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.

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

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

Exenatide improves glycemic control and reduces body weight in subjects with type 2 diabetes: a dose-ranging study.

BACKGROUND: Exenatide is the first of a new class of agents known as incretin mimetics that are in development for the treatment of type 2 diabetes. Exenatide has been shown to reduce fasting and postprandial glucose in patients with type 2 diabetes, as well as provide sustained reductions in hemoglobin A 1c (HbA 1c). This study was designed to assess the dose dependencies of the glucoregulatory effects and tolerability of exenatide when added to diet and exercise or metformin monotherapy in patients with type 2 diabetes. METHODS: In this randomized, triple-blinded, placebo-controlled Phase 2 clinical trial, 156 patients were randomized to placebo or exenatide at 2.5, 5.0, 7.5, or 10.0 microg administered b.i.d. for 28 days. RESULTS: After 28 days of therapy, exenatide was associated with significant (P < 0.0001, linear contrast testing), dose-dependent reductions in HbA 1c (0.1 +/- 0.1%, -0.3 +/- 0.1%, -0.4 +/- 0.1%, +/-0.5 +/- 0.0%, and -0.5 +/- 0.1% for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively) and significant (P = 0.0006, linear contrast testing) reductions in fasting plasma glucose (+6.8 +/- 4.1, -20.1 +/- 5.2, -21.2 +/- 3.9, -17.7 +/- 4.8, and -17.3 +/- 4.4 mg/dL for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively) by Day 28. These reductions were similar for patients treated with diet/exercise and those treated with metformin. In addition, patients receiving exenatide exhibited dose-dependent reductions in body weight (0.0 +/- 0.3, -0.7 +/- 0.3, -0.7 +/- 0.2, -1.4 +/- 0.3, and -1.8 +/- 0.3 kg for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively; P < 0.01 for 7.5 and 10.0 microg b.i.d. exenatide doses compared with placebo) at Day 28. The most common adverse event was mild-to-moderate nausea that was dose-dependent (seven of 123 patients randomized to exenatide withdrew from the study because of gastrointestinal effects). CONCLUSIONS: Exenatide dose-dependently improved glycemic control and reduced body weight over 28 days in patients with type 2 diabetes treated with diet/exercise or metformin.