Exenatide (Byetta) was approved by the FDA on April 28 2005 for the treatment of type 2 diabetes. To review information on Byetta provided by Amylin and Lilly, see www.Byetta.com

Review Prescribing Information updated October 30 2009 and Patient Safety Information for Byetta

To review safety issues surrounding use of GLP-1R agonists to treat diabetes, see GLP-1: Adverse Events

A small study compared the effects of exenatide vs. insulin glargine over 1 year in patients with T2DM. Sixtynine patients ages 30-75, with a mean initial HbA1c of 6.5-9.5% not achieving optimal glycemic control on metformin were randomized to either exenatide (36) or insulin glargine (33). Exenatide was initiated at 5 ug twice daily for 1 month, then increased to 10 ug twice daily, and titrated to a maximum dose of 20 ug t.i.d., or a maximum tolerated dose, for A1c levels not at target (below 7.1%). Glargine was started at 10U hs, and patients were instructed to titrate dose based on FBS targeting 4.5-5.6 mM FBS, with a mean final glargine dose of ~33.6 units per day. Arginine-stimulated C-peptide secretion was assessed at baseline, after 52 weeks, and after a 4 week "washout" period. During the clamp procedure, patients randomized to the exenatide treatment arm received exenatide 15 minutes prior to the onset of the hyperglycemic clamp. Similar levels of HbA1c reduction were achieved (0.7-0.8%); patients on exenatide lost weight (-3.6 kg) whereas insulin glargine-treated patients gained weight (~1 kg). After discontinuation of therapy, body weight tended to revert towards baseline. Subjects receiving exenatide for 52 weeks and immediately prior to the clamp exhibited increased first and second phase glucose-stimulated insulin secretion, which was not sustained 4 weeks after discontinuation of the exenatide. Subjects treated with glargine experience more hypoglycemia, whereas mild to moderate nausea was more common with exenatide (47%), more patients on exenatide withdrew from the study and one patient randomized to exenatide developed pancreatitis. One-Year Treatment With Exenatide Improves Beta-Cell Function, Compared To Insulin Glargine, In Metformin Treated Type 2 Diabetes Patients: A Randomized, Controlled Trial Diabetes Care published online on February 5, 2009 as 10.2337/dc08-1797

Comparison of twice daily exenatide to oral glimepiride therapy in diabetic subjects not attaining glycemic control (European Exenatide=EUREXA study)revealed a greater proportion of patients failed to achieve a HbA1c on glimepiride (avergae dose about 2 mg) vs. exenatide. Furthermore, patients on exenatide failed therapy at a slower rate (median time to failure of 180 weeks vs. 142 weeks for exenatide vs. glimepiride, respectively). More patients attained a HbA1c of less than 7% in the exenatide group (45 vs. 31%). Nevertheless, significantly more patients in the exenatide group discontinued therapy (49 vs. 17 patients). Systlic blood pressure and body weight was reduced and heart rate was increased in the exenatide group to a greater extent than in patients treated with glimepiride. Significantly more hypoglycemia was reported for glimepiride therapy. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial. Lancet. 2012 Jun 8. [Epub ahead of print]

Longer term follow up of these patients was reported by Bunck and colleagues Effects of Exenatide on Measures of {beta}-Cell Function After 3 Years in Metformin-Treated Patients With Type 2 Diabetes Diabetes Care. 2011 Sep;34(9):2041-7 Exenatide therapy was associated with slightly better glucose control, significant weight loss, and somewhat better beta cell function assessed 4 weeks off drug as determined through calculation of the disposition index in glucose clamp studies. To review an overview of this paper, see Incretin-Based Therapy and the Quest for Sustained Improvements in {beta}-Cell Health Diabetes Care. 2011 Sep;34(9):2133-5

The AMIGO Registration studies

Exenatide (Byetta) plus insulin: A 30 week placebo-controlled randomized trial compared the efficacy of adding exenatide vs. placebo to patients not achieving glycemic control (baseline A1c 8.3 and 8.5%) on insulin glargine alone, or insulin glargine with metformin and/or pioglitazone. Patients with a recent history of more than 1 episode of major hypoglycemia were excluded and for patients with a baseline A1c of greater than 8%, the dose of insulin glargine was reduced by 20%. Of the 112 (from 138) patients treated with exenatide, HbA1c decreased by 1.7% whereas patients treated with placebo experienced a 1.04% reduction in A1c. Weight decreased (1.k kg) and increased (1.0 kg) with exenatide vs placebo respectively.  The rate of AEs, principally nausea, vomiting, headaches and diarrhea, was significantly higher with exenatide. Blood pressure decreased and heart rate increased with exenatide. Rates of hypoglycemia were not significantly different in exenatide vs. placebo-treated groups. See Use of Twice-Daily Exenatide in Basal Insulin-Treated Patients With Type 2 Diabetes: A Randomized, Controlled Trial Ann Intern Med. 2010 Dec 6. [Epub ahead of print]

Patients receiving suboptimal therapy on metformin alone were randomized to received exenatide or rosiglitazone, alone or in combination for 20 weeks. Hyperglycemic clamps and meal tolerance tests were used to assess b-cell function and hyperinsulinemic-euglycemic clamps to assess insulin sensitivity, although patients received study medications immediately prior to the clamps, limiting the understanding of the chronic vs, the acute effects of individual drugs. Much smaller improvements in b-cell function were observed using the meal tolerance test b-cell function prior to and after study treatment, Nausea was reported by 47% of the Exenatide-treated subjects. Effects Of Exenatide Plus Rosiglitazone On Beta Cell Function And Insulin Sensitivity In Subjects With Type 2 Diabetes On Metformin. Diabetes Care. 2010 Jan 27. [Epub ahead of print]

The AMIGO studies compare the effects of adding exenatide to previous therapy with sulfonylurea alone, metformin alone, or metformin plus a sulfonylurea

Exenatide at doses of 5 or 10 ug twice daily, or placebo, was added to sulfonylurea therapy in patients with Type 2 diabetes. Mean age of study subjects was ~ 55, mean body weight was 95 kg, BMI ~ 33, and mean initial HbA1c was ~ 8.6%. The average duration of diabetes was just over 6 years in most study subjects. At the end of the 30 week study, Exenatide significantly reduced fasting glucose, HbA1c (-0.86% in the 10 ug twice a day arm), and body weight, with all endpoints more notably improved in subjects receiving 10 ug twice daily. Protocol design included provisions for reduction in dose or discontinuation of sulfonylurea if hypoglycemia was reported. 69% of the subjects completed the entire study. Patients with greater initial HbA1cs (more than 9%) exhibited more pronounced reductions in HbA1c (1.22%). Body weight loss was progressive yet modest over the study period, with a mean 1.6 kg weight loss in the 10 ug twice a day arm. There did not seem to be a correlation between the presence of nausea and the weight loss achieved. The most frequent side effects of exenatide treatment were nausea, dizziness, and mild to moderate (36%) hypoglycemia. At the end of the study, 41% of patients had detectable antibodies to exenatide, however antibodies did not predict the extent of drug responsivity or correlate with glycemic control. See Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With Type 2 Diabetes. Diabetes Care. 2004 Nov;27(11):2628-2635

Analysis of the effects of Exenatide, either 5 or 10 ug twice daily, added to metformin in subjects with type 2 diabetes was reported in a separate publication.  Mean age of the patients was 53 + 10 years with BMI of 34.2 +  5.9 kg/m(2) and HbA(1c) of 8.2 + 1.1%. The glucose-lowering effects of exenatide were greatest in the subjects receiving the highest dose, 10 ug twice daily. Similarly, weight loss was also observed in exenatide-treated subjects in a dose-dependent manner.  The most frequently reported side effects were mild to moderate nausea and mild to moderate hypoglycemia. See Effects of Exenatide (Exendin-4) on Glycemic Control and Weight Over 30 Weeks in Metformin-Treated Patients With Type 2 Diabetes. Diabetes Care. 2005 May;28(5): 1092-1100

The results of exenatide added to existing therapy with sulfonylurea and and metformin was examined in the third arm of the AMIGO studies. 34% of patients treated with Exenatide reached a HbA1c of 7% or less. Mild to moderate hypoglycemia was greater in the exenatide-treated patients than in subjects treated with metformin/sulfonylurea, however weight loss was also significantly greater (mean ~ 1.9 kg) in subjects treated with exenatide. See 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 May;28(5):1083-1091

Exenatide has been studied in combination with either pioglitazone (at least 30 mg) or rosiglitazone (at least 4 mg) over 16 weeks in subjects with T2DM. 79% of study subjects were receiving a TZD plus metformin and 21% were receiving a TZD alone. Not all patients were receiving maximum dose metformin or TZDs. A mean HbA1c reduction of 0.89% was observed in the exenatide-treated group. HOMA-B increased by 19% in the exenatide-treated subjects but deteriorated by 6% in patients not receiving exenatide. A 1.5 kg weight loss differential was achieved in subjects on exenatide vs. the control subjects. Only 71% of exenatide-treated subjects completed the 16 weeks of the trial, compared with 79% of the control subjects. 16% of patients in the exenatide-treated group discontinued treatment due to adverse events, principally nausea and vomiting. 40% of patients exposed to exenatide had anti-exenatide antibodies at the end of the study period. See The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2007 Apr 3;146(7):477-85

Twice daily exenatide was compared vs once daily insulin glargine  in a 26 week open label randomized control trial in patients with type 2 diabetes inadequately controlled with oral agents. Exenatide and insulin glargine produced comparable reductions in levels of HbA1c (~1.1%). The incidence of gastrointestinal side effects and the drop out rate (19.4 vs. 9.7%) was higher with exenatide, however the rate of nocturnal hypoglycemia and the degree of weight gain (1.8 kg gain with glargine, 2.3 kg weight loss with Exenatide) was higher with insulin glargine. To review the data, see Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005 Oct 18;143(8):559-69

A head to head study of exenatide versus biphasic insulin aspart 70/30 was carried out in 372 patients with T2DM not achieving adequate glycemic control on metformin/sulfonylurea. Three arms of the study comprised patients randomized to receive either BIAsp 30 QD (12 U before supper); BIAsp 30 BID (12 U divided equally between pre-breakfast and pre-supper); or exenatide (5 microg BID for 4 weeks and 10 microg BID thereafter. Glycemic control achieved with both insulin aspart regimens was markedly superior to that achieved in exenatide-treated patients and significantly more insulin-treated patients achieved target A1c goals of less than 7 or 6.5%. Patients on insulin gained weight, whereas exenatide-treated patients lost weight and nausea/vomiting leading to drug discontinuation was more common in subjects receiving exenatide. See Efficacy and safety of biphasic insulin aspart 70/30 versus exenatide in subjects with type 2 diabetes failing to achieve glycemic control with metformin and a sulfonylurea Curr Med Res Opin. 2009 Jan;25(1):65-75.

A subsequent smaller study compared the effects of exenatide vs. insulin glargine over 1 year in patients with T2DM. Sixtynine patients ages 30-75, with a mean initial HbA1c of 6.5-9.5% not achieving optimal glycemic control on metformin were randomized to either exenatide (36) or insulin glargine (33). Exenatide was initiated at 5 ug twice daily for 1 month, then increased to 10 ug twice daily, and titrated to a maximum dose of 20 ug t.i.d., or a maximum tolerated dose, for A1c levels not at target (below 7.1%). Glargine was started at 10U hs, and patients were instructed to titrate dose based on FBS targeting 4.5-5.6 mM FBS, with a mean final glargine dose of ~33.6 units per day. Arginine-stimulated C-peptide secretion was assessed at baseline, after 52 weeks, and after a 4 week "washout" period. During the clamp procedure, patients randomized to the exenatide treatment arm received exenatide 15 minutes prior to the onset of the hyperglycemic clamp. Similar levels of HbA1c reduction were achieved (0.7-0.8%); patients on exenatide lost weight (-3.6 kg) whereas insulin glargine-treated patients gained weight (~1 kg). After discontinuation of therapy, body weight tended to revert towards baseline. Subjects receiving exenatide for 52 weeks and immediately prior to the clamp exhibited increased first and second phase glucose-stimulated insulin secretion, which was not sustained 4 weeks after discontinuation of the exenatide. Subjects treated with glargine experience more hypoglycemia, whereas mild to moderate nausea was more common with exenatide (47%), more patients on exenatide withdrew from the study and one patient randomized to exenatide developed pancreatitis. One-Year Treatment With Exenatide Improves Beta-Cell Function, Compared To Insulin Glargine, In Metformin Treated Type 2 Diabetes Patients: A Randomized, Controlled Trial Diabetes Care published online on February 5, 2009 as 10.2337/dc08-1797

Parameters of bone and mineral homeostasis were also examined in this exenatide vs. insulin glargine clinical trial. No effects on bone mineral density were observed in either exenatide vs. insulin glargine-treated patients after 44 weeks. Markers of bone turnover or gut peptides were not reported Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes Diabetes Obes Metab. 2010 Dec 22. doi: 10.1111/j.1463-1326.2010.01355.x.

A related trial examined the efficacy of exenatide versus twice daily injections of insulin aspart (30/70-30% rapid acting insulin) in patients with T2DM not adequately controlled on metformin and a sulfonylurea.  Mean BMI was ~30.1 and mean entry HbA1c was 8.6%. The insulin doses were adjusted at the discretion of the investigators, but there was no mandatory forced titration. Glycemic control, as assessed by end of study HbA1c, was similar at the end of the 52 week open label study, however there was a significant weight differential of 5.5 kg at the end of 52 weeks in favor of exenatide. In contrast the withdrawal rate was 21.3% for exenatide vs. 10.1% for insulin aspart.  No further reduction in HbA1c was noted after week 16 in both treatment arms, despite a progressive reduction in body weight from week 16-52 in exenatide-treated subjects. Blood glucose tended to be lower before meals in subjects treated with insulin, whereas glucose was lower after meals in subjects treated with exenatide. 45% of patients treated with exenatide were antibody positive.  Rates of hypoglycemia were similar in both treatment groups.  See A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2006 Dec 8; [Epub ahead of print

A pilot study compared the effects of adding sitagliptin or exenatide to patients (~16 per group, duration of diabetes only 5-6 years) not achieving adequate glucose control on metformin plus insulin glargine. There was a 4-8 week run in period to establish insulin glargine therapy in all patients at bedtime, with titration of dose to a fasting glucose of 5.6 mM. Subjects were then randomized to continue on insulin/metformin alone, or either exenatide or sitagliptin was added, for a total of 4 weeks. The primary outcome was 6 hrs PPG following a standard breakfast. Baseline HbA1c was 7.9% in the insulin alone or insulin plus sitagliptin group and 8.4% in the insulin plus exenatide group. Both sitagliptin and exenatide improved PPG to a similar extent after 4 weeks, with a greater HbA1c reduction in the exenatide group which started from a higher baseline. However, more patients in the sitagliptin group achieved a HbA1c of less than 7%. Fewer patients reported hypoglycemia on sitagliptin compared to exenatide and more AEs were reported on exenatide. No serious hypoglycemia was observed. Further improvement in postprandial glucose control when adding exenatide (EXE) or sitagliptin (SITA) to combination therapy with insulin glargine (GLAR) and metformin (MET) - a proof-of-concept study. Diabetes Care. 2010 Mar 31. [Epub ahead of print]

                 

                                                                                              Exploratory Studies using Exenatide

The effects of exenatide on weight reduction were examined in obese non-diabetic subjects (BMI greater than 30, average BMI 39.6). 163 patients were randomized, and 102 completed the 24 week treatment of either placebo, or exenatide, 10 ug twice daily. Both arms of the study received a program encompassing structured physicial activity and diet. The withdrawal rate was 32-34%, comparable in both arms of the study. Exenatide was more effective than placebo at achieving more than 5% body weight loss (32 vs 17%). Nausea (25%) and diarrhea (14%). The placebo-subtracted change in body weight over 24 weeks was 3.5 kg Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance in Obese Subjects With and Without Prediabetes.  Diabetes Care. 2010 Mar 23. [Epub ahead of print].

Twice daily exenatide (10 ug bid) was also administered for 3 months to adolescents (13)with severe obesity. 22 patients completed the randomized double blind placebo controlled trial; exenatide produced a significant change in BMI (-2.7%) and body weight (-3.26 kg). BMI continued to drop during the open label extension, ending with a reduction of 4%. The Effect of Glucagon-Like Peptide-1 Receptor Agonist Therapy on Body Mass Index in Adolescents With Severe Obesity: A Randomized, Placebo-Controlled, Clinical Trial.

JAMA Pediatr. 2013 Feb 4:1-6

A similar yet smaller study of exenatide in non-diabetic obese women was carried out for 35 weeks (two separate 16 week treatment periods and a 3 week washout) in 48 obese subjects randomized to exenatide or placebo. The mean weight loss reported was 2.49 vs. 0.43 kg, however stratification of responders and non-responders revealed a subset of subjects, ~ 30% of the cohort, that lost more than 5% of initial body weight. Conversely, the 'non-responders", representing 31% of subjects, actually gained 1.93 kg Short-Term Exenatide Treatment Leads to Significant Weight Loss in a Subset of Obese Women Without Diabetes Diabetes Care. 2011 Oct 31. [Epub ahead of print]

The feasibility of using exenatide for the control of postprandial glucose in pediatric patients with T1DM was examined in a pilot study of eight subjects with T1DM, ages 13-22, with established T1DM for more than a year, HbA1c less than 8.5%. An earlier pilot study by the same group demonstrated significant hypoglycemia at the "approved doses" of exenatide used for T2DM, so this study employed lower doses of 1.25 or 2.5 ug, and doses of prandial insulin were reduced by 20%. Patients were given a test liquid meal, with insulin and exenatide at breakfast, then metabolic parameters were monitored for several hours. Exenatide reduced PPG and decreased gastric emptying, with no significant change in plasma levels of glucagon (a modest but non-significant reduction was observed) or C-peptide. One patient had severe nausea, and one patient had hypoglycemia requiring glucose administration. The Role of Adjunctive Exenatide Therapy in Pediatric Type 1 Diabetes.  Diabetes Care. 2010 Mar 23. [Epub ahead of print]

Exenatide use has also been explored alone, or in combination with metformin, in overweight women wih polycystic ovary disease wit abnormal menstrual cycles. Both exenatide alone or in combination with metformin for 24 weeks improved menstrual cyclicity, ovulation rate, free androgen index, and insulin sensitivity in association with weight loss and reduction of central adiposity. About 70% of patients completed the study as outlined in Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008 May 6. [Epub ahead of print]

 

To review a description of a clinical trial sponsored by the NIDDK evaluating the potential effectiveness of Exenatide therapy in the treatment of Subjects with Type 1 diabetes, see Effect of AC2993 with or without Immunosuppression on Beta Cell Function in Patients with Type I Diabetes

Exenatide has  been studied as initial monotherapy for the treatment of type 2 diabetes. The December 6 2007 Press Release demonstrated that exenatide 10 ug twice daily resulted in a reduction in HbA1c of 0.9 percentage points, respectively, from an average baseline A1C ranging from 7.8 to 7.9 percent with about 60% of patients achieving a target of 7% or less. See Exenatide Monotherapy Press Release. Eli Lilly provided an updated on the startus of Byetta and the LAR Clinical Development Program in their Lilly Investor Presentation Dec 06 2007. Exenatide was approved for use as initial monotherapy in patients with type 2 diabetes on October 30 2009.

 

Overview of Exenatide and early human studies

The insulinotropic properties of exendin-4 also known as Amylin Pharmaceuticals Inc AC2993, or more recently as exenatide, have been assessed in several short term infusion studies in human subjects. Exendin-4 reduced food intake, inhibited gastric emptying, and stimulated insulin secretion in healthy volunteers. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab. 2001 Jul; 281(1): E155-61. The ability of exendin-4 to rapidly restore glucose-stimulated insulin secretion has been demonstrated in short term studies of human type 2 diabetics infused with exenatide in the setting of acute intraveneous glucose challenge, as outlined in Exenatide Augments First and Second Phase Insulin Secretion in Response to Intravenous Glucose in Subjects with Type 2 Diabetes. J Clin Endocrinol Metab. 2005 Sep 6; [Epub ahead of print]

Similarly, single dose exendin-4 administered before breakfast also reduced blood glucose in short term studies of human subjects with Type 1 diabetes, likely due to inhibition of glucagon and slowing of gastric emptying. See Exendin-4 normalized postcibal glycemic excursions in type 1 diabetes. J Clin Endocrinol Metab. 2004 Jul;89(7):3469-73.

The mechanisms mediating the acute glucose-lowering actions of exenatide were examined in 12 subjects with type 2 diabetes following an intravenous infusion of exenatide. The predominant glucoregulatory mechanisms observed following exenatide infusion included a) a suppression of hepatic glucose production associated with reduced levels of circulating glucagon and b) a reduction of gastric emptying, as outlined in Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab. 2008 May;294(5):E846-52.

Exenatide has also been assessed in human subjects with type 1 diabetes following islet transplantation. Exenatide was administered for 3 months to 11 C-peptide positive patients following islet transplantation. Ten of the patients responded, either with a drop in insulin requirements and/or improvement in glycemic control. Evidence for responsivity of the transplanted islets to exenatide was obtained from results of hyperglycemic clamps, demonstrating a rise in second phase insulin release (before exenatide: 246+/-88 pM; during exenatide: 644+/-294 pM, P<0.01). Following cessation of Exenatide, there was no evidence for persisting improvement of β-cell function.  See Effect of exenatide on Beta cell function after islet transplantation in type 1 diabetes. Transplantation. 2007 Jan 15;83(1):24-8   and Islet Transplantation for Brittle Type 1 Diabetes: The UIC Protocol. Am J Transplant. 2008 Apr 29. [Epub ahead of print]

Exendin-4 action has also been examined using intravenous infusion-glucose clamp studies in both normal and diabetic human subjects. Evidence for inhibition of gastric emptying and the insulinotropic actions of exendin-4 was detected in both normal and diabetic subjects. See The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab. 2002 Mar;87(3):1282-90.

Similarly, acute administration of exenatide to normal human healthy volunteers in the presence of graded hypoglycemia did not impair the inhibition of insulin secretion nor the counterregulatory hormone response in healthy human subjects. See Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes. 2004 Sep;53(9):2397-403

Exendin-4 (exenatide) was tested in clinical trials of patients with Type 2 diabetes by Amylin Pharmaceuticals Inc. In a 28-day, triple-blind, placebo-controlled Phase 2 study, 109 subjects with type 2 diabetes who were inadequately controlled with sulfonylureas and/or metformin (HbA1c³8) were enrolled in 24 research centers in the US. Active arms received 0.08 µg/kg of exenatide by subcutaneous injection two or three times a day.  To maintain the study blind, patients treated twice a day received a third injection each day consisting of placebo.  Participants maintained their current diabetes treatment regimens for the duration of the trial.  Study assessments included changes from baseline in HbA1c, serum fructosamine (a clinically accepted measure of average glucose concentrations over approximately three weeks) and body weight.  Exenatide treatment led to statistically significant reductions in mean HbA1c (range of means: -1.1 to -0.7%) compared with placebo (-0.3%).  Reductions in HbA1c of ³0.5% were achieved by 90% of Exenatide-treated subjects compared with 33% of placebo subjects.  The change in body weight between exenatide (range of means: -0.5 to +0.2 kg) and placebo treated subjects (+0.9 kg) did not achieve statistical significance.  The most common adverse event reported was mild to moderate nausea.

A subset of this Phase 2 data, published in the JCEM, demonstrated that 24 subjects receiving sc injections of 0.1 micro g/kg AC2993 (exenatide) or placebo twice daily with meals for 5 days exhibited significant reductions in mean postprandial circulating concentrations of glucose, insulin, and glucagon occurred following treatment with Exenatide. In study B, 13 subjects received a single dose of study medication (0.05, 0.1, or 0.2 m g/kg exenatide or placebo) following an overnight fast had reduced fasting plasma glucose concentrations during the subsequent 8-h period.  Exenatide was well tolerated with mild transient headache, nausea, and vomiting  the main adverse events. See Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003 Jul;88(7):3082-9

The 28 day Phase 2 data comparing placebo versus exenatide added to either metformin, a sulfonylurea, or metformin plus a sulfonylurea has been published in 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 Aug;26(8):2370-7. All exenatide-treated groups had reductions in HbA(1c)  from 0.7 to 1.1%. End-of-study HbA(1c) <7% was achieved by 15% of Exenatide-treated patients (versus 4% of placebo patients). The most common adverse event was transient nausea.

A separate study of ~500 patients with Type 2 diabetes compared exenatide with Lantus (insulin glargine). Both Exenatide and insulin glargine achieved similar A1C reductions, with endpoint A1Cs of 7.2 percent for both groups at the end of the study. Subjects on Exenatide lost an average of 5 pounds, while those on insulin glargine gained an average of 3 pounds. Review the information presented in the July 26 2004 Press Release.

Review the Aug 22 2005 Press Release describing Phase 2 study results for Exenatide LAR. Amylin/Lilly announced in a March 24 2006 Press Release that a Phase 3 trial of LAR vs twice daily Exenatide had been initiated.

A long acting form of exenatide, AC2993 LAR, to be given once a month, has completed a Phase 2 clinical trial. Review the published data describing Phase 2 study results for Exenatide LAR. The preliminary Phase 3 data for the once weekly Exenatide LAR trial was reported in a October 31 2007 Exenatide LAR Press Release

The Clinical Trial Protocol for the Phase 3 Exenatide LAR trial comparing exenatide twice a day with once weekly exenatide LAR may be found at www.clinicaltrials.gov

Below is an excerpt from the June 25 2002 Press Release describing the Exenatide LAR Phase 2 Clinical Trial.

"SAN DIEGO, June 25 /PRNewswire-FirstCall/ -- Amylin Pharmaceuticals, Inc., (Nasdaq: AMLN) today announced the initiation of the first Phase 2 study of the AC2993 LAR development program. The goal of the AC2993 LAR development program is a once a month injection of Amylin's drug candidate AC2993 (synthetic exendin-4), being developed as a treatment for people with type 2 diabetes. AC2993 LAR is based on Alkermes' proprietary Medisorb(R) injectable sustained release drug delivery technology.

This double-blind, placebo-controlled, multi-center study will focus on the safety and tolerability, as well as the pharmacokinetic profiles of rising doses of two formulations of AC2993 LAR. The study will also examine effects of the AC2993 LAR formulations on fructosamine, HbA1c, and fasting and post-meal glucose concentrations. The study, being conducted by Amylin in the United States, will include up to 100 people who are currently managing their diabetes with diet and exercise alone, or in combination with metformin and/or a thiazolidinedione. All participants will continue their existing treatment regimen during the study period. Preliminary data from this study is expected to be available in late 2002..."

Egan, Meneilly and Elahi have reported on the results of a one month study of daily exendin-4 administration in subjects with Type 2 diabetes. Glycosylated hemoglobin and β cell function improved significantly in exenatide-treated subjects. See Effects of One Month Bolus Subcutaneous Administration of Exendin-4 in Type 2 Diabetes. Am J Physiol Endocrinol Metab. 2002 Dec 10 [epub ahead of print]

The importance of the specific site of injection of exenatide on subsequent bioavailability and bioactivity was examined in 24 diabetic patients alternatively injected with 10 ug exenatide in either the arm, thigh, or abdomen. No major differences in bioavailability were observed in this study with Cmax values ranging from 220 pg/ml (abdomen) to 193 pg/ml (thigh). Intriguingly, 3 patients received an unintentional 10-fold overdose of exenatide, resulting in nausea, vomiting, and in one instance, sever hypoglycemia. See A randomized, open-label, crossover study examiningthe effect of injection site on bioavailability of exenatide (synthetic exendin-4). Clin Ther. 2005 Feb;27(2):210-5

For more information on basic preclinical studies, see the section on Exendin-4. To review common adverse events and safety concerns surrounding use of GLP-1R agonists to treat diabetes, see GLP-1: Adverse Events