] kg), with progressive reductions after 2 years (-4.7 [0.3] kg; P < 0.001 vs baseline). Patients with normal baseline alanine aminotransferase (ALT) (132/283 [47%]; normal: female < or =19 IU/L; male < or =30 IU/L) had no significant ALT change. However, patients with elevated ALT at baseline (151/283 [53%]) had a mean (SEM) reduction of ALT (-11 [1] IU/L from baseline 38 [1] IU/1; P < 0.05) and 39% achieved normal ALT by week 104. Patients with elevated ALT at baseline lost significantly more weight than patients with normal ALT at baseline (P = 0.04). However, weight change was minimally correlated with baseline ALT (r = -0.09) or ALT change (r = 0.31). Also, homeostasis model assessment of the beta-cell function (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. The most frequently reported adverse event was mild-to-moderate nausea. CONCLUSIONS: In these patients with T2DM, adjunctive exenatide treatment for 2 years was generally well tolerated and resulted in a sustained reduction of HbA(1c), progressive reduction in weight, and improvements in HOMA-B, blood pressure, and the hepatic injury biomarkers, AST and ALT.

Metabolic effects of the incretin mimetic exenatide in the treatment of type 2 diabetes.

Interventional studies have demonstrated the impact of hyperglycemia on the development of vascular complications associated with type 2 diabetes, which underscores the importance of safely lowering glucose to as near-normal as possible. Among the current challenges to reducing the risk of vascular disease associated with diabetes is the management of body weight in a predominantly overweight patient population, and in which weight gain is likely with many current therapies. Exenatide is the first in a new class of agents termed incretin mimetics, which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1 (GLP-1). Currently approved in the US as an injectable adjunct to metformin and/or sulfonylurea therapy, exenatide improves glycemic control through multiple mechanisms of action including: glucose-dependent enhancement of insulin secretion that potentially reduces the risk of hypoglycemia compared with insulin secretagogues; restoration of first-phase insulin secretion typically deficient in patients with type 2 diabetes; suppression of inappropriately elevated glucagon secretion to reduce postprandial hepatic output; and slowing the rate of gastric emptying to regulate glucose appearance into the circulation. Clinical trials in patients with type 2 diabetes treated with subcutaneous exenatide twice daily demonstrated sustained improvements in glycemic control, evidenced by reductions in postprandial and fasting glycemia and glycosylated hemoglobin (HbA(1c)) levels. Notably, improvements in glycemic control with exenatide were coupled with progressive reductions in body weight, which represents a distinct therapeutic benefit for patients with type 2 diabetes. Acute effects of exenatide on beta-cell responsiveness along with significant reductions in body weight in patients with type 2 diabetes may have a positive impact on disease progression and potentially decrease the risk of associated long-term complications.

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.

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.