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
`
`Effects of Exenatide (Exendin-4) on
`Glycemic Control Over 30 Weeks in
`Sulfonylurea-Treated Patients With Type
`2 Diabetes
`S ulfonylureas, a class of commonly
`
`1
`JOHN B. BUSE, MD, PHD
`2
`ROBERT R. HENRY, MD
`3
`JENNY HAN, MS
`DENNIS D. KIM, MD
`
`3
`
`3
`MARK S. FINEMAN, BS
`3
`ALAIN D. BARON, MD
`FOR THE EXENATIDE-113 CLINICAL STUDY
`GROUP*
`
`OBJECTIVE — This study evaluated the ability of the incretin mimetic exenatide (exendin-4)
`to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of
`a sulfonylurea as monotherapy.
`
`RESEARCH DESIGN AND METHODS — This was a triple-blind, placebo-controlled,
`30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in
`period, 377 subjects were randomized (60% men, age 55 ⫾ 11 years, BMI 33 ⫾ 6 kg/m2, HbA1c
`8.6 ⫾ 1.2% [⫾SD]) and began 4 weeks at 5 ␮g subcutaneous exenatide twice daily (before
`breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated
`to 10 ␮g b.i.d. exenatide. All subjects continued sulfonylurea therapy.
`
`RESULTS — At week 30, HbA1c changes from baseline were ⫺0.86 ⫾ 0.11, ⫺0.46 ⫾ 0.12,
`and 0.12 ⫾ 0.09% (⫾SE) in the 10-␮g, 5-␮g, and placebo arms, respectively (adjusted P ⬍
`⬎ 7% (n ⫽ 237), 41% (10 ␮g), 33% (5 ␮g),
`0.001). Of evaluable subjects with baseline HbA1c
`ⱕ 7% (P ⬍ 0.001). Fasting plasma glucose concentrations
`and 9% (placebo) achieved HbA1c
`decreased in the 10-␮g arm compared with placebo (P ⬍ 0.05). Subjects in the exenatide arms
`had dose-dependent progressive weight loss, with an end-of-study loss in the 10-␮g exenatide
`arm of ⫺1.6 ⫾ 0.3 kg from baseline (P ⬍ 0.05 vs. placebo). The most frequent adverse events
`were generally mild or moderate and gastrointestinal in nature. No severe hypoglycemia was
`observed.
`
`CONCLUSIONS — Exenatide significantly reduced HbA1c in patients with type 2 diabetes
`failing maximally effective doses of a sulfonylurea. Exenatide was generally well tolerated and
`was associated with weight loss.
`
`Diabetes Care 27:2628 –2635, 2004
`
`● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
`
`From the 1Diabetes Care Center, University of North Carolina School of Medicine, Chapel Hill, North
`Carolina; the 2Veterans Administration Medical Center, University of California, San Diego, California; and
`3Amylin Pharmaceuticals, San Diego, California.
`Address correspondence and reprint requests to Alain D. Baron, MD, Senior Vice-President, Clinical
`Research, Amylin Pharmaceuticals, 9360 Towne Centre Dr., Suite 110, San Diego, CA 92121. E-mail:
`abaron@amylin.com.
`Received for publication 9 April 2004 and accepted in revised form 13 August 2004.
`J.B.B. is on the advisory board for Amylin Pharmaceuticals. R.R.H. has received honoraria from and served
`as a consultant for Amylin Pharmaceuticals.
`*A list of the principle investigators of the Exenatide-113 Clinical Study Group can be found in the
`APPENDIX.
`Abbreviations: GLP, glucagon-like peptide; ITT, intent to treat.
`A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
`factors for many substances.
`© 2004 by the American Diabetes Association.
`
`2628
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`DIABETES CARE, VOLUME 27, NUMBER 11, NOVEMBER 2004
`
`prescribed antidiabetic drugs, are
`generally safe and efficacious in
`monotherapy and in combination with
`other oral agents and insulin in patients
`with type 2 diabetes. However, hypogly-
`cemia and weight gain often accompany
`their use (1–3), and sulfonylurea therapy
`eventually fails to provide adequate glyce-
`mic control in the majority of patients
`with type 2 diabetes (4 – 6).
`Exenatide (exendin-4) is a 39 –amino
`acid peptide incretin mimetic that exhib-
`its glucoregulatory activities similar to
`those observed with the mammalian in-
`cretin hormone glucagon-like peptide
`(GLP)-1 (7–12). The present study was
`undertaken to evaluate the ability of ex-
`enatide to improve glycemic control over
`a 30-week period in patients with type 2
`diabetes failing maximally effective doses
`of a sulfonylurea.
`
`RESEARCH DESIGN AND
`METHODS — Subjects were 22–76
`years of age and had type 2 diabetes
`treated with at least the maximally effec-
`tive dose of a sulfonylurea as mono-
`therapy (defined below) for at least 3
`months before screening. General inclu-
`sion criteria were a screening fasting
`plasma glucose concentration ⬍240 mg/
`dl, BMI 27– 45 kg/m2, and HbA1c 7.1–
`11.0%, inclusive. In addition, subjects
`had stable weight (⫾10%) for 3 months
`before screening and had no clinically rel-
`evant (for a type 2 diabetic population)
`abnormal laboratory test values (⬎25%
`outside normal laboratory values). Fe-
`male subjects were postmenopausal or
`surgically sterile or using contraceptives
`for at least 3 months before screening and
`continuing throughout the study. Sub-
`jects were excluded if they had used met-
`formin, thiazolidinediones, meglitinides,
`␣-glucosidase inhibitors, exogenous in-
`sulin therapy, or weight-loss drugs within
`the prior 3 months. Further exclusion cri-
`teria included therapy with corticoste-
`
`MPI EXHIBIT 1079 PAGE 1
`
`

`

`Buse and Associates
`
`Figure 1— Study flow chart and subject baseline demographics. Values are means ⫾ SD or n (%).
`
`roids, drugs known to affect gastrointestinal
`motility, transplantation medications, or
`any investigational drug. Subjects were ex-
`cluded if they had evidence of clinically sig-
`nificant comorbid conditions.
`Three hundred seventy-seven adults
`with sulfonylurea-treated type 2 diabetes
`participated at 101 sites in the U.S. (Feb-
`ruary 2002 to August 2003). Data from
`100 sites were used in statistical analyses
`
`(1 site was closed during study conduct
`due to protocol noncompliance). A com-
`mon clinical protocol was approved for
`each site by an institutional review board
`and in accordance with the principles de-
`scribed in the Declaration of Helsinki, in-
`cluding all amendments through the
`1996 South Africa revision (13). All sub-
`jects provided written informed consent
`before participation.
`
`This was a balanced, randomized, tri-
`ple-blind, placebo-controlled, parallel-
`group, pivotal clinical study designed
`after consultation with the U.S. Food and
`Drug Administration to evaluate glycemic
`control, as assessed by HbA1c, and safety.
`The study commenced with a 4-week,
`single-blind, lead-in period with subcuta-
`neous injection of placebo twice daily.
`Thereafter, subjects were randomized to
`
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`

`Exenatide and glycemic control
`
`one of four treatment arms. Nausea had
`been the most frequent treatment-
`emergent adverse event in earlier clinical
`trials, but gradual dose escalation has
`been shown to attenuate this side effect
`(14). Therefore, the present study design
`included an acclimation period (4 weeks)
`at a lower exenatide fixed dose (5 ␮g
`b.i.d.) in treatment arms A and B, before
`the fixed dose of exenatide was either in-
`creased to 10 ␮g b.i.d. (arm B) or re-
`mained at 5 ␮g b.i.d. (arm A) for the
`duration of the study. Equivalent volumes
`of placebo to those administered to arms
`A and B were administered in treatment
`arms C and D. Study medication was self-
`injected subcutaneously in the abdomen
`within 15 min before meals in the morn-
`ing and evening.
`In an effort to standardize sulfonyl-
`urea use at study initiation, if required,
`subjects had their sulfonylurea dose ad-
`justed before the placebo lead-in period
`to the maximally effective dose (4 mg/day
`glimepiride, 20 mg/day glipizide, 10 mg/
`day glipizide XL, 10 mg/day glyburide, 6
`mg/day micronized glyburide, 350 mg/
`day chlorpropamide, or 500 mg/day to-
`lazamide) (15–17). To address the risk of
`hypoglycemia, the protocol recom-
`mended progressive 50% reductions in
`sulfonylurea dose, eventual discontinua-
`tion (depending on the recurrence of hy-
`poglycemia) in the event of a documented
`episode of hypoglycemia (glucose ⬍60
`mg/dl), or two undocumented but sus-
`pected episodes of hypoglycemia.
`Any subject with either an HbA1c
`change of 1.5% from baseline at any clinic
`visit before study termination or an HbA1c
`ⱖ11.5% at week 18 or 24 could be with-
`drawn from the study (loss of glucose
`control). Similarly, subjects could be
`withdrawn if they had fasting plasma glu-
`cose values ⬎240 mg/dl on two consecu-
`tive study visits or consistently recorded
`finger-stick fasting blood glucose values
`⬎260 mg/dl for at least 2 weeks, not sec-
`ondary to a readily identified illness or
`pharmacological treatment.
`
`Study end points
`Primary objectives were to evaluate glyce-
`mic control, primarily as assessed by
`HbA1c, and safety. Secondary objectives
`included examining the effects of ex-
`enatide on fasting plasma glucose concen-
`trations, body weight, and fasting
`concentrations of circulating insulin, pro-
`insulin, and lipids. Safety end points in-
`
`cluded adverse events, clinical laboratory
`tests, physical examination, 12-lead elec-
`trocardiogram, and vital signs. Treat-
`ment-emergent adverse events were
`defined as those occurring upon or after
`receiving the first randomized dose. The
`emergence of anti-exenatide antibodies
`was also assessed.
`
`Statistical analysis
`Randomization was stratified according
`to screening HbA1c values (⬍9.0% and
`ⱖ9.0%) to achieve a balanced distribu-
`tion of subjects across treatment arms. A
`minimum sample size of 300 subjects
`who had 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 values between at least one ex-
`enatide treatment arm and placebo (␣ ⫽
`0.05; Fisher’s protected testing proce-
`dure). Placebo arms C and D were com-
`bined for all analyses.
`All inferential statistical tests were
`conducted at the 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 across
`treatments (18,19). Factors in the model
`included treatment (placebo and two ac-
`tive treatment arms), strata of baseline
`HbA1c (⬍9.0% and ⱖ9.0%), and study
`site as fixed effects. Before data analysis,
`sites were pooled according to geographic
`location to prevent the loss of too many
`degrees of freedom in the model. This
`pooling took into account the number of
`endocrinologists, patient accessibility to
`specialty diabetes care, and managed care
`in the geographic locations.
`The intent-to-treat (ITT) population
`was defined as all randomized subjects
`who received at least one injection of ran-
`domized medication starting from the
`evening of day 1. All efficacy and safety
`analyses were performed on the ITT pop-
`ulation, with the exception of the percent-
`ⱕ7% by
`age of subjects achieving HbA1c
`week 30. For the latter analysis, the more
`clinically relevant population of evaluable
`subjects was used (see below). For ITT
`subjects who had recorded values for at
`least one scheduled visit subsequent to
`the baseline measurement, missing data
`(including missing values at intermediate
`visits) were imputed from scheduled vis-
`its using the last observation carried for-
`ward method. The least square means and
`SEs were derived from the general linear
`
`model for each treatment. Pairwise com-
`parisons of the treatment effects were per-
`formed using Fisher’s protected testing
`procedure to control type I errors due to
`multiple comparisons (20). Similar anal-
`yses were performed for body weight,
`each fasting metabolic parameter, and
`postprandial plasma glucose concentra-
`tions without adjusting for the multiple
`comparison. 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 ITT population. Treatment-emergent
`adverse events were defined as those oc-
`curring upon or after receiving the first
`randomized dose. The intensity of hypo-
`glycemic episodes was defined as mild/
`moderate or severe. For mild/moderate
`hypoglycemia, subjects reported symp-
`toms consistent with hypoglycemia that
`may have been documented by a plasma
`glucose concentration value (⬍60 mg/dl).
`For severe hypoglycemia, subjects re-
`quired the assistance of another person to
`obtain treatment for their hypoglycemia,
`including intravenous glucose or intra-
`muscular glucagon.
`
`Assays
`Plasma analytes were quantitated by
`Quintiles Laboratories (Smyrna, GA) or
`Esoterix Endocrinology (Calabasas Hills,
`CA) using standard methods. Serum in-
`sulin was quantitated by a two-site sand-
`wich chemiluminescent immunoassay,
`and serum proinsulin was quantitated by
`a two-site immunochemiluminometric
`assay. HbA1c was measured using a high-
`performance liquid chromatography
`methodology (21,22). Plasma exenatide
`and anti-exenatide antibodies were mea-
`sured as described previously (8).
`
`RESULTS — Three hundred seventy-
`seven subjects were randomized to treat-
`ment and received at least one dose of
`study medication (ITT population), 260
`subjects completed the entire study
`(69%), and 117 withdrew early (31%)
`
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`

`

`Buse and Associates
`
`thrombotic agent, and 37% with a serum
`lipid–reducing agent.
`
`HbA1c and plasma glucose
`HbA1c values declined in all treatment
`arms during the period between screen-
`ing and randomization, averaged 8.6% at
`baseline, and were comparable across
`treatment arms (Fig. 2A). HbA1c values
`declined in both exenatide arms during
`the initial 12 weeks of the study, in con-
`trast to relatively little change in the pla-
`cebo arm. Thereafter, HbA1c values in the
`exenatide arms plateaued, followed by a
`slight rise toward baseline by the end of
`the study in parallel with a similar change
`in the placebo arm. At week 30, the HbA1c
`change from baseline was ⫺0.86 ⫾
`0.11% in the 10-␮g exenatide arm and
`⫺0.46 ⫾ 0.12% in the 5-␮g exenatide
`arm compared with an increase of 0.12 ⫾
`0.09% in the placebo arm (adjusted P ⱕ
`0.0002 for pairwise comparisons). For
`the ITT population at week 30 with base-
`⬎7% (n ⫽ 353), 41 subjects
`line HbA1c
`(34.2%) in the 10-␮g exenatide arm and
`31 subjects (26.7%) in the 5-␮g exenatide
`ⱕ7%, and these
`arm reached an HbA1c
`proportions of the population were signif-
`icantly greater than in the placebo arm (9
`subjects [7.7%]; P ⬍ 0.0001 for pairwise
`comparisons). For the evaluable popula-
`⬎7%
`tion at week 30 with baseline HbA1c
`(n ⫽ 237), 33 subjects (41.3%) in the
`10-␮g exenatide arm and 28 subjects
`(32.6%) in the 5-␮g exenatide arm
`ⱕ7%, and these pro-
`reached an HbA1c
`portions of the evaluable population were
`significantly greater than in the placebo
`arm (6 subjects [8.8%]; P ⱕ 0.0002 for
`pairwise comparisons).
`When stratified by baseline HbA1c
`ⱖ9%, the 10- and 5-␮g exenatide arms
`had changes in HbA1c from baseline of
`⫺1.22 ⫾ 0.19% (n ⫽ 46) and ⫺0.58 ⫾
`0.24% (n ⫽ 46), respectively, compared
`with an increase of 0.13 ⫾ 0.17% in the
`placebo arm at week 30 (n ⫽ 46; adjusted
`P ⬍ 0.05 for pairwise comparisons) (Fig.
`2B). For subjects with baseline HbA1c
`⬍9%, the 10- and 5-␮g exenatide arms
`had changes in HbA1c from baseline of
`⫺0.65 ⫾ 0.12% (n ⫽ 83) and ⫺0.39 ⫾
`0.12% (n ⫽ 79), respectively, compared
`with an increase of 0.11 ⫾ 0.12% in the
`placebo arm at week 30 (n ⫽ 77; adjusted
`P ⬍ 0.01 for pairwise comparisons).
`Baseline fasting plasma glucose con-
`centrations were similar across treatment
`arms (Fig. 1). By week 30, fasting plasma
`
`Figure 2— Glycemic control in subjects with type 2 diabetes treated with a sulfonylurea and
`exenatide or placebo. A: HbA1c values over the course of the study (ITT population). Baseline
`HbA1c values were 8.6 ⫾ 0.1% in the 10-␮g exenatide arm (F, n ⫽ 129), 8.5 ⫾ 0.1% in the 5-␮g
`exenatide arm (Œ, n ⫽ 125), and 8.7 ⫾ 0.1% in the placebo arm (E, n ⫽ 123). Data are means ⫾
`SE. B: Change in HbA1c values at week 30 stratified by baseline HbA1c (ITT population). Baseline
`HbA1c values were 7.9 ⫾ 0.1% (10 ␮g), 7.8 ⫾ 0.1% (5 ␮g), and 7.9 ⫾ 0.1% (placebo) in subjects
`⬍9%. Baseline HbA1c values were 10.0 ⫾ 0.1% (10 ␮g), 9.7 ⫾ 0.1% (5 ␮g),
`with baseline HbA1c
`and 10.1 ⫾ 0.1% (placebo) in subjects with baseline HbA1c
`ⱖ9%. Data are means ⫾ SE. The
`adjusted P values shown are with placebo as the reference arm. Subjects in the 10-␮g b.i.d.
`exenatide treatment arm received 5 ␮g b.i.d. exenatide during weeks 0 – 4. Subjects in all treatment
`arms were maintained on a sulfonylurea.
`
`(Fig. 1). All subjects were treated with a
`sulfonylurea (45% glipizide, 33% gly-
`buride, 20% glimepiride, 1% tolazamide,
`
`and 0.3% chlorpropamide). Thirty-nine
`percent of ITT subjects were also treated
`with an ACE inhibitor, 34% with an anti-
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`

`Exenatide and glycemic control
`
`Figure 3— Change in body weight from baseline over time in ITT subjects with type 2 diabetes
`treated with a sulfonylurea and exenatide or placebo. Baseline weights were 95.2 ⫾ 1.6 kg in the
`10-␮g exenatide arm (F, n ⫽ 129), 94.9 ⫾ 1.9 kg in the 5-␮g exenatide arm (Œ, n ⫽ 125), and
`99.1 ⫾ 1.7 kg in the placebo arm (E, n ⫽ 123). Subjects in the 10-␮g b.i.d. exenatide treatment
`arm received 5 ␮g b.i.d. exenatide during weeks 0 – 4. Subjects in all treatment arms were main-
`tained on a sulfonylurea. Data are means ⫾ SE. *P ⱕ 0.05 compared with placebo treatment.
`
`arm at week 30, the mean proinsulin-to-
`insulin ratio was reduced ⫺0.13 com-
`pared with baseline and was significantly
`lower than that in placebo (P ⫽ 0.001).
`There was a similar trend in the 5-␮g ex-
`enatide arm.
`
`Clinical laboratory findings and
`safety
`There were no adverse trends apparent in
`vital sign measurements, physical exami-
`nation findings, heart rate, or blood pres-
`sure between the treatment arms. Twelve
`subjects had mild-to-moderate abnor-
`malities in their blood creatine phos-
`phokinase concentrations; however, all
`changes were transient, with no consis-
`tent pattern. There were small reductions
`in LDL (P ⬍ 0.05 for pairwise compari-
`sons) and apolipoprotein B (P ⬍ 0.05 for
`pairwise comparisons) concentrations in
`exenatide arms compared with placebo.
`However, other lipid parameters (total
`cholesterol, triglycerides, LDL-to-HDL
`ratios) did not differ significantly among
`treatment arms.
`The incidence of serious treatment-
`emergent adverse events was low, with no
`discernable treatment pattern (4% in the
`10-␮g exenatide arm, 3% in the 5-␮g ex-
`enatide arm, and 8% in the placebo arm).
`One subject in the 10-␮g arm and one
`subject in the placebo arm experienced a
`myocardial infarction, and one subject in
`the placebo arm experienced clinical
`manifestations of coronary artery disease.
`The most frequent adverse events
`were generally mild or moderate in inten-
`sity and gastrointestinal in nature (Table
`1). The incidence of treatment-emergent
`
`glucose concentrations in the 10- and
`5-␮g exenatide arms were reduced by
`⫺0.6 ⫾ 0.3 and ⫺0.3 ⫾ 0.2 mmol/l from
`baseline, respectively, compared with an
`increase of 0.4 ⫾ 0.3 mmol/l in the pla-
`cebo arm (P ⬍ 0.05 vs. placebo for the
`10-␮g arm only).
`
`Body weight
`Body weights averaged ⬃96 kg at baseline
`(Fig. 1) and were slightly higher in the
`placebo arm than in the exenatide arms.
`Subjects in the 10-␮g exenatide arm had
`progressive weight loss over the entire 30
`weeks, with an end-of-study loss of
`⫺1.6 ⫾ 0.3 kg from baseline (P ⬍ 0.05
`vs. placebo) (Fig. 3). Subjects in the 5-␮g
`exenatide arm had an end-of-study
`weight loss of ⫺0.9 ⫾ 0.3 kg from base-
`line (NS vs. placebo), and subjects in the
`placebo arm had an end-of-study weight
`loss of ⫺0.6 ⫾ 0.3 kg from baseline.
`
`Insulin and proinsulin
`Baseline fasting insulin and proinsulin
`concentrations were similar across treat-
`ment arms (Fig. 1), and there were no
`significant differences in fasting plasma
`insulin concentrations across treatment
`arms over the course of the study. How-
`ever, there was a significant reduction in
`fasting proinsulin concentrations in the
`
`10-␮g exenatide arm compared with
`baseline (⫺16 pmol/l, 95% CI ⫺26.1 to
`⫺6.0) and with placebo (P ⬍ 0.01), with
`a similar trend noted in the 5-␮g ex-
`enatide arm. Overall, there was a dose-
`dependent decrease in the proinsulin-to-
`insulin ratio toward more physiological
`proportions. Baseline proinsulin-to-
`insulin ratios were 0.66 ⫾ 0.04, 0.59 ⫾
`0.03, and 0.64 ⫾ 0.04 in the 10-␮g ex-
`enatide, 5-␮g exenatide, and placebo
`arms, respectively. In the 10-␮g exenatide
`
`Table 1—Treatment-emergent adverse events related to the gastrointestinal tract and hypo-
`glycemia
`
`Adverse event
`
`Placebo
`
`n
`Nausea
`Hypoglycemia
`Dizziness
`Feeling jittery
`Vomiting
`Diarrhea
`Headache
`Constipation
`Sweating increased
`Weakness
`Data are n (%).
`
`123
`9 (7)
`4 (3)
`8 (7)
`2 (2)
`3 (2)
`5 (4)
`8 (7)
`4 (3)
`1 (1)
`4 (3)
`
`5 ␮g
`
`125
`49 (39)
`18 (14)
`19 (15)
`15 (12)
`12 (10)
`14 (11)
`11 (9)
`2 (2)
`3 (2)
`7 (6)
`
`Exenatide
`10 ␮g
`
`129
`66 (51)
`46 (36)
`19 (15)
`19 (15)
`17 (13)
`11 (9)
`10 (8)
`12 (9)
`10 (8)
`2 (2)
`
`All
`
`254
`115 (45)
`64 (25)
`38 (15)
`34 (13)
`29 (11)
`25 (10)
`21 (8)
`14 (6)
`13 (5)
`9 (4)
`
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`Buse and Associates
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`ment of glycemic control and discourage
`patient compliance (1– 6,25).
`Exenatide is an incretin mimetic, hav-
`ing glucoregulatory activities similar to
`those of mammalian hormone GLP-1.
`These actions include glucose-dependent
`enhancement of insulin secretion, sup-
`pression of inappropriately high glucagon
`secretion, and slowing of gastric emptying
`( 7 – 1 2 , 2 6 ) . E x e n a t i d e ’ s g l u c o s e -
`dependent enhancement of insulin secre-
`tion may be mediated by exenatide
`binding to the pancreatic GLP-1 receptor
`(27). In animal models of diabetes and in
`insulin-secretory cell lines, exenatide and
`GLP-1 reportedly improve ␤-cell function
`by increasing the expression of key genes
`involved in insulin secretion, by increas-
`ing insulin biosynthesis, and by augment-
`ing ␤-cell mass through multiple
`mechanisms (9,28). Data obtained in an-
`imal models (9,10,28,29) also indicate
`that exenatide and GLP-1 reduce food in-
`take, cause weight loss, and have an insu-
`lin-sensitizing effect.
`The data from the current trial dem-
`onstrate that long-term use of exenatide at
`fixed doses of 5 and 10 ␮g b.i.d. dose
`dependently improve overall glycemia
`(HbA1c) in patients failing sulfonylurea
`therapy. Previous studies have docu-
`mented how other therapies (i.e., acar-
`bose, metformin, or thiazolidinediones),
`when added to a background of sulfonyl-
`urea, also elicit a glucose-lowering effect.
`It is difficult to draw comparisons with
`this current data because the majority of
`such studies (30 –35) have observed drug
`effects in patients with worse glycemic
`control, hence much higher baseline
`HbA1c levels, where HbA1c lowering oc-
`curs more readily with intervention. A re-
`cent study (36) that approximates the
`treatment conditions of our study showed
`that when either metformin or pioglita-
`zone are added to background sulfonyl-
`urea therapy, one observes HbA 1 c
`lowering similar to that observed in our
`study. As each therapeutic agent comes
`with its own benefits and potential toler-
`
`Table 2—Post-hoc analysis of weight change in subjects with or without at least one episode of
`nausea
`
`Subject group
`
`Never had nausea (kg)
`At least one episode of nausea (kg)
`Data are means ⫾ SD (n).
`
`10 ␮g exenatide
`5 ␮g exenatide
`Placebo
`⫺0.7 ⫾ 3.1 (110) ⫺0.6 ⫾ 3.0 (75) ⫺1.4 ⫾ 3.6 (61)
`0.6 ⫾ 4.7 (9)
`⫺1.3 ⫾ 2.9 (48) ⫺1.7 ⫾ 3.2 (65)
`
`DIABETES CARE, VOLUME 27, NUMBER 11, NOVEMBER 2004
`
`2633
`
`Figure 4—Time-dependent incidence of subjects experiencing treatment-emergent nausea (ITT
`population).
`
`emergent anti-exenatide antibodies de-
`veloped low titer antibodies of unknown
`biological relevance.
`
`CONCLUSIONS — In most individ-
`uals with type 2 diabetes, hyperglycemia
`results from a failure of ␤-cell insulin se-
`cretory capacity to adequately compen-
`sate for insulin resistance in peripheral
`tissues (23). Results from the U.K. Pro-
`spective Diabetes Study (4 – 6) indicate
`that ␤-cell failure is progressive despite
`therapy with diet, metformin, sulfonyl-
`ureas, or insulin. Reductions in HbA1c
`have been shown to lower the risk of
`microvascular complications. Unfortu-
`nately, glycemic control in this popula-
`tion is often inadequate, with average
`HbA1c values well above 8% (4 – 6,24). In
`addition, many available therapeutic
`treatments may not be tolerated by all pa-
`tients or may have undesirable side ef-
`fects, such as weight gain, hypoglycemia,
`and edema, that can impede the attain-
`
`nausea was generally mild or moderate in
`intensity and peaked during the initial
`weeks of dosing (weeks 0 – 8), then de-
`creased in incidence thereafter (Fig. 4). In
`contrast, weight loss was progressive over
`30 weeks, and subjects who never re-
`ported nausea also lost weight (Table 2).
`The incidence of severe nausea was low
`(5% in the 10-␮g exenatide arm, 6% in
`the 5-␮g exenatide arm, and 2% in pla-
`cebo arm). Withdrawals due to nausea
`were also low (4% in the 10-␮g exenatide
`arm, 2% in the 5-␮g exenatide arm, and
`0% in placebo arm).
`There were no cases of severe hypo-
`glycemia. The overall incidence of mild-
`to-moderate hypoglycemia was 36% in
`the 10-␮g exenatide arm, 14% in the
`5-␮g exenatide arm, and 3% in the pla-
`cebo arm. Only one subject withdrew due
`to hypoglycemia (5-␮g exenatide arm).
`The incidence of treatment-emergent,
`dose-dependent hypoglycemia peaked
`during the initial weeks of dosing, then
`decreased over time.
`Subjects who had a detectable anti-
`exenatide antibody titer at any time dur-
`ing the study were considered antibody
`positive for the purpose of stratifying
`treatment-emergent adverse events. The
`presence of anti-exenatide antibodies
`(41% at 30 weeks) had no predictive ef-
`fect on glycemic control or adverse
`events. Most subjects with treatment-
`
`MPI EXHIBIT 1079 PAGE 6
`
`

`

`Exenatide and glycemic control
`
`ability issues and safety considerations,
`further studies are necessary to better un-
`derstand the available therapeutic options
`when choosing adjunctive therapy for
`sulfonylureas.
`When assessing the glycemic effect of
`a therapeutic, it is perhaps more impor-
`tant to ascertain the proportion of sub-
`ⱕ7%.
`jects who achieved a goal of HbA1c
`At the 10- and 5-␮g doses, 41 and 33% of
`subjects who completed the study
`achieved this goal, respectively, com-
`pared with 9% of subjects administered
`placebo. In addition, more subjects with-
`drew from the study due to loss of glyce-
`mic control in the placebo arm than in the
`exenatide arms. The exenatide glucose-
`lowering effect would appear to be attrib-
`uted to a robust effect on daytime
`postprandial glycemia (7,8) because the
`glucose-lowering effect on fasting plasma
`glucose was modest in both exenatide
`treatment arms (a significant reduction in
`the 10-␮g arm but not in the 5-␮g arm).
`The reduction (⬃⫺0.9% at week 30) was
`in line with reductions in HbA1c reported
`in a 28-day phase 2 study of ⫺0.7 to
`⫺1.1% (8); however, due to differences
`in study designs, inclusion criteria, and
`dosing regimens, it is difficult to directly
`compare these results. The proinsulin-to-
`insulin ratio improved over the 30 weeks
`of exenatide treatment, suggesting an im-
`provement in ␤-cell function (37).
`Exenatide treatment at a fixed dose of
`10 ␮g was associated with reductions in
`body weight that did not appear to pla-
`teau by week 30. This progressive weight
`loss is consistent with the known ability of
`exenatide to reduce food intake (12,29).
`Nausea may be suspected to be the cause
`for the weight loss; however, the inci-
`dence of nausea was greatest in the first
`few weeks following initiation of therapy,
`whereas weight loss was progressive over
`30 weeks. Moreover, subjects who never
`reported nausea also lost weight, thus em-
`phasizing the dissociation of the two ef-
`fects. Although the effect on plasma lipids
`was not a primary objective of the study,
`the effect of exenatide to improve overall
`glycemia while causing weight loss, most
`significantly in the 10-␮g arm, leads one
`to anticipate potential effects on circulat-
`ing lipids. That said, there was a small
`reduction in LDL cholesterol and apoli-
`poprotein B levels, but other lipid param-
`eters were unchanged.
`Overall, exenatide was generally well
`tolerated. There did not appear to be any
`
`evidence of a clear safety concern, but
`there were some important observations
`pertaining to tolerability in some patients.
`The most common treatment-emergent
`adverse event was dose-dependent nau-
`sea, and this was most notable at the time
`of initiating therapy and was reported at
`lower incidence thereafter. Nausea was
`mostly mild or moderate in intensity,
`with a low incidence of severe nausea
`(⬃6%) and low withdrawal from the
`study due to nausea (⬃3%).
`Hypoglycemia occurred more readily
`in the exenatide-treated patients in a
`dose-dependent fashion. Events were of
`mild or moderate intensity with no severe
`hypoglycemia reported (requiring the as-
`sistance of another person). Interestingly,
`exenatide itself does not appear to intrin-
`sically increase the risk of hypoglycemia
`because in a similarly designed study,
`when it was added to a background of
`metformin therapy, there was no increase
`in reported hypoglycemia, even though
`overall glycemia had improved (38). With
`this in mind, it is possible to speculate
`that the increase in hypoglycemia ob-
`served in this study was likely caused by
`the background susceptibility to hypogly-
`cemia often observed in sulfonylurea-
`treated patients coupled with lower
`ambient glycemia.
`In summary, exenatide reduced
`HbA1c and was associated with sustained
`weight loss. The most frequent adverse
`events were mild or moderate and gastro-
`intestinal in nature. The incidence of
`hypoglycemic risk associated with sulfo-
`nylurea treatment increased with ex-
`enatide administration as overall
`glycemic control improved. Long-term
`use of exenatide at fixed subcutaneous
`doses of 5 and 10 ␮g b.i.d. appears to
`have potential for the treatment of pa-
`tients with type 2 diabetes not adequately
`controlled with sulfonylurea agents, with
`41% able to reach and maintain an HbA1c
`ⱕ7% in the 10-␮g b.i.d. arm at the end of
`30 weeks.
`
`APPENDIX
`
`Principal investigators in the
`Exenatide-113 Clinical Study Group
`Ahmann A, Albery R, Albu J, Angelo J,
`Argoud G, Banov C, Baron M, Beasey M,
`Black J, Blonde L, Bock A, Bradley V, Buse
`J, Canadas R, Casner P, Cathcart H, Co-
`hen L, Collins G, Conway M, Corder C,
`Cyrus J, Daboul N, de la Garza C, De-
`
`Fronzo R, Duckor S, Durden J, Eliosoff R,
`Farnsworth K, Farrell J, Fishman N,
`Freedman L, Gaman W, Gavin L, Gee D,
`Goldstein B, Hamad M, Harvey W, Hav-
`licek R, Herring C, Heuer M, Holloway R,
`Horowitz B, James D, Jost-Vu E, Kaplan R,
`Kawley A, Kennedy L, Kim K, Klaff L,
`Klein E, Klonoff D, Levinson L, Littlejohn
`T, McIlwain H, McInroy R, Miller J, Miller
`S, Mills R, Moretto T, Mudaliar S, Myers
`L, Norwood P, Osei K, Patel M, Patel N,
`Pullman J, Raad G, Radparvar A, Riff D,
`Rigby S, Robinson J, Rood R, Rosenstock
`P, Saponaro J, Schmidt L, Shockey G,
`Schumacher D, Schwartz S, Shapiro J,
`Shapiro W, Snyder J, Sugimoto D, Sulli-
`van J, Taber L, Troupin B, Ward W, War-
`ren K, Weinstein R, Weiss D, Weiss R,
`Weissman P, Whitehouse F, Williams K,
`Wofford M, Wright D, Wysham C, Yates
`S, Zayed A, Zegarelli L, Zigrang W.
`
`Acknowledgments —
`This trial was supported by Amylin Pharma-
`ceuticals and Eli Lilly.
`The authors thank the Exenatide-113 Clin-
`ical Study Group for their excellent assistance
`in the conduct, reporting, and quality control
`of the study and all of the patients who volun-
`teered to participate. In addition, the following
`individuals are gratefully acknowledged for
`their valuable contributions to the conduct,
`reporting, and quality control of the study and
`to the development of the manuscript: Miriam
`Ahern, Roberta Allen, Maria Aisporna,
`Thomas Bicsak, Amy Halseth, John Hol-
`combe, Orville Kolterman, Szecho Lin, David
`Maggs, Loretta Nielsen, Terri Poon, Larry
`Shen, Michael Sierzega, Kristin Taylor, Mi-
`chael Trautmann, Amanda Varns, Barbara
`Wilkinson, Matthew Wintle, and Liping Xie.
`
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