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Effects of Exenatide (Exendin-4) on Glycemic Control and Weight Over 30 Weeks in Metformin-Treated Patients With Type 2 Diabetes RALPH A. DEFRONZO, MD1

ROBERT E. RATNER, MD2

JENNY HAN, MS3

DENNIS D. KIM, MD3

MARK S. FINEMAN, BS3

ALAIN D. BARON, MD3

OBJECTIVE — This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses.

RESEARCH DESIGN AND METHODS — A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients com- pleted the study. The intent-to-treat population baseline was 53 � 10 years with BMI of 34.2 � 5.9 kg/m2 and HbA1c of 8.2 � 1.1%. After 4 weeks of placebo, subjects self-administered 5 �g exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 �g exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy.

RESULTS — At week 30, HbA1c changes from baseline � SE for each group were �0.78 � 0.10% (10 �g), �0.40 � 0.11% (5 �g), and �0.08 � 0.10% (placebo; intent to treat; adjusted P � 0.002). Of evaluable subjects, 46% (10 �g), 32% (5 �g), and 13% (placebo) achieved HbA1c �7% (P � 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (�2.8 � 0.5 kg [10 �g], �1.6 � 0.4 kg [5 �g]; P � 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Inci- dence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia.

CONCLUSIONS — Exenatide was generally well tolerated and reduced HbA1c with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.

Diabetes Care 28:1092–1100, 2005

I n most individuals with type 2 diabe- tes, hyperglycemia results from a fail- ure of insulin secretion from the �-cells

to adequately compensate for insulin re- sistance in peripheral tissues (1). Results

from the U.K. Prospective Diabetes Study (UKPDS) indicate that �-cell failure is a progressive phenomenon and probably explains why the therapeutic need in- creases with time despite therapy with

diet, metformin, sulfonylureas, or insulin (2,3). Although reductions in HbA1c lower the risk of vascular complications, glycemic control is often inadequate with average HbA1c values well above 8% (4,5). Moreover, many available thera- peutic agents have undesirable side effects (such as weight gain, hypoglycemia, and edema) that can impede the attainment of glycemic control and discourage patient compliance (6,7).

Metformin, a commonly prescribed first-line antidiabetic drug, has proven to be safe and efficacious when used as monotherapy or in combination with other oral antidiabetic agents or insulin in patients with type 2 diabetes (7–10). However, for patients failing to achieve optimal glycemic control with met- formin, many of the currently available treatment choices come with the above- mentioned undesirable side effects and the likelihood of eventual loss of glycemic control (2,3,7–10).

Exenatide (exendin-4) is a 39 –amino acid peptide incretin mimetic that exhib- its glucoregulatory activities similar to the mammalian incretin hormone glucagon- like peptide 1 (GLP-1) (11–22). These ac- t i o n s i n c l u d e g l u c o s e - d e p e n d e n t enhancement of insulin secretion, sup- pression of inappropriately high glucagon secretion, and slowing of gastric empty- ing. Exenatide’s glucose-dependent en- hancement of insulin secretion may be mediated by exenatide binding to the pancreatic GLP-1 receptor (23). In animal models of diabetes and in insulin- secreting cell lines, exenatide and GLP-1 reportedly improve �-cell function by in- creasing the expression of key genes in- volved in insulin secretion, increasing insulin biosynthesis, and augmenting �-cell mass through multiple mecha- nisms (17). Data obtained in animal mod- els also indicate that exenatide and GLP-1 reduce food intake, cause weight loss, and h a v e a n i n s u l i n - s e n s i t i z i n g e f f e c t (13,14,17,24,25). This study evaluated

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

From the 1Division of Diabetes, University of Texas Health Science Center, San Antonio, Texas; the 2MedStar Research Institute, Hyattsville, Maryland; and 3Amylin Pharmaceuticals, San Diego, California.

Address correspondence and reprint requests to Alain D. Baron, MD, Amylin Pharmaceuticals, 9360 Towne Centre Dr., Suite 110, San Diego, CA 92121. E-mail: [email protected].

Received for publication 27 September 2004 and accepted in revised form 1 February 2005. R.A.D. is a member of advisory panels for Bristol Myers Squibb, Takeda, Eli Lilly, Novartis, and Amylin

Pharmaceuticals; has received honoraria from Bristol Myers Squibb, Takeda, Novartis, and Amylin Pharma- ceuticals; and is the recipient of grants from Bristol Myers Squibb, Takeda, Eli Lilly, Novartis, and Amylin Pharmaceuticals. R.E.R. is the recipient of grants from Amylin Pharmaceuticals and Eli Lilly.

Abbreviations: GLP-1, glucagon-like peptide 1. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion

factors for many substances. © 2005 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby

marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s O R I G I N A L A R T I C L E

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the effects of exenatide on glycemic con- trol over a 30-week period in patients with type 2 diabetes failing to achieve gly- cemic control with metformin.

RESEARCH DESIGN AND METHODS — Subjects were 19 –78 years of age with type 2 diabetes treated with metformin monotherapy. General inclusion criteria were screening fasting plasma glucose concentration of �13.3 mmol/l (�240 mg/dl), BMI of 27– 45 kg/ m2, and HbA1c of 7.1–11.0%. The met-

formin dose was �1,500 mg/day for 3 months before screening. Subjects were weight stable (�10%) for 3 months be- fore screening with no clinically signifi- cant (for a type 2 diabetes population) abnormal laboratory test values (�25% outside normal laboratory values). Female subjects were postmenopausal, surgically sterile, or using contraceptives for 3 months before screening and continuing throughout the study. Exclu- sion criteria included use of sulfonyl- ureas, meglitinides, thiazolidinediones,

�-glucosidase inhibitors, exogenous insulin therapy, weight loss drugs, corti- costeroids, drugs known to affect gastro- intestinal motility, transplantation medications, or any investigational drug, or evidence of clinically significant co- morbid conditions for 3 months before screening.

Adults (n 336) with type 2 diabetes treated with metformin participated at 82 sites in the U.S. (January 2002 to June 2003). A common clinical protocol was approved for each site by an institutional

Figure 1—Subject disposition and baseline demographics (mean � SD). ITT, intent to treat.

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review board in accordance with the prin- ciples described in the Declaration of Hel- sinki, including all amendments through the 1996 South Africa revision (26). All subjects provided written informed con- sent before participation.

This was a balanced, randomized, tri- ple-blind, placebo-controlled, parallel- group clinical study (30-week duration) designed after consultation with the U.S. Food and Drug Administration to evalu- ate glycemic control, as assessed by HbA1c, and safety. The study commenced with a 4-week, single-blind, lead-in pe-

riod with subcutaneous injection of pla- cebo twice daily. Thereafter, subjects were randomly assigned to one of four treatment arms. Nausea had been the most frequent treatment-emergent ad- verse event in earlier clinical trials, but gradual dose escalation has been shown to attenuate this side effect (27). There- fore, the present study design included an acclimation period (4 weeks) at a lower exenatide fixed dose (5 �g twice daily) in treatment arms A and B before the fixed dose of exenatide was either increased to 10 �g twice daily (arm B) or kept at 5 �g

twice daily (arm A) for the duration of the study. Volumes of placebo equivalent to those administered to arms A and B were administered in treatment arms C and D. Study medication was self-injected sub- cutaneously in the abdomen within 15 min before meals in the morning and evening. All subjects continued their cur- rent regimen of metformin treatment (�1,500 mg/day).

Subjects were instructed to fast over- night during the study. Any subject with either an HbA1c change of �1.5% from baseline at any clinic visit or an HbA1c �11.5% at week 18 or 24 could be termi- nated from the study for safety reasons at the investigator’s discretion (loss of glu- cose control). Similarly, subjects could be withdrawn if fasting plasma glucose val- ues were �13.3 mmol/l (�240 mg/dl) on two consecutive study visits or if recorded fingerstick fasting blood glucose values were �14.4 mmol/l (�260 mg/dl) for at least 2 weeks, not secondary to a readily identified illness or pharmacological treatment.

A subset of subjects (meal cohort) un- derwent a standardized meal tolerance test on weeks 0, 4, and 30. After an over- night fast (�8 h), subjects took their morning dose of metformin within 1 h of their clinic visit. Exenatide or placebo was injected 15 min before a standardized breakfast. Meal size was calculated indi- vidually at screening to provide 20% of a subject’s total daily caloric requirements with a macronutrient composition of 55% carbohydrate, 15% protein, and 30% fat based on body weight and activity level. The size of the standardized breakfast was the same on each test day for each indi- vidual subject.

Study end points Primary end points included glycemic control, as assessed by HbA1c, and safety. Secondary end points included percent- age of patients achieving HbA1c �7% by week 30, effect of exenatide on fasting and postprandial (meal cohort only) plasma glucose concentrations, body weight, fasting and postprandial concentrations of blood insulin, fasting proinsulin, and lipids.

Statistical analysis Randomization was stratified according to screening HbA1c values (�9.0% and �9.0%) to achieve a balanced distribu- tion of subjects across treatment arms (A,

Figure 2—Glycemic control in subjects with type 2 diabetes treated with metformin and exenatide or placebo. A: HbA1c values over the course of the study in the intent-to-treat population. Baseline HbA1c values (mean � SE) were 8.18 � 0.09% in the 10-�g exenatide arm, 8.26 � 0.11% in the 5-�g exenatide arm, and 8.20 � 0.10% in the placebo arm. B: Percentage of evaluable subjects achieving HbA1c �7% at week 30. Subjects in the 10-�g exenatide arm received 5 �g exenatide twice daily during weeks 0 – 4. Subjects in all treatment arms were maintained on a stable met- formin dose.

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B, C, or D in a 2:2:1:1 ratio). A minimum sample size of 300 subjects with at least one postbaseline HbA1c measurement was estimated to provide 90% power to detect a difference of 0.6% in the change from baseline in HbA1c measurement be- tween at least one exenatide treatment arm and placebo (� 0.05; Fisher’s pro- tected testing procedure). Placebo arms C and D were combined for all analyses.

All inferential statistical tests were

conducted at a significance level of 0.05 (two-sided). A general linear model was used to test for differences in the change from baseline to each visit in HbA1c and weight across treatments (28,29). Factors in the model included treatment (placebo and two active treatment arms), strata of baseline HbA1c (�9.0% and �9.0%), and study site as fixed effects. Before data analysis, sites were pooled according to geographic location to prevent loss of too

many degrees of freedom in the model. This pooling took into account the num- ber of endocrinologists, patient accessi- bility to specialty diabetes care, and quality of managed care in the geographic locations.

The intent-to-treat population was defined as all randomized subjects who received at least one injection of medica- tion starting from the evening of day 1. All efficacy and safety analyses were per- formed on the intent-to-treat population with the exception of the percentage of subjects achieving HbA1c �7% (evalu- able population) and the meal tolerance cohort. For intent-to-treat subjects, miss- ing data (including missing values at inter- mediate visits) were imputed from scheduled visits using the last-observation- carried-forward method. The least square means and SE were derived from the gen- eral linear model for each treatment. Pair- wise comparisons of the treatment effects were performed using Fisher’s protected testing procedure to control type I errors due to multiple comparisons (30). Similar analyses were performed for each fasting metabolic parameter and for postprandial plasma glucose concentrations without adjusting for the multiple comparisons. Post hoc evaluation of change in body weight versus duration of nausea was per- formed using regression analysis. The proportion of subjects achieving HbA1c �7% was compared across treatment groups using the Cochran-Mantel- Haenszel test, wherein strata of baseline HbA1c values served as the stratification factor. Results are given as means � SE unless otherwise indicated.

The evaluable population was de- fined as all randomized subjects who completed treatment through week 30 and received at least 80% of the study medication injections. Subjects who missed 7 consecutive days of injections during the last 2 months of the study were excluded.

Safety analysis All safety analyses were performed using the intent-to-treat population. Safety end points included adverse events, clinical laboratory tests, physical examination, 12-lead electrocardiogram, vital signs, and titering of anti-exenatide antibodies. Treatment-emergent adverse events were defined as those occurring upon or after receiving the first randomized dose. The intensity of hypoglycemic episodes was

Figure 3—Meal tolerance subgroups. Postprandial plasma glucose concentrations after a stan- dardized meal at week 0 (A) and at week 30 (B) and postprandial plasma insulin levels at week 30 (C). Exenatide or placebo were administered at time zero. Evaluable population: 10 �g exenatide, n 16; 5 �g exenatide, n 7; placebo, n 13. Data are mean � SE.

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defined as mild/moderate or severe. For mild/moderate hypoglycemia, subjects reported symptoms consistent with hypo- glycemia that may have been documented by a plasma glucose concentration value �3.3 mmol/l. For severe hypoglycemia, subjects required the assistance of an- other person to obtain treatment for their hypoglycemia, including intravenous glucose or intramuscular glucagon.

Assays Plasma analytes and HbA1c were quanti- tated by Quintiles Laboratories (Smyrna, GA) using standard methods. HbA1c was

measured using a high-performance liq- u i d c h r o m a t o g r a p h y m e t h o d o l o g y (31,32). Serum insulin and proinsulin were quantitated by Esoterix Endocrinol- ogy (Calabasas Hills, CA) by two-site im- munochemiluminometric assays. Intra- assay variability ranged from 3 to 12% and interassay variability from 7 to 14%. Cross-reactivities for the insulin assay were �0.001% with IGF-I and IGF-II, �0.01% with C-peptide, and �0.1% with proinsulin. There was no significant cross-reaction for the proinsulin assay with IGF-I, IGF-II, C-peptide, or insulin. Plasma exenatide and anti-exenatide anti-

bodies were measured as described previ- ously (12).

RESULTS Study population demographics were evenly balanced across treatment arms (Fig. 1). The intent-to-treat population comprised 336 subjects with 272 subjects completing the study (81%) and 64 with- drawing early (19%). Withdrawal rates were equally distributed across treatment arms. Other than metformin, the most frequently used concomitant medications were ACE inhibitors (114 subjects, 34%), hydroxymethylglutaryl-CoA reductase

Figure 4—Body weight in the intent-to- treat population. A: Change in body weight from baseline. Baseline weights were 101 � 2 kg in the 10-�g exenatide arm, 100 � 2 kg in the 5-�g exenatide arm, and 100 � 2 kg in the placebo arm. B: Change in weight from baseline stratified by base- line BMI �30 and �30 kg/m2. For baseline BMI �30 kg/m2, baseline body weights were 84.0 � 1.9 kg in the 10-�g exenatide arm, 80.8 � 2.0 kg in the 5-�g exenatide arm, and 80.3 � 2.2 kg in the placebo arm. For baseline BMI �30 kg/m2, baseline body weights were 106.9 � 2.1 kg in the 10-�g exenatide arm, 108.3 � 2.3 kg in the 5-�g exenatide arm, and 105.8 � 1.8 kg in the placebo arm. *P � 0.05 compared with placebo treatment. **P � 0.001 compared with placebo treatment. Data are mean � SE.

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inhibitors (112 subjects, 33%), and plate- let aggregation inhibitors, excluding hep- arin (101 subjects, 30%).

HbA1c and plasma glucose HbA1c values declined in all treatment arms during the placebo lead-in period and the initial 2 weeks of the study after randomization (Fig. 2A). At week 4, sig- nificant reductions in HbA1c from base- line were observed in both exenatide treatment arms compared with placebo (P � 0.0005). At week 30, a significant dose-dependent reduction in HbA1c was observed in both exenatide-treated arms compared with placebo (P � 0.001, over- all F test).

For intent-to-treat subjects at week 30 with baseline HbA1c �7%, 40% (41 subjects) in the 10-�g exenatide arm and 27% (27 subjects) in the 5-�g exenatide arm reached an HbA1c �7%. This pro- portion of the population was signifi- cantly greater than in the placebo arm (11% [11 subjects]; P � 0.01 for pairwise comparisons). Similarly, for the evaluable population with baseline HbA1c values �7%, 46% (39 subjects) in the 10-�g ex- enatide arm and 32% (25 subjects) in the 5-�g exenatide arm achieved an HbA1c �7% by week 30. These proportions of the evaluable population were signifi- cantly greater than in the placebo arm (13% [10 subjects]; P � 0.0001 and P � 0.01, respectively) (Fig. 2B).

Fasting plasma glucose concentra- tions were equivalent among treatment arms at baseline (Fig. 1). At week 30, fast-

ing plasma glucose concentrations were �0.6 � 0.2 mmol/l (�10.1 � 4.4 mg/dl; P 0.0001) and �0.4 � 0.3 mmol/l (�7.2 � 4.6 mg/dl; P � 0.005) for the 10- and 5-�g exenatide arms, respec- tively, compared with �0.8 � 0.2 mmol/l (�14.4 � 4.2 mg/dl) for the placebo arm. The end of study difference from placebo averaged �1.4 mmol/l (�25 mg/dl) in the 10-�g exenatide arm (P 0.0001).

In subjects who underwent a stan- dardized meal tolerance test, baseline data at week 0 (all arms received placebo) showed a similar rise in postprandial plasma glucose concentrations across treatment arms (Fig. 3A). Geometric mean area under the curve 15–180 min values at baseline were similar. At week 4, postprandial plasma glucose concentra- tions were reduced in both exenatide arms compared with placebo (P 0.006). Postprandial plasma glucose geo- metric mean area under the curve 15–180 min values averaged 34% lower than baseline in each exenatide arm, compared with only 9% lower than baseline in the placebo arm. This pattern was sustained to week 30 with a robust lowering of post- prandial glucose concentrations in the 10-�g (P 0.004) and 5-�g exenatide arms (P 0.03; Fig. 3B). At week 30, there was a rise in plasma insulin in re- sponse to the meal in all three arms, with a greater early increment noted in the 10-�g exenatide arm compared with pla- cebo, despite lower baseline and post- prandial glucose concentrations (Fig. 3C).

Body weight Body weight averaged 100 kg across all treatment arms at baseline (Fig. 1). Dur- ing the study, exenatide arms had pro- gressive weight loss from baseline (Fig. 4A). Reductions in body weight were ob- served regardless of baseline BMI (Fig. 4B).

Insulin and proinsulin Baseline fasting insulin and proinsulin concentrations were similar across treat- ment arms (Fig. 1). Despite the reduction in fasting plasma glucose concentrations in the exenatide arms, there were no sig- nificant differences in fasting plasma in- sulin concentrations from baseline in any treatment arm (�2.1 � 7.8 pmol/l [10 �g], �3.5 � 14.7 pmol/l [5 �g], �5.6 � 10.4 pmol/l [placebo]). There was a trend toward a decline in fasting plasma proin- sulin concentrations from baseline (�9.6 � 3.8 pmol/l [10 �g], �5.2 � 5.9 pmol/l [5 �g], �0.9 � 4.5 pmol/l [pla- cebo]) and a significant decrease in the proinsulin-to-insulin ratio toward more physiological proportions in the 10-�g exenatide arm (P � 0.001), with a similar trend observed in the 5-�g exenatide arm (Fig. 5).

Clinical laboratory findings and safety Exenatide treatment was not associated with an increased incidence of cardiovas- cular, hepatic, or renal adverse events. No changes in plasma lipids, laboratory safety parameters, heart rate, blood pres-

Figure 5—Week 30 change in fasting proinsulin–to–insulin ratio from baseline in the intent-to-treat population. Data are mean � SE.

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sure, or electrocardiogram variables were observed between treatment arms.

The incidence of serious (2.7, 4.5, and 3.5% for 10-�g, 5-�g, and placebo arms, respectively) and severe (9.7, 11.8, and 8.8% in the 10-�g, 5-�g, and placebo arms, respectively) treatment-emergent adverse events was low and evenly dis- tributed across treatment arms. The most frequent adverse events were mild or moderate and were gastrointestinal in na- ture (Table 1). Nausea was the most fre- quent severe adverse event, and it was higher in exenatide-treated subjects than in placebo-treated subjects. Nausea was generally mild or moderate in intensity, with the incidence of severe nausea (3.5, 2.7, and 1.8% in the 10-�g, 5-�g, and placebo arms, respectively) and with- drawals due to nausea low (4 of 11 with- drawals [1.8%] in the exenatide arms). Nausea was reported at a higher incidence during the initial weeks of therapy (weeks 0 – 8) and declined thereafter (Fig. 6). There was no correlation between change in body weight and duration of nausea. Post hoc analysis of nausea and body weight change showed a lack of correla- tion between change in body weight and nausea duration (10 �g exenatide: Y �0.006X � 3.538, R2 0.009; 5 �g ex- enatide: Y �0.004X � 2.182, R2 0.004; placebo: Y �0.002X � 0.435, R2 0.0002). Moreover, subjects who never experienced nausea also lost weight: �2.2 � 0.7 kg (10-�g exenatide arm) and �1.4 � 0.4 kg (5-�g exenatide arm).

There were no cases of severe hypo- glycemia. The overall incidence of mild to moderate hypoglycemia was 5.3% (six subjects) in the 10-�g exenatide arm, 4.5% (five subjects) in the 5-�g exenatide

arm, and 5.3% (six subjects) in the pla- cebo arm. The incidence of anti-exenatide antibodies (43% at 30 weeks) had no pre- dictive effect on glycemic control or ad- verse events. Most treatment-emergent anti-exenatide antibodies were low titer (1/125) and of unknown biological relevance.

CONCLUSIONS — The data demon- strate that when exenatide at doses of 5 and 10 �g twice daily is added to a back- ground of metformin for 30 weeks in a group of type 2 diabetic patients with less- than-optimal glycemic control (baseline HbA1c 8.2%), there was an overall im- provement in glycemia (end of study

HbA1c 7.4%), with nearly 50% of pa- tients able to reach an HbA1c treatment goal of �7% when treated with the 10-�g dose. The magnitude of HbA1c reduction was notable, as the baseline HbA1c was relatively low (8.2%). Many previous tri- als in this disease population have studied patients with higher baseline HbA1c lev- els, where it is possible to exert a greater HbA1c-lowering effect (33,34). Reduction of HbA1c was the result of a modest decrease in fasting plasma glucose con- centrations in keeping with the pharma- cokinetic profile of exenatide and, more importantly, a sustained robust glucose- lowering effect postprandially, as indi- cated by the meal challenge cohort.

It is also noteworthy that the im- provement in glycemia was coupled with overall weight loss and no increase in hy- poglycemia. Exenatide treatment elicited dose-dependent reductions in body weight ( 3% at the 10-�g dose) that did not appear to fully plateau by week 30. This occurred in the setting of a signifi- cant improvement in overall glycemia, where one would ordinarily see weight gain with most other therapies. Weight loss occurred in subjects who had not ex- perienced nausea and was independent of nausea in the cohort at large, as weight loss was sustained over the course of the study but nausea was more pronounced during the first weeks of therapy.

Figure 6—Time-dependent incidence of subjects experiencing treatment-emergent nausea in the intent-to-treat (ITT) population.

Table 1—Treatment-emergent adverse events

Placebo 5-�g exenatide 10-�g exenatide

n 113 110 113 Nausea 26 (23) 40 (36) 51 (45) Diarrhea 9 (8) 13 (12) 18 (16) Upper respiratory tract infection 12 (11) 15 (14) 11 (10) Vomiting 4 (4) 12 (11) 13 (12) Dizziness 7 (6) 10 (9) 5 (4) Sinusitis 6 (5) 5 (5) 7 (6) Hypoglycemia 6 (5) 5 (5) 6 (5) Back pain 3 (3) 3 (3) 7 (6)

Data are n (%). Adverse events had an overall incidence �5% in any treatment arm and a higher incidence in an exenatide arm for the intent-to-treat population.

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The improvement in the proinsulin- to-insulin ratio noted in the exenatide- treated patients is an indication of a beneficial effect on the �-cell. In addition, the meal challenge data indicate a robust insulin secretory response to the meal stimulus despite lower fasting and post- prandial glucose concentrations. More detailed analysis of pancreatic �-cell func- tion in long-term treatment with ex- enatide will be necessary to better characterize the potential positive effects of exenatide on the �-cell.

These results are consistent with those reported in a similar 30-week pla- cebo-controlled phase III study of the ef- fects of exenatide on glycemic control and safety in subjects with type 2 diabetes fail- ing to achieve glycemic control with sul- funonylureas (35). In that study, at week 30 the 10-�g exenatide arm had signifi- cant placebo-adjusted reductions of �1.0% in HbA1c and �1.0 kg in weight. In addition, a reduction in the proinsulin- to-insulin ratio in the 10-�g exenatide arm indicated that exenatide had a bene- ficial effect on the �-cell (32). In a parallel, 30-week placebo-controlled phase III study in subjects with type 2 diabetes fail- ing to achieve glycemic control with met- formin and a sulfonylurea, the 10-�g exenatide arm had significant placebo- adjusted reductions of �1.0% in HbA1c and �0.7 kg in weight at week 30 (36). Thus, exenatide appears to elicit similar glycemic effects whether patients are on background metformin or sulfonylurea or a combination of both.

Combining exenatide with met- formin did not increase the risk of hypo- glycemia. It is acknowledged that metformin is antihyperglycemic in its ac- tion and has little or no hypoglycemic po- tential. That noted, although there was a background incidence of hypoglycemia in the metformin-plus-placebo group, it was mild or moderate in nature and of questionable clinical significance. Impor- tantly, despite a decrease of nearly 1% in HbA1c with exenatide, there was no in- crease in hypoglycemia above that seen in the placebo arm and no severe hypogly- cemic events. This is a clear representa- tion of the glucose-dependent action of exenatide and offers a potential advantage over other therapies in this area, such as the oral insulin secretagogues and exog- enously administered insulin.

T h e m o s t c o m m o n t r e a t m e n t - emergent adverse event was dose-related

nausea. Nausea was mostly mild-to- moderate in intensity with a low inci- dence of severe nausea; only 3% of subjects in the 10-�g exenatide arm with- drew from the clinical trial due to nausea. The incidence of treatment-emergent nausea was highest at initiation of the maintenance dose (weeks 4 – 8 for 10 �g and weeks 0 – 4 for 5 �g) and became less frequent with subsequent dosing. Lastly, anti-exenatide antibodies were detected in a subset of patients but this was not associated with any apparent loss of effi- cacy or increased incidence of immune system-associated adverse events.

In summary, in patients treated with metformin who are not achieving ade- quate glycemic control, exenatide elicited a substantial reduction in HbA1c with no increase in the incidence of hypoglycemia and was associated with significant and sustained weight loss. This combination of beneficial effects suggests that long- term use of exenatide at subcutaneous doses of 5 �g and 10 �g twice daily has potential for the treatment of patients with type 2 diabetes not adequately con- trolled with metformin.

Acknowledgments — This study was sup- ported by Amylin Pharmaceuticals, San Diego, California, and Eli Lilly, Indianapolis, Indiana.

The authors thank the Exenatide-112 Clin- ical Study Group for their excellent assistance in the conduct, reporting, and quality control of the study and all patients who volunteered to participate. The following are gratefully ac- knowledged for their valuable contributions to the conduct, reporting, and quality control of the study and to the development of the manu- script: Miriam Ahern, Maria Aisporna, Thomas Bicsak, Arvinder Dhillon, Eling Gaines, John Holcombe, Orville Kolterman, David Maggs, Loretta Nielsen, Terri Poon, James Ruggles, Larry Shen, Michael Sierzega, Kristin Taylor, Michael Trautmann, Amanda Varns, Matthew Wintle, and Liping Xie.

APPENDIX — Principal investigators in the Exenatide-112 Clinical Study Group were A. Ahmann, R. Albery, J. Albu, M. Beasey, L. Blonde, A. Bock, R. Canadas, P. Casner, H. Cathcart, J. Ca- vanaugh, S. Chandiok, J. Cohen, L. Co- hen, G. Collins, M. Conway, C. Corder, J. Cyrus, L. Davis, C. de la Garza, R. De- Fronzo, S. Duckor, J. Farrell, K. Farns- worth, N. Fishman, W. Gaman, L. Gavin, B. Geary, D. Gee, B. Goldstein, B. Harri- son, W. Harvey, C. Herring, M. Heuer, R.

Holloway, B. Horowitz, E. Klein, D. Klonoff, J. Kopin, E. LaCava, S. Landgar- ten, T. Littlejohn, J. Miller, S. Miller, R. Mills, H. McIlwain, R. McInroy, A. Men- delson, T. Moretto, S. Mudaliar, L. Myers, P. Norwood, K. Osei, J. Pullman, G. Raad, A. Radparvar, R. Ratner, D. Riff, J. Robin- son, R. Rood, J. Saponaro, B. Schactman, D. Schumacher, S. Schwartz, J. Shapiro, W. Shapiro, G. Shockey, M. Strauss, J. Snyder, J. Sullivan, L. Taber, B. Troupin, W. Ward, M. Weerasinghe, R. Weinstein, D. Weiss, R. Weiss, P. Weissman, F. Whitehouse, K. Williams, M. Wofford, C. Wysham, A. Zayed, and W. Zigrang.

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