Exenatide: A novel approach for treatment of type 2 diabetes.

Abstract: Exenatide (synthetic exendin-4) is the analog of glucagon-like peptide 1 (GLP-1), the major physiologic incretin. The latter is an intestinal hormone that enhances glucose-induced insulin secretion after meals. In addition, GLP-1 stimulates insulin synthesis, inhibits glucagon secretion, delays gastric emptying, and may promote satiety. These glucoregulatory actions help control plasma glucose in the postprandial period. However, in diabetes, the GLP-1 response to nutrient intake is impaired, leading to exacerbation of postprandial hyperglycemia. Exenatide was recently approved as adjunctive therapy in diabetic patients failing sulfonylureas and/or metformin. In clinical trials lasting 30 weeks, exenatide therapy was associated with moderate reduction in mean hemoglobin Alc (HbA1c) levels of approximately 0.8%, and an average weight loss of approximately 2 kg compared with baseline. Hypoglycemia was generally mild and occurred more commonly when exenatide was used in conjunction with sulfonylureas. The requirement of subcutaneous injections twice a day, and the frequent occurrence of nausea and vomiting, represent the main limitations of exenatide. Nevertheless, this agent may be a useful add-on therapy in obese diabetic patients with suboptimal control as a result of continuing weight gain and/or severe postprandial hyperglycemia. The introduction of GLP-1-based antidiabetic drugs is a novel and promising strategy to treat diabetes.

Key Words: incretin, GLP-1, diabetes mellitus, exenatide

**********

Background and Concept of Incretin

In his "Lessons on diabetes" (1) published in 1877, the French investigator Claude Bernard recorded the finding that much larger amounts of glucose can be given orally rather than intravenously without production of glycosuria. In 1906, Moore, Edie and Abram (2) at the Royal Infirmary in Liverpool, England, proposed that the "duodenum supplies a chemical excitant for the internal secretion of the pancreas and that in certain cases of diabetes, the appearance of sugar in the urine might be due to functional disturbance occasioned by the absence of such an intestinal excitant." They administered porcine duodenal extract to 5 diabetic patients, but without clear success.2 The term "incretin" was initially introduced by LaBarre from Belgium in 1932. (3) LaBarre showed that the IV injection of crude secretin resulted in hypoglycemia in dogs via stimulation of the endocrine pancreas. He suggested that crude secretin contained 2 active components: "incretin" stimulating the internal secretion of the pancreas and "excretin" stimulating the xocrine pancreas.

During the next few decades, the notion of incretin was relatively abandoned, in part due to the negative results of animal experiments reported by Loew et al. (4) However, the interest in this area revived in the mid-1960s when several groups (5-8) demonstrated that the plasma insulin response to glucose given via the oral, (5) gastric, (6) or jejunal (7,8) route was substantially greater compared with IV glucose administration producing similar (5,6) or even higher (7,8) degrees of hyperglycemia.

Taken together, the previous observations pointed to the existence of intestinal factor(s) that enhanced glucose-induced insulin secretion from the pancreas. In 1969, Unger (9) called this connection between the gut and the pancreas the entero-insular axis. Ten years later, Creutzfeldt (10) put forward the current definition of incretin as a gut-derived endocrine transmitter, released by nutrients, especially carbohydrates, that stimulates pancreatic insulin secretion in the presence of glucose. Subsequently, studies (11,12) that documented the concomitant potentiation of postprandial C-peptide and insulin plasma levels provided further support that the enhanced insulin response following glucose ingestion was mainly due to increased pancreatic insulin secretion and not due to reduced hepatic insulin extraction, as claimed by Gibby and Hales. (13) In normal subjects, the incretin effect ie, the difference between insulin secretion (reflected by C-peptide values) after oral glucose versus isoglycemic IV glucose, or simply the alimentary augmentation of insulin secretion, contributes to approximately 28 to 63% of the total insulin secretory response after oral glucose, depending on the size of the glucose load. (12)

Therapeutic Strategy Based on Incretin Hormones

First isolated and characterized by Brown (14) in 1971, gastric inhibitory polypeptide (GIP), also called glucose-dependent insulinotropic polypeptide, is a 42-amino acid peptide secreted by the enteroendocrine K cells located in the duodenum and proximal jejunum. (15) Initially, it was thought that GIP was the main incretin. Yet studies in patients with resected parts of the small intestine showed that the incretin effect was diminished despite a normal GIP release. (16) In turn, the incretin activity was preserved in rats after removal of GIP from their guts by immunoadsorption. (17) These human and animal findings suggested the presence of one or more additional incretin(s). In 1983, Bell et al (18) identified the second incretin GLP-1, a peptide of 30 amino acids derived from the glucagon precursor proglucagon. GLP-1 has 50% sequence homology to glucagon, but clearly exerts different actions. GLP-1 is mainly synthesized within L-cells present in the ileum, colon (15) and duodenum. (19) In addition to the pancreatic islet cells, GLP-1 receptors have been identified in human stomach, brain, heart, kidney and lungs. (15) These receptors may explain most of the extrapancreatic effects of GLP-1.

Of the 2 incretin hormones, GLP-1 is considered the peptide of major physiologic importance for at least 4 reasons. First, it is estimated that GLP-1 accounts for 70 to 80% of the incretin response, whereas GIP accounts for most of the remaining 20 to 30%. (17,20) Second, in healthy subjects, the insulinotropic effect of exogenous GLP-1 is substantially greater on a molar basis than GIP. (21-23) Third, in patients with type 2 diabetes. GLP-1 administered in physiologic (21,24) and supraphysiological (24-26) doses proved a potent insulin secretagogue, whereas GIP given in approximate equivalent doses had minimal, (24,27) or no effect (22) on insulin secretion. Fourth, in addition to its insulinotropic action, GLP-1 inhibits glucagon release, delays gastric emptying, and may promote early satiety (see below). Thus, even in patients with type 1 diabetes, GLP-1 lowered blood glucose as a result of inhibition of glucagon secretion (25,29) and delay of gastric emptying. (30) In contrast, GIP does not inhibit glucagon secretion, (21-24) has no effect on gastric emptying, (28) and does not induce satiety. (15) For the same reasons, a large number of investigators were interested in GLP-1 as a candidate antidiabetic drug. This interest was reinforced by the fact that the GLP-1 response to meals in diabetes is impaired, as discussed in the following section.

Status of GLP-1 in Diabetes and Subjects at Risk for Diabetes

In the fasting state, plasma GLP-1 levels in patients with type 1 (31) and type 2 diabetes (32-34) are generally similar to those in control subjects. However, most but not all (19) studies showed that the GLP-1 response to nutrient intake in type 2 diabetes was decreased (33,35) or absent. (34) Discrepancies between the results could be attributed to the degree of specificity of the assay used to measure GLP-1. It has been shown that the impaired GLP-1 response to meals in type 2 diabetes was more evident when using assays detecting the intact, biologically active, GLP-1 (7-36) as opposed to nondiscriminatory assays measuring the sum of concentrations of intact GLP-1 and its primary metabolite. (35) Elimination of GLP-1 in patients with type 2 diabetes was similar to that in healthy subjects, (36) implying that the impaired GLP-1 response in diabetes may be caused by a decreased secretion rather than rapid elimination of the peptide. In one study of patients with early type 1 diabetes, the incretin effect was reduced despite normal postprandial rise of GLP-1 levels, suggesting a decreased response to GLP-1. (31) To the author's knowledge, no GLP-1 receptor mutations have been reported in diabetes, although this issue was not extensively investigated.

Whether the abnormal GLP-1 response to meals is a primary or secondary defect in the evolution of diabetes is unclear. Data in favor of a pathophysiological role of GLP-1 in diabetes include the demonstration of attenuated early (0-30 min) GLP-1 response in subjects at high risk for diabetes development, such as men with insulin resistance, (37) nonobese women with impaired glucose tolerance, (38) and women with history of gestational diabetes and normal glucose tolerance. (39) In addition, Greenbaum et al (31) and Lugari et al (34) have shown abnormal GLP-1 response in subjects with early stages of type 1 and type 2 diabetes, respectively. On the other hand, studies showing normal GLP-1 action in first-degree relatives of diabetic patients (40,41) argue against a causative role. Moreover, in a study of 12 identical twins discordant for type 2 diabetes, the GLP-1 response was decreased in the twins with frank diabetes, but similar to control subjects in the nondiabetic twins. (42) Nonetheless, whether the altered GLP-1 response is a cause or consequence of diabetes, it most likely contributes to the uncontrolled postprandial hyperglycemia prevailing in this disease.

Development of the GLP-1 Analog Exendin-4

Due to the rapid degradation of GLP-1 by dipeptidyl peptidase IV (DPP-IV), its plasma half-life is approximately 2 minutes with IV administration. (36) Therefore, there was need for an incretin mimetic that exerts the same antidiabetic actions of GLP-1 but has a longer duration of action. Exendin-4 is a GLP-1 receptor agonist that was originally isolated from the venom of the Gila monster (Heloderma suspectum) (43) where it was found to circulate after meal ingestion by the lizard. (44) Exendin-4 is formed of 39 amino acids and shares 53% homology with native GLP-1. (45) However, exendin-4 is not a product of the proglucagon gene but is encoded by a separate gene in the Gila monster. (46) Exendin-4 binds to the GLP-1 receptor and stimulates glucose-dependent insulin secretion in islet cells in vitro (45,47,48) and in animal studies in vivo. (47,49) Exendin-4 also mimics most of the peripheral actions of GLP-1 in the cardiovascular system, stomach and brain. (15) However, not all actions of GLP-1 and exendin-4 are identical. For instance, GLP-1, and not exendin-4, inhibits gastric acid secretion. (50) Moreover, while intraportal infusion of GLP-1 may stimulate hepatic vagal afferent nerves, exendin-4 did not. (51) Unlike GLP-1, exendin-4 is resistant to DPP-IV and has a plasma half-life of approximately 26 minutes with IV administration. (52) Exenatide (Byetta), the synthetic analog of exendin-4, has a half-life of approximately 2.5 hours when given subcutaneously, (53) and therefore is convenient for clinical use. Animal (47,49) and human (54) studies showed that exendin-4 is at least as potent as (47) or even more potent (54) than native GLP-1 in inducing insulin release, most likely due to the resistance of exendin-4 to cleavage by the DPP-IV. (54)

Glucoregulatory Effects of GLP-1 and Its Analog Exendin-4

Stimulation of Insulin Synthesis and Secretion

At the cellular level, GLP-1 stimulates proinsulin gene expression and proinsulin biosynthesis, actions that are most likely mediated by cyclic adenosine monophosphate (cAMP). (55) GLP-1 also potentiates insulin secretion in part by mobilization of more insulin secretory granules to dock at the plasma membranes of pancreatic [beta]-cells. (56) As pointed out by Creutzfeldt, (15) one important feature of an incretin was the fact that its insulinotropic action occurred in the presence of glucose. For instance, Holz et al (57) found that either GLP-1 or glucose alone had no effect on the depolarization (an event that precedes insulin secretion) of cultured rat [beta]-cells. Yet, when glucose and GLP-1 coexisted in the culture medium, the glucose insensitive [beta]-cells were capable of responding to glucose, a phenomenon that they referred to as "glucose competence." (57) In healthy humans, the glucose-dependent insulinotropic effect of exenatide was best illustrated by the elegant studies of Degn et al, (58) using the hyperinsulinemic euglycemic and hypoglycemic clamp. During euglycemia (plasma glucose approximately 5.0 mmol/L or 90 mg/dL), exenatide IV infusion increased insulin secretion rate by approximately 3.5-fold compared with rates achieved with placebo. Meanwhile, when plasma glucose was allowed to drop to 4.0 mmol/L (72 mg/dL) and lower, plasma insulin sharply decreased despite continued exenatide infusion, and became similar to placebo levels. However, when administered in pharmacological doses, the glucose-dependence mechanism of GLP-1 may be overridden. In the latter condition, GLP-1 has caused severe hypoglycemia in healthy subjects. (21,59) Furthermore, an exaggerated endogenous secretion of GLP-1 was implicated in the mechanism of reactive hypoglycemia occurring in patients with dumping syndrome following gastrectomy. (21,60)

Inhibition of Glucagon Secretion

It is well established that glucagon, or more precisely, the insulin-glucagon balance is critical for the maintenance of normal glucose homeostasis. (61) Indeed, more than 35 years ago, Unger (61) underscored the fact that diabetes mellitus was a bihormonal disease with both [alpha]- and [beta]-cell defects and predicted the development of antidiabetic therapy targeted toward suppression of circulating glucagon levels in diabetes. In type 2 diabetes, plasma glucagon levels are generally increased both in the fasting and postprandial states. (62,63) These inappropriate glucagon levels can exacerbate hyperglycemia by increasing hepatic glucose output, (62) in part by accelerating glycogenolysis. (64) GLP-1 (25) and exendin-4 (54,65,66) inhibit postprandial glucagon secretion in type 1 (25,66) and type 2 diabetes. (54,65) Similar to their insulinotropic action, the glucagonos-tatic effect of GLP-1 (67) and exendin-4 (58,65) is glucose-dependent. Interestingly, fasting patients with type 1 diabetes having extremely low or undetectable plasma C-peptide levels still exhibited significant reduction in their fasting glucose levels from 13.7 mmol/L (246 mg/dL) to 10.0 mmol/L (180 mg/dL) and glucagon levels (approximately 50% reduction) after single infusion of GLP-1 in supraphysiological doses. (29) The latter results suggest that glucagon suppression by GLP-1, albeit in higher than physiologic doses, may be an important mechanism whereby the peptide improves hyperglycemia, independently of functioning [beta]-cells and delay of gastric emptying (patients were fasting).

Effect on Gastric Emptying

GLP-1 (68) and exendin-4 (52,66) delay gastric emptying by unclear mechanisms. GLP-1 also decreases postprandial gastric acid secretion. (69) Slowing the passage of gastric contents to the intestine attenuates postprandial glucose excursions.

Effect on Satiety

Available data suggest that GLP-1 may induce early satiety and decrease appetite. A meta-analysis of 7 studies suggested that acute administration of GLP-1 in healthy individuals and obese patients with type 2 diabetes decreased energy intake by approximately 11%, and reduced the feelings of hunger and induced early satiety. (70) In addition, significant reduction of fluid intake has been reported. (71) Animal (72) and preliminary human (52) studies using exendin-4 suggest that it may also decrease appetite. Thus, IV infusion of exendin-4 in 8 healthy volunteers for 4 hours starting before breakfast was associated with decreased caloric intake during lunch by 19%. (52) No significant change in fullness or nausea was reported in this small single-dose study. (52) In one large trial, only 3.5% of exenatide-treated patients reported anorexia. (73) The mechanism of decrease appetite with GLP-1 or exendin-4 is not fully elucidated, but is possibly multifactorial. The observation of Turton et al (74) that intracerebroventricular (IVC) application of GLP-1 was a powerful inhibitor of food intake in rats, whereas intraperitoneal (IP) administration of the peptide did not have any effect suggested a centrally mediated pathway. However, De Fonseca et al (75) later showed that both GLP-1 and exendin-4 decreased food intake in obese rats either after subcutaneous or ICV administration. In addition, the delay in gastric emptying per se may contribute to the sensation of early fullness and satiety. Thus, both central and peripheral mechanisms may be involved in the appetite-suppressive effect of GLP-1 or exendin-4. However, this effect, at least in humans, appears to be mild and only evident in a small subset of individuals.

Uncertain Effects of GLP-1 and Exendin-4 in Humans

Effect on Insulin Sensitivity 

Animal studies suggest that GLP-1 and exendin-4 (49) might decrease insulin resistance. In humans, some studies (76-79) found that GLP-1 enhanced insulin action, but others (80-83) did not. Fasting plasma insulin levels, an approximate measurement of insulin resistance, (84) did not change after 30 weeks of exenatide treatment in obese patients with type 2 diabetes, despite the decrease in fasting plasma glucose and body weight. (85) Overall, the balance of evidence suggests that if GLP-1 or exendin-4 has any direct role in increasing insulin sensitivity in humans, this effect is minimal, and most likely of no clinical significance.

Effect on [beta]-cell Regeneration

Experiments in animal models have shown that exendin-4 may increase [beta]-cell mass by stimulation of [beta]-cell replication and neogenesis. (86) In randomized trials, (73,85,87,88) the lack of progressive reduction of HbA1c levels beyond 12 weeks of exenatide therapy is not consistent with [beta]-cell regeneration in humans.

GLP-1 Effects Unrelated to Glycemic Control

A recent pilot study showed that short-term infusion over 72 hours of pharmacological doses of GLP-1 was associated with amelioration of left ventricular ejection fraction in 10 patients with recent acute myocardial infarction. (89) Another report demonstrated that 3 hours of GLP-1 infusion in the same doses used in the previous study (89) induced natriuresis in healthy and in insulin-resistant obese men. (90) A third group showed that GLP-1 might improve some parameters of endothelial function in patients with type 2 diabetes, but not in healthy subjects. (91) The underlying mechanisms of these preliminary findings are unclear but could be relevant to the presence of GLP-1 receptors in the heart and kidneys, (15) and possibly in endothelial cells. (91)

Clinical Efficacy and Safety of Exenatide

Efficacy

Three well designed trials evaluated exenatide in more than 1,400 obese patients (mean body mass index approximately 34 kg/[m.sup.2]) with type 2 diabetes uncontrolled (mean baseline HbA1c value approximately 8.7%) with sulfonylurea, (87) metformin (85) or both. (88) Average reduction in HbA1c levels was approximately 0.8% versus baseline and 1.0% versus placebo after 30 weeks of maximum doses of exenatide (10 [micro]g given subcutaneously within 1 h before lunch and dinner). This reduction in HbA1c values appeared to be largely attributed to the amelioration of postprandial hyperglycemia. Thus, the mean decreases in fasting and postprandial plasma glucose compared with baseline values were 10 mg/dL and 52 mg/dL, respectively. (88) Although a greater number of exenatide-treated patients achieved the HbA1c target level of less 7% compared with placebo, 54% (88) to 66% (85) of subjects still did not reach that goal at the end of the trials. In a fourth trial, (73) exenatide was compared with insulin glargine as add-on therapy in 549 patients with type 2 diabetes sub-optimally controlled with sulfonylurea plus metformin (mean baseline HbA1c approximately 8.3%). The dose of insulin glargine was titrated to maintain fasting blood glucose less than 5.6 mmol/L (100 mg/dL). After 26 weeks, the mean reduction in HbA1c was 1.1% in both groups, with 48% of patients reaching HbA1c value below 7% at the end of the trial. However, the effects on daily glucose profile were different. Insulin glargine was superior to exenatide in decreasing fasting and premeal hyperglycemia, whereas exenatide as expected was more effective in decreasing postprandial hyperglycemia. (73) As outlined earlier, in the 4 previous trials, (73,85,87,88) the maximum reduction in HbA1c values with exenatide was achieved after 12 weeks followed by a plateau. Preliminary data published in abstract forms suggested that the reduction in mean HbA1c values in selected patients who participated in open-label extension studies was sustained, reaching 1.2% versus baseline after 82 weeks. (92)

Effect on Body Weight

Available data showed that exenatide therapy was generally accompanied with slight weight loss. The average weight loss with the highest dose of exenatide ranged from 1.6 to 2.8 kg compared with baseline, and 0.7 and 2.5 kg compared with placebo. (85,87,88) When exenatide was compared with insulin glargine as add-on therapy, patients randomized to exenatide lost an average weight of 2.3 kg as opposed to a weight gain of 1.8 kg in the glargine group. (73) The reasons of weight loss associated with exenatide are not well-defined. Decreased appetite, sensation of early fullness, nausea, and the delay in gastric emptying may be contributing factors. Open-label extension studies of a cohort of 265 patients showed that weight loss with exenatide therapy might be progressive, reaching an average of 4.6 kg after 82 weeks. (92) Importantly, this weight reduction was associated with significant improvement in cardiovascular risk factors such as plasma triglycerides, high-density lipoprotein cholesterol levels and diastolic blood pressure. (92) However, these data derived from a selected group of patients have to be interpreted with caution since motivated patients with a positive drug response are usually more likely to participate in open-label extension studies.

Adverse Effects of Exenatide

Nausea and Vomiting

Nausea was the commonest adverse effect of exenatide reported by 45 to 51% of patients (versus 7-23% with placebo), particularly during the first 8 weeks of therapy. (85,87,88) It was generally mild to moderate in intensity, but was severe and the cause of withdrawal of approximately 5% of patients. (73,85,87,88) The etiology of nausea is not fully clear but may be related to the delay in gastric emptying. That nausea constituted a major factor in the weight loss induced by exenatide was unlikely because there was no significant correlation between exenatide use and the duration of nausea. (85,88) Vomiting occurred in 12 to 14% in exenatide-treated patients compared with 2 to 4% with placebo. (85,87,88)

Hypoglycemia

Consistent with the glucose-dependent insulinotropic effect of exenatide, hypoglycemia caused by the drug was generally mild to moderate. Studies in healthy volunteers suggest that glucagon and other hormonal counterregulatory response to hypoglycemia were preserved with short-term administration of exenatide. (58) Similar results were obtained by Nauck et al (67) using GLP-1, except that growth hormone was the only counterregulatory hormone that remained suppressed during hypoglycemia.

In clinical trials using metformin alone as background treatment, the frequency of hypoglycemia in the exenatide and placebo groups was similar. (85) However, in trials that included sulfonylurea as background therapy, (87,93) hypoglycemia was more frequent with exenatide compared with placebo occurring in 36% and 13%, respectively in one study. (87) An interaction between sulfonylurea and exenatide that might precipitate hypoglycemia could not be excluded. In one study, (94) GLP-1 and glyburide exhibited a synergistic effect on insulin release in perfused rat pancreas and in a small group of 8 obese patients with type 2 diabetes. Adjustment of the dose of sulfonylurea is therefore recommended when starting exenatide. The incidence of hypoglycemia with exenatide was unexpectedly similar to that with insulin glargine. (73) Overall, the latter was better tolerated than exenatide, with withdrawal rates of 0.7% and 9.5%, respectively, due to adverse effects. (73)

Other Adverse Effects

Other adverse effects reported by higher proportions of exenatide-treated patients compared with placebo included diarrhea (9-17% versus 4-8% with placebo), feeling jittery (12-15% versus 2-7% with placebo), dizziness (9-15% versus 6-7% with placebo), constipation (9% versus 3% with placebo), sweating (8% versus 1% with placebo), and backache (6% versus 3% with placebo). (85,87,88)

Precautions and Contraindications of Exenatide

Although gastroparesis was not clearly mentioned as exclusion criterion in the exenatide clinical trials, (73,85,87,88) the drug should not be prescribed to patients with diabetic gastroparesis. Delay in gastric emptying by exenatide may decrease the extent and rate of drug absorption. Thus, for oral medications that are dependent on threshold concentration for efficacy, such as oral contraceptives, analgesics, and antibiotics, it is recommended to take those drugs at least one hour before exenatide injection. (53) 41% (87) to 49% (88) of patients developed anti-exenatide antibodies, mostly low-titer. Although these antibodies did not seem to affect the drug efficacy or to increase its adverse effects, (87,88) their long-term consequences have yet to be determined. Pregnant women were appropriately excluded from clinical trials of exenatide. The latter is classified as pregnancy category C (53) ie, animal studies have revealed adverse fetal effects while adequate controlled studies in humans are lacking. (95) Indeed, increased neonatal deaths and bony abnormalities were observed in animals receiving high-dose exenatide during gestation. (53) A single study (96) using the ex vivo placental model suggested that passage of exenatide across the human placenta might be negligible. However, it is wise to avoid using the drug during pregnancy until more safety data become available. Exenatide is cleared by the kidneys. (97) Preliminary data suggest that no dose adjustment is required in mild to moderate renal dysfunction (defined as creatinine clearance of 34 to 78 mL/min), but the drug should not be used in more severe kidney disease. (97)

Newer GLP-1 Based Antidiabetic Agents

Long-acting GLP-1 Analogs

Liraglutide (NN2211) is another GLP-1 analog with a long duration of action (half-life approximately 12 h) owing to its stability against DPP IV, albumin-binding acylated side chain, and self-association resulting in slow absorption from subcutaneous tissue. (98,99) It is given by a single daily subcutaneous injection (98) and is currently under evaluation in phase 3 trials. In the largest randomized trial (n = 190) of lira-glutide published to date, (99) the mean reduction in HbAlc after 12 weeks was 0.7% as compared with placebo, which was similar to the reduction achieved by submaximal dose of glimepiride (2.7 mg). The drug's main adverse effect was nausea, and body weight remained unchanged.

DPP-IV Inhibitors

The use of DPP-IV inhibitors to prevent the rapid degradation of native GLP-1 represents another strategy to take advantage of the antidiabetic actions of GLP-1. One example of such inhibitors is vildagliptin (LAF 237), which can be administered orally once daily. Vildagliptin was evaluated in a randomized placebo-controlled, double-blind trial including patients with type 2 diabetes as add-on treatment to ongoing metformin therapy. Approximately 100 patients completed a 12-week core study, and 57 completed a 40-week extension double-blind phase. (100,101) After 52 weeks, the mean reduction in HbAlc levels in the vildagliptin group was 0.5% versus baseline, and 1.0% versus placebo. (100) Like exenatide, this reduction in HbAlc values was attained at 12 weeks, then levels plateaued. (100) Moderate hypoglycemia (plasma glucose < 3.6 mmol/L or 65 mg/dL) was documented in 4 of 56 vildagliptin-treated patients. (100) There were no significant changes in weight in any group. (100) It should be emphasized that DPP-IV is a ubiquitous enzyme and the major means of degradation of over 20 peptides including GIP, insulin-like growth factor-1, Substance P, and others. (102) Thus, there is a concern regarding the possible increase in plasma levels and activity of these peptides.

Current Directions and Future Needs

The development of GLP-1 based drugs is a useful addition to diabetes therapy. These agents can be used as mono-therapy or added to current antidiabetic drugs, given their unique and multifaceted mechanisms of action. While the weight-loss inducing effect of exenatide represents the most attractive aspect of its profile, the drug suffers from important limitations. More than 50% of patients still had HbA1c levels above 7.0% after 6 to 7 months of treatment, and 5 to 10% could not tolerate it mainly due to nausea and vomiting. The inconvenience of subcutaneous injections, in addition to its cost (approximately $ 240/mo), are other significant obstacles to its widespread use. Nevertheless, based on the available data, the use of exenatide may be considered in obese patients with type 2 diabetes uncontrolled with sulfonylurea and/or metformin (HbAlc Alc approximately 8%) who do not desire to initiate or continue taking insulin due to weight gain. Other candidates may include obese diabetic patients with severe postprandial hyperglycemia.

The use of exenatide in conjunction with insulin in obese, insulin-resistant patients with poorly controlled diabetes should be assessed. In this patient group, increasing insulin doses in an attempt to improve glycemic control frequently leads to worsening obesity and subsequent increase in insulin resistance and insulin requirements. The addition of exenatide in this setting might reverse this vicious circle by alleviation of the weight-gain inducing effect of insulin and by decreasing insulin dosage. Adding exenatide to a glitazone drug may be another potentially useful combination. Preliminary short-term (48 hours) data suggest that the combination of GLP-1 and pioglitazone may have an additive effect on reducing the plasma glucose. (103) It is worthwhile to evaluate exenatide in patients with type 1 diabetes as the drug has multiple glu-coregulatory effects independent of [beta]-cell function. (29,30) The long-term efficacy and safety of exenatide, and its impact on clinical outcomes, must be addressed in randomized trials. In addition, its effects in different organs containing GLP-1 receptors, such as the brain, heart and kidneys, should be thoroughly investigated.

Acknowledgments

The author thanks Marsha Kmec and Armineh Harutu-nian, who provided expert assistance with the literature review.

References

1. Bernard C. Lecons sur le diabete. Paris, JB Baillere, 1877.

2. Moore B, Edie ES, Abram JH. On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem J 1906;1:28-38.

3. Labarre J. Sur les possibilites d'un traitement du diabetes par l'incretine. Bull Acad Roy Med Belg 1932:12:620-634 .

4. Loew ER, Gray JS, Ivy AC. Is a duodenal hormone involved in carbohydrate metabolism? Am J Physiol 1940;129:659-663 .

5. Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest 1967;46:1954-1962.

6. Elrick H, Stimmler L, Hlad CJ Jr, et al. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 1964;24:1078-1082.

7. McIntyre N. Holdsworth CD, Turner DS. New interpretation of oral glucose tolerance. Lancet 1964;41:20-21.

8. McIntyre N, Holdsworth CD, Turner DS. Intestinal factors in control of insulin secretion. J Clin Endocrinol Metab 1965:25:1317-1323.

9. Unger RH, Eisentraut AM. Entero-insular axis. Arch Intern Med 1969;123:261-266.

10. Creutzfeldt W. The incretin concept today. Diahetologia 1979;16:75-85.

11. Hampton SM, Morgan ML, Tredger JA, et al. Insulin and C-peptide levels after oral and intravenous glucose: contribution of enteroinsular axis to insulin secretion. Diabetes 1986;35:612-616.

12. Nauck MA, Homberger E, Siegel EG, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 1986;63:492-498.

13. Gibby OM, Hales CN. Oral glucose decreases hepatic extraction of insulin. Br Med J 1983;286:921-923.

14. Brown JC. A gastric inhibitory polypeptide, I: the amino acid composition and the tryptic peptides. Can J Biochem 1971;49:255-261.

15. Drucker DJ. Glucagon-like peptides. Diabetes 1998;47:159-169.

16. Lauritsen KB, Moody AJ, Christensen KC, et al. Gastric inhibitory polypeptide (GIP) and insulin release after small-bowel resection. Scand J Gastroenterol 1980;15:833-840.

17. Ebert R, Unger H, Creutzfeldt W. Preservation of incretin activity after removal of gastric inhibitory polypeptide (GIP) from gut extracts by immunoadsorption. Diabetologia 1983;24:449-454.

18. Bell GI, Santerre RF, Mullenbach GT . Hamster pre-proglucagon contains the sequence of glucagon and two related peptides. Nature 1983;302:716-718.

19. Theodorakis MJ, Carlson O, Michopoulos S, et al. Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol Endocrinol Metab 2006;290:E550-E559.

20. Habener JF. The incretin notion and its relevance to diabetes. Endocrinol Metab Clin North Am 1993;22:775-794.

21. Kreymann Ghatei MA, Williams G, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 1987;2:1300-1304.

22. Elahi D, McAloon-Dyke M, Fukagawa NK, et al. The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regul Pept 1994;51:63-74.

23. Schirra J, Sturm K, Leicht P, et al. Exendin (9-39) amide is an antagonist of glucagon-like peptide-1 (7-36) amide in humans. J Clin Invest 1998;101:1421-1430.

24. Nauck MA, Heimesaat MM, Orskov C, et al. Preserved incretin activity of GLP-1 (7-36 amide) but not of synthetic human GIP in patients with type 2 diabetes mellitus. J Clin Invest 1993;91:301-307.

25. Gutniak M, Orskov C, Holst JJ, et al. Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med 1992;326:1316-1322.

26. Nathan DM, Schreiber E, Fogel H, et al. Insulinotropic action of glucagon-like peptide-I-(7-37) in diabetic and nondiabetic subjects. Diabetes Care 1992;15:270-276.

27. Krarup T, Saurbrey N, Moody AJ, et al. Effect of porcine gastric inhibitory polypeptide on beta-cell function in type I and type II diabetes mellitus. Metabolism 1987;36:677-682.

28. Meier JJ, Goetze O, Anstipp J, et al. Gastric inhibitory polypeptide does not inhibit gastric emptying in humans. Am J Physiol 2003;286:E621-E625.

29. Creutzfeldt WO, Kleine N, Wilms B, et al. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I (7-36) amide in type 1 diabetic patients. Diabetes Care 1996;19:580-586.

30. Behme MT, Dupre J, McDonald TJ. Glucagon-like peptide 1 improved glycemic control in type 1 diabetes. BMC Endocr Disord 2003;3:3.

31. Greenbaum CJ, Prigeon RL, D'Alessio DA. Impaired beta-cell function, incretin effect, and glucagon suppression in patients with type 1 diabetes who have normal fasting glucose. Diabetes 2002;51:951-957.

32. Mannuci E, Ognibene A, Cremasco F, et al. Glucagon-like peptide (GLP)-1 and leptin concentrations in obese patients with type 2 diabetes. Diabet Med 2000;17:713-719.

33. Vilsboll T, Krarup T, Deacon C, et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetes. Diabetes 2001;50:609-613.

34. Lugari R, Dei Cas A, Ugolotti D, et al. Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non-insulin dependent) diabetes. Horm Metab Res 2002;34:150-154.

35. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 2001;86:3717-3723.

36. Vilsboll T, Agerso H, Krarup T, et al Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. J Clin Endocrinol Metab 2003;88:220-224.

37. Rask E, Olsson T, Soderberg S, et al. Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men. Diabetes Care 2001;24:1640-1645.

38. Rask E, Olsson T, Soderberg S, et al. Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance. Metabolism 2004;53:624-631.

39. Forbes S, Moonan M, Robinson S, et al. Impaired circulating glucagon-like peptide-1 response to oral glucose in women with previous gestational diabetes. Clin Endocrinol (Oxf) 2005;62:51-55.

40. Nyholm B, Walker M, Gravholt CH, et al. Twenty-four-hour insulin secretion rates, circulating concentrations of fuel substrates and gut incretin hormones in healthy offspring of type II (non-insulin-dependent) diabetic parents: evidence of several aberrations. Diabetologia 1999;42:1314-1323.

41. Nauck MA, El-Ouaghlidi A, Gabrys B, et al. Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes. Regul Pept 2004;122:209-217.

42. Vaag AA, Holst JJ, Volund A, et al. Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM): evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol 1996;135:425-432.

43. Eng J, Kleinman WA, Singh L, et al. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma-suspectum venom: further evidence for an exendin receptor on dispersed acini from guinea pig pancreas J Biol Chem 1992;267:7402-7405.

44. Young A, Blase E, Petrella E, et al. Exendin-4 is a circulating meal-related peptide in the Gila monster (Heloderma suspectum). Diabetes 1999;48 (Suppl 1):A425.

45. Goke R, Fehmann HC, Linn T, et al. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide-1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem 1993;268:19650-19655.

46. Chen YE, Drucker D. Tissue-specific expression of unique mRNAs that encode pro-glucagon-derived peptides or exendin-4 in the lizard. J Biol Chem 1997;272:4108-4115.

47. Parkes DG, Pittner R, Jodka C, et al. Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro. Metabolism 2001;50:583-589.

48. Thorens B, Porret A, Buhler L, et al. Cloning and functional expression of the human islet GLP-1 receptor: demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes 1993;42:1678-1682.

49. Young AA, Gedulin BR, Bhavsar S, et al. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic Rhesus monkeys (Macaca mulatta). Diabetes 1999;48:1026-1034.

50. Gedulin B, Lawler R, Jodka C, et al.Amylin inhibits pentagastrin-stimulated gastric acid secretion: comparison with glucagon-like peptide-1 and exendin-4 (abstract). Diabetes 1997;46 (Suppl):188A.

51. Nishizawa M, Nakabayashi H, Kawai K, et al. The hepatic vagal reception of intraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor. J Auton Nerv Syst 2000;80:14-21.

52. Edwards CM, Stanley SA, Davis R, et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab 2001;281:E155-E161.

53. Byetta[R] (Exenatide). Product monograph. Amylin Pharmaceuticals, 2005.

54. Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab 2002;87:1282-1290.

55. Fehmann HC, Habener JF. Insulinotropic hormone glucagon-like peptide-1 (7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma betaTC-1 cells. Endocrinology 1992;130:159-166.

56. Kwan EP, Gaisano HY. Glucagon-like peptide 1 regulates sequential and compound exocytosis in pancreatic islet beta-cells. Diabetes 2005;54:2734-2743.

57. Holz GG IV, Kuhtreiber WM, Habener JF. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). Nature 1993;361:362-365.

58. Degn KB, Brock B, Juhl CB, et al. Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes 2004;53:2397-2403.

59. Edwards CBM, Todd JF, Ghatei MA, et al. Subcutaneous glucagon-like peptide-1 (7-36) amide is insulinotropic and can cause hypogly-caemia in fasted healthy subjects. Clin Sci 1998;96:719-724.

60. Toft-Nielsen M, Madsbad S, Holst JJ. Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia. Diabetologia 1998;41:1180-1186.

61. Unger RH. Glucagon physiology and pathophysiology. N Engl J Med 1971;285:443-449.

62. Baron AD, Schaffer L, Shragg P, et al. Role of hypergluconemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 1987;36:274-283.

63. Reaven GM, Chen YD, Golay A, et al. Documentation of hyperglu-conemia throughout the day in nonobese and obese patients with non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metabol 1987;64:106-110.

64. Shah P, Vella A, Basu A, et al. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes. J Clin Endocrinol Metab 2000;85:4053-4059.

65. Kolterman OG, Buse JB, Fineman MS, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003;88:3082-3089.

66. Dupre J, Behme MT, McDonald TJ. Exendin-4 normalized post cibal glycemic excursions in type 1 diabetes. J Clin Endocrinol Metab 2004;89:3469-3473.

67. Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 2002;87:1239-1246.

68. Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide I inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997;36:E981-E-988.

69. Layer P, Holst JJ, Grandt D, et al. Ileal release of glucagon-like peptide-1 (GLP-1): association with inhibition of gastric acid secretion in humans. Dig Dis Sci 1995;40:1074-1082.

70. Verdich C, Flint A, Gutzwiller JP, et al. A meta-analysis of the effect of glucagon-like peptide -1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab 2001;86:4382-4389.

71. Gutzwiller JP, Goke B, Drewe J, et al. Glucagon-like peptide-1: a potent regulator of food intake in humans. Gut 1999;44:81-86.

72. Szayna M, Doyle ME, Betkey JA, et al. Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats. Endocrinology 2000;141:1936-1941.

73. Heine RJ, Van Gaal LF, Johns D, et al, for the GWAA Study Group.Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005;143:559-569.

74. Turton MD, O'Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996;379:69-72.

75. Rodriguez de Fonseca F, Navarro M, Alvarez E, et al. Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker rats. Metabolism 2000;49:709-717.

76. D'Alessio DA, Prigeon RL, Ensinck JW. Enteral enhancement of glucose disposition by both insulin-dependent and insulin-independent processes: a physiological role of glucagon-like peptide I. Diabetes 1995;44:1433-1437.

77. Zander M, Madsbad S, Madsen JL, et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002;359:824-830.

78. Egan JM, Meneilly GS, Habener JF, et al. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin Endocrinol Metab 2002;87:3768-3773.

79. Meneilly GS, McIntosh CHS, Pederson RA, et al. Effect of glucagon-like peptide 1 (7-36 amide) on insulin-mediated glucose uptake in patients with type 1 diabetes. Diabetes Care 2003;26:837-842.

80. Vella A, Shah P, Basu R, et al. Effect of glucagon-like peptide 1 (7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes. Diabetes 2000;49:611-617.

81. Toft-Nielsen M, Madsbad S, Holst JJ. The effect of glucagons-like peptide I (GLP-I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones. Diabetes 1996;45:552-556.

82. Ryan AS, Egan JM, Habener JF, et al. Insulinotropic hormone glucagon-like peptide-1 (7-37) appears not to augment insulin-mediated glucose uptake in young men during euglycemia. J Clin Endocrinol Metab 1998;83:2399-2404.

83. Ahren B, Larsson H, Holst JJ. Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997;82:473-478.

84. Saad MF, Anderson RL, Laws A, et al. A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance: Insulin Resistance Atherosclerosis Study. Diabetes 1994;43:1114-1121.

85. DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28:1092-1100.

86. Xu G, Stoffers DA, Habener JF, et al. Exendin-4 stimulates both betacell replication and neogenesis, resulting in increased beta-cell mass and improved tolerance in diabetic rats. Diabetes 1999;48:2270-2276.

87. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004;27:2628-2635.

88. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005;28:1083-1091.

89. Nikolaidis LA, Mankad S, Sokos GG, et al, Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004;109:962-965.

90. Gutzwiller JP, Tschop S, Bock A, et al. Glucagon-like peptide-1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab 2004;89:3055-3061.

91. Nystrom T, Gutniak MK, Zhang Q, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab 2004;287:E1209-E1215.

92. Kendall DM, Kim D, Poon T, et al. Improvements in cardiovascular risk factors accompanied sustained effects on glycemia and weight reduction in patients with type 2 diabetes treated with exenatide for 82 weeks (abstract). Diabetes 2005;54(Suppl 1):A4.

93. Fineman MS, Bicsak TA, Shen L, et al. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care 2003;26:2370-2377.

94. Gutniak MK, Junitti-Berggren L, Hellstrom P, et al. Glucagon-like peptide 1 enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas. Diabetes Care 1996;19:857-863.

95. Durfee RB, Pernoll ML. Early pregnancy risks. In: Pernoll ML, ed. Current Obstetric and Gynecologic Diagnosis and Treatment. 7th edition. Norwalk, Conn/San Mateo, Calif, Appleton & Lange, 1991, pp 300-325.

96. Hiles RA, Bawdon RE, Petrella EM. Ex vivo human placental transfer of the peptides pramlintide and exenatide (synthetic exendin-4). Hum Exp Toxicol 2003;22:623-628.

97. Linnebjerg H, Kothare P, Park S, et al. Exenatide pharmacokinetics in patients with mild to moderate renal dysfunction and end stage renal disease (abstract). Diabetes 2005;54(Suppl 1):A116.

98. Harder H, Nielsen L, Tu DT, et al. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes Care 2004;27:1915-1921.

99. Madsbad S, Schmitz O, Ranstam J, et al. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide I analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care 2004;27:1335-1342.

100. Ahren B, Gomis R, Standl E, et al. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004;27:2874-2880.

101. Ahren B, Pacini G, Foley JE, et al. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care 2005;28:1936-1940.

102. Uwaifo GI, Ratner RE. Novel pharmacologic agents for type 2 diabetes. Endocrinol Metab Clin North Am 2005;34:155-197.

103. Zander M, Christiansen A, Madsbad S, et al. Additive effects of glucagon-like peptide 1 and pioglitazone in patients with type 2 diabetes. Diabetes Care 2004;27:1910-1914.

One of the virtues of being very young is that you don't let the facts
get in the way of your imagination.
--Sam Levenson

Nasser Mikhail, MD, MSc

From the Endocrinology Division, Olive View-UCLA Medical Center, Sylmar, CA.

Reprint requests to Nasser Mikhail, MD, MSc, Department of Medicine, 14445 Olive View Drive, Sylmar, CA, 91342, Olive View-UCLA Medical Center. Email: [e-mail]

RELATED ARTICLE: Key Points

* Exenatide (synthetic exendin-4) is the agonist of GLP-1, the main incretin, i.e. an intestinal hormone that enhances glucose-induced insulin secretion.

* The antidiabetic effects of exenatide include stimulation of insulin synthesis and secretion, inhibition of glucagon secretion, delaying gastric emptying and possibly promotion of early satiety.

* The advantages of exenatide include moderate HbA1c reduction (approximately 0.8%) and slight weight loss (approximately 2 kg), but the drug is associated with increased frequency of nausea and has to be administered by subcutaneous injections twice daily.

* Exenatide may be a useful add-on therapy to obese patients with uncontrolled diabetes and/or postprandial hyperglycemia.