The effect of chronic twice daily exenatide treatment on ß-cell function in new onset type 2 diabetes.

OBJECTIVE: To determine the effect of chronic daily exenatide treatment on ß-cell function in type 2 diabetes (T2DM). BACKGROUND: Glucagon-like peptide receptor agonists, such as exenatide, are commonly used to treat patients with T2DM. Drugs in this class are insulinotropic but lower blood glucose by multiple mechanisms such that effects on ß-cell function can be difficult to discern by conventional measures. DESIGN: Seventy-nine subjects with previously untreated T2DM were studied before and after 24 weeks of treatment with one of the two doses of exenatide, 5- or 10-µg twice daily, or placebo. All subjects had oral glucose tolerance tests (OGTT) before and after randomization with measurement of plasma glucose, insulin and C-peptide concentrations. Insulin secretion rates (ISR), peripheral insulin sensitivity (OGIS) and hepatic insulin resistance index (Hep-IR) were calculated. RESULTS: During the trial, all three groups lost similar, small but significant, amounts of weight. Compared to placebo, 24 weeks of daily high- or low-dose exenatide treatment reduced HbA1c and improved fasting and postprandial hyperglycaemia. Exenatide was associated with improved OGIS and Hep-IR independent of changes in weight. Plasma insulin levels and ISR during the OGTT did not differ before or after treatment with exenatide or placebo. However, when considered as a function of plasma glucose and insulin sensitivity, both doses of exenatide improved ISR proportionately to the improvement in plasma glucose. The higher dose of exenatide was associated with a significant improvement in ß-cell sensitivity to glucose. CONCLUSIONS: These findings demonstrate that in persons with early T2DM, chronic treatment with exenatide enhanced ISR and increased ß-cell sensitivity to glucose. These improvements in ß-cell function were not clearly reflected in plasma insulin and C-peptide levels, but became apparent when glycemia and insulin sensitivity were accounted for.

Exenatide exhibits dose-dependent effects on glycemic control over 12 weeks in Japanese patients with suboptimally controlled type 2 diabetes.

This study assessed the dose-dependent efficacy and safety of exenatide over 12 weeks in Japanese patients with type 2 diabetes suboptimally controlled despite therapeutic doses of sulfonylurea (SU), SU plus biguanide, or SU plus thiazolidinedione. Patients were randomly assigned to placebo (N = 40), 2.5 microg (N = 38), 5 microg (N = 37), or 10 microg (N = 38) exenatide administered subcutaneously twice daily (BID). Patients randomly assigned to 10 microg exenatide received 5 microg BID for the first 4 weeks, with the dose escalated to 10 microg BID for the final 8 weeks. Patients were 60.3 +/- 9.7 years old, with body mass index 25.3 +/- 4.3 kg/m(2) and hemoglobin A1c (HbA1c) 8.0 +/- 0.8%. Baseline-to-endpoint HbA1c changes (%) were +0.02 +/- 0.1 (placebo), -0.9 +/- 0.1 (2.5 microg), -1.2 +/- 0.1 (5 microg), and -1.4 +/- 0.1 (10 microg) (all p < 0.001 vs. placebo). Of patients with baseline HbA1c -7%, 5.1% (placebo), 50.0% (2.5 microg), 71.4% (5 microg), and 79.4% (10 microg) achieved HbA1c <7% at endpoint (p < 0.001, trend test). Baseline-to-endpoint fasting plasma glucose changes (mg/dL) were +6.0 +/- 4.8 (placebo), -18.6 +/- 5.7 (2.5 microg), -25.0 +/- 7.0 (5 microg), and -28.9 +/- 5.9 (10 microg) (all p < or = 0.001 vs. placebo). Treatment-emergent adverse events were mostly mild; dose-dependent increases in incidence were observed for hypoglycemia, nausea, anorexia, decreased appetite, and diarrhea (all p < or = 0.044, trend test). Over 12 weeks, exenatide dose-dependently improved glycemic control in Japanese patients with type 2 diabetes.

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 >or=18 years with type 2 diabetes were randomly assigned to receive exenatide 5 microg, exenatide 10 microg, 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 or=1 treatment-emergent adverse event. Nausea was reported with the greatest incidence (5 microg, 3%; 10 microg, 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-microg 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 beta-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.

Efficacy and safety of exenatide administered before the two largest daily meals of Latin American patients with type 2 diabetes.

OBJECTIVE: To evaluate whether exenatide administered before breakfast and dinner (BD) or before lunch and dinner (LD) provided similar glycemic control in Latin American patients with type 2 diabetes mellitus (T2DM) who consume a small breakfast. METHODS: In this open-label, 2-arm study, patients taking metformin, sulfonylureas, and/or thiazolidinediones were randomized to exenatide before BD or before LD (5-mug exenatide for 4 weeks, then 10-microg exenatide for 8 weeks). Treatment assignment was determined by a computer-generated random sequence using an interactive response system. Patients were eligible for study inclusion if they consumed <15% of their total caloric intake at breakfast. The primary endpoint was HbA(1c) change from baseline to endpoint. Secondary endpoints included fasting serum glucose (FSG) level, 7-point SMBG profile, and safety. Clinicaltrials.gov Identifier: NCT00359879. RESULTS: 377 participants (55% female, age 54 +/- 10 years, weight 82 +/- 15 kg, BMI 31 +/- 4 kg/m(2), HbA(1c) 8.4 +/- 0.9%; mean +/- SD) from Brazil and Mexico were randomized to study treatment. HbA(1c) reduction with exenatide administration before BD was non-inferior to administration before LD (mean difference between (LD-BD) treatments: 0.14%; 95% CI -0.04 to 0.32%, p=0.120). Both treatments resulted in statistically significant HbA(1c) reductions at endpoint (BD -1.2% and LD -1.1%, respectively, p<0.001). In Brazil, the non-inferiority criteria were met for HbA(1c) reduction between treatment arms (-0.12%; CI -0.37 to 0.13%, p=0.344), whereas in Mexico, there was a difference favoring exenatide administration before BD (0.41%; CI 0.16 to 0.66%, p=0.002). At endpoint, there were no statistical significant differences between the BD and LD arms in mean change in FSG (0.50 mmol/L; CI -0.02 to 1.02 mmol/L, p=0.058) and daily mean change in SMBG (0.19 mmol/L; CI -0.17 to 0.54 mmol/L, p=0.295). The rates of symptomatic hypoglycemia (5.2 events/patient-year vs. 6.1 events/patient-year) and nausea (23% vs. 25%), were similar between the BD and LD arms, respectively. A limitation of the study design was that caloric intake of patients and meal times were not monitored. CONCLUSIONS: In T2DM patients who consume a small breakfast, exenatide administration before breakfast or lunch resulted in significant improvement in glycemic control.

Quantifying the effect of exenatide and insulin glargine on postprandial glucose excursions in patients with type 2 diabetes.

In this report, we quantify the effects of exenatide and glargine on the relative contributions of fasting and postprandial glucose (PPG) excursion to overall hyperglycemia based on self-monitored blood glucose. After 26 weeks of treatment, insulin glargine reduced fasting glucose to a greater extent than exenatide without significant effect on PPG excursion. The principal effect of exenatide on hyperglycemia was mitigating the rise in PPG with moderate improvement on fasting glucose. These findings may be limited by the fact that glucose measurements were collected through self-monitoring with six time points measured during the daytime, the meals were not standardized and the exact time for glucose measurements was unknown.

Exploring the substitution of exenatide for insulin in patients with type 2 diabetes treated with insulin in combination with oral antidiabetes agents.

OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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: a randomized trial.

BACKGROUND: 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. OBJECTIVE: To compare the effects of exenatide versus placebo on glycemic control. DESIGN: Placebo run-in, randomized, double-blind, placebo-controlled trial conducted from May 2004 to August 2005. SETTING: 49 sites in Canada, Spain, and the United States. PATIENTS: 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%. INTERVENTIONS: Subcutaneous abdominal injections of 10 microg of exenatide or placebo twice daily, added to a TZD (with or without metformin) for 16 weeks. MEASUREMENTS: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSIONS: 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 versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial.

BACKGROUND: 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. OBJECTIVE: 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. DESIGN: 26-week multicenter, open-label, randomized, controlled trial. SETTING: 82 outpatient study centers in 13 countries. PATIENTS: 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. INTERVENTION: 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). MEASUREMENTS: Hemoglobin A1c level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability. RESULTS: 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%). LIMITATIONS: 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). CONCLUSIONS: 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.