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■ Stimulation of glycogen synthesis (predominantly liver)

improvement of glycemic control without weight gain and an improvement in beta-cell function without causing hypoglycemia in monotherapy or in combination with metformin (Fig. 2) (45,60-64,66). Hypoglycemia occurred only in patients receiving a combination of exenatide and sulfonylureas (45,62,65,66). Patients in an open extension of the studies comparing the efficacy and safety of exenatide to placebo receiving 10 mg exenatide b.i.d. subcutaneously had a sustained reduction of their HbA1c-concentrations over a period of 2 years and also a reduction of their fasting glucose concentrations (63). The patients (mean BMI >30 kg/m2) also continuously lost weight (63). In a head to head comparison of a combination therapy of oral antidiabetic drugs plus insulin glargine with a combination therapy of oral antidiabetic drugs plus exenatide, the exenatide-treated patients had less hypoglycemic events, less variations in their diurnal glucose concentrations and a significant weight loss compared to the patients receiving insulin glargine. Both treatment arms were equally effective in lowering HbA1c (64). Exenatide also restores the diminished first phase of insulin secretion during an intravenous glucose load in patients with type 2 diabetes (67). Currently, a long acting release form of exenatide (exenatide LAR) designed for a once weekly injection is tested in clinical trials. Exenatide LAR reduces HbA1c and body weight very effectively, with approximately 85% of patients reaching an HbA1c of <7% (68).

A synthetic GLP-1 analog, liraglutide (NN2211) (Novo Nordisk Pharmaceuticals, Copenhagen, Denmark) is DPP-4-resistant and possesses a biologically longer half-life than native GLP-1 due to the addition of a fatty acid side chain to the peptide molecule. The mechanism of protraction is a combination of albumin binding and self-association in vivo, resulting in slow absorption after injection, stability against dipeptidyl-peptidase-4, and a long plasma half-life. It is suitable for once-daily injection. Liraglutide also improves plasma glucose and HbA1c without an intrinsic risk for hypoglycemia and promotes weight loss (50,69). Animal studies using primary neonatal rat islets showed that native GLP-1 and liraglutide similarly inhibited both cytokine- and free fatty acid-induced apoptosis in a dose-dependent manner, suggesting that liraglutide may be useful for retaining beta-cell mass in both type 1 and type 2 diabetic patients (70). An increase of beta-cell mass and an improvement of beta-cell function in experimental animal models have been shown for exenatide and liraglutide likewise (70-73).

Exenatide Lar Animal

FIGURE 2 Effects of exenatide on glycemic control and body weight In subjects with type 2 diabetes. Patients were treated with metformin and sulfonylurea plus exenatide or placebo. (A) HbAic values over the course of the study. (B) Change in HbA1c over 30 weeks. (C) Week 30 change in HbA1c stratified by baseline HbA1c.(D) Effects of exenatide on body weight. Subjects in all treatment arms were maintained on metformin-sulfonylurea therapy. *< 0.001 compared with placebo treatment. Data are mean ± SE. Source: From Ref. 66.

FIGURE 2 Effects of exenatide on glycemic control and body weight In subjects with type 2 diabetes. Patients were treated with metformin and sulfonylurea plus exenatide or placebo. (A) HbAic values over the course of the study. (B) Change in HbA1c over 30 weeks. (C) Week 30 change in HbA1c stratified by baseline HbA1c.(D) Effects of exenatide on body weight. Subjects in all treatment arms were maintained on metformin-sulfonylurea therapy. *< 0.001 compared with placebo treatment. Data are mean ± SE. Source: From Ref. 66.

Unlike insulin therapy that requires frequent dose adjustment, standard doses of GLP-1 receptor agonists facilitate diabetes treatment, additionally the probability of hypoglycemia is low.

Treatment with GLP-1 analogs is safe and adverse reactions are rare. There were no clinically relevant changes in hematology, clinical chemistry, or urinalysis analyte values in any of the studies. Side effects are mostly gastrointestinal in nature, nausea and fullness being the most frequent side effects occurring in approximately 40% of the patients (55,56,62). Nausea occurs most likely during the beginning of treatment, but usually ceases within a few days to weeks. Nausea is less prominent, when GLP-1 analogs are dose-titrated starting with a lower dose in the beginning. The majority (>90%) of the reported nausea and all hypoglycemic cases were mild or moderate in intensity, with no reports of hypoglycemia requiring the assistance of another individual. Hypoglycemia only occurred in patients who were taking a sulfonylurea (45). In patients treated with exenatide, formation of antibodies to the drug that are not cross-reacting with GLP-1 and that are not neutralizing antibodies was observed in approximately 45% of patients (63). In clinical studies with liraglutide no antibody formation has been observed so far (74).

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