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Safety of Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus Treated With a Thiazolidinedione Alone or in Combination With Metformin for 2 Years
Clinical Therapeutics/Volume 34, Number 10, 2012
Safety of Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus Treated With a Thiazolidinedione Alone or in Combination With Metformin for 2 Years Paul Norwood, MD, FACP1; Joanne F. Liutkus, MSW, MD, FRCP2; Harry Haber, MPH3; Ella Pintilei, MD4; Marilyn K. Boardman, PharmD5; and Michael E. Trautmann, MD5 1
University of California at San Francisco, Fresno, California; 2Cambridge Memorial Hospital, Cambridge, Ontario, Canada; 3Pharmanet/i3, Inc, Ann Arbor, Michigan; 4Consultmed SRL, Iasi, Romania; and 5Eli Lilly and Company, Indianapolis, Indiana ABSTRACT Background: Patients with type 2 diabetes mellitus are routinely treated with combinations of glucoselowering agents. The adverse event (AE) profile and effects on glycemic control have not been assessed for the glucagon-like peptide-1 receptor agonist exenatide once weekly in combination with a thiazolidinedione (TZD) with or without metformin. Objective: This study was conducted to examine the long-term safety profile and changes in glycemic control and weight for exenatide once weekly with TZD with or without metformin in patients with type 2 diabetes mellitus over 2 years. Methods: In this single-arm, open-label trial with treatment up to 104 or 117 weeks, patients received 2 mg exenatide once weekly while continuing treatment with a TZD with or without metformin. Patients were either exenatidenaïve before this study or had previously received exenatide twice daily, which was discontinued on initiating exenatide once weekly. Patients were on a stable dosage of TZD (rosiglitazone or pioglitazone) and, if applicable, metformin. Treatment-emergent AEs were defined as those first occurring or worsening post baseline. Descriptive statistics were used for absolute and change-from-baseline data, and a onesample t test for within-group change in glycosylated hemoglobin (HbA1c). Results: Of 134 patients in the intent-to-treat population (baseline mean [SD] HbA1c,7.2% [1.0%]), 44 were exenatide-naïve (baseline HbA1c, 7.8% [1.0%]) and 90 switched from exenatide twice daily (baseline HbA1c, 7.0% [0.8%]). Of intent-to-treat patients, 106 (79%) completed the final treatment visit (week 104 or week 117). The most common AEs were nausea (17% of patients) and injection-site nodule (12% of patients). Serious AEs were reported in 14% of patients and 5% withdrew because of a treatment-emergent AE. No iden-
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tifiable pattern of serious AEs was observed. There were 4 reports of edema and no reports of heart failure. No major hypoglycemia was reported; minor hypoglycemia was reported in 4% of patients. Exenatide-naïve patients experienced mean (SE) HbA1c reductions of ⫺0.7% (0.2%) and weight reductions of ⫺2.7 (0.8) kg, whereas patients with prior exposure to exenatide twice daily experienced a reduction of ⫺0.4% (0.1%) in HbA1c and no change in weight. Conclusions: Adverse events over 2 years were consistent with the reported safety profiles of exenatide once weekly and TZDs. Exenatide-naïve patients experienced improvements in HbA1c and weight, while patients with the benefit of prior exenatide therapy experienced an additional reduction from baseline in HbA1c and no additional change in weight after 2 years. ClinicalTrials.gov identifier: NCT00753896. (Clin Ther. 2012;34:2082– 2090) © 2012 Elsevier HS Journals, Inc. All rights reserved. Key words: exenatide, GLP-1 receptor agonist, metformin, glucose control, HbA1c, type 2 diabetes mellitus, TZD.
INTRODUCTION Exenatide is a glucagon-like peptide-1 receptor (GLP1R) agonist that has been approved for the treatment Earlier versions of the analyses in this article were presented in abstract and poster format at the 72nd Annual Scientific Sessions of the American Diabetes Association, Philadelphia, Pennsylvania, June 8⫺12, 2012. The abstract was published in Diabetes. 2012;61(Suppl 1):A293. Abstract: 1135-P. Accepted for publication September 10, 2012. http://dx.doi.org/10.1016/j.clinthera.2012.09.007 0149-2918/$ - see front matter © 2012 Elsevier HS Journals, Inc. All rights reserved.
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P. Norwood et al. of type 2 diabetes mellitus (T2DM) in twice-daily and once-weekly formulations. Exenatide has been shown to work through multiple mechanisms of action, including glucose-dependent enhancement of insulin secretion, inhibition of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake.1 Exenatide twice daily and exenatide once weekly have been shown to cause reductions in glycosylated hemoglobin (HbA1c) and have been associated with reductions in fasting and postprandial glucose concentrations and weight.2– 6 Both agents are generally well tolerated, with gastrointestinal events (for exenatide once weekly and twice daily) and injection-site reactions (for exenatide once weekly) being the most commonly reported adverse events (AEs).2–7 Thiazolidinediones (TZDs), which are peroxisome proliferator⫺activated receptor ␥ agonists, work through mechanisms of action that are different than, and possibly complementary to, exenatide, in that TZD therapy improves glucose disposal by reducing insulin resistance.8,9 However, TZD use has been associated with increased weight, fluid retention, heart failure, and, in the case of rosiglitazone, myocardial infarction.10 –15 Routinely, patients with T2DM are treated with combinations of glucose-lowering agents to achieve blood glucose targets. Current treatment guidelines for T2DM position GLP-1R agonists both directly after metformin and among options for dual and triple combination therapy with metformin or TZD, or both.16,17 In a previous study of patients with T2DM suboptimally controlled with a TZD (with or without metformin), treatment with exenatide twice daily for 16 weeks resulted in improved glycemic control and weight loss, with AEs consistent with the known safety profile of exenatide.18 Similar results for glycemic control and safety were observed in a 26-week study and in a post hoc pooled analysis of patients treated with exenatide twice daily and a TZD for 12 to 30 weeks.19,20 In the present study, we assessed the long-term (104 to 117 weeks) safety profile of an extended-release formulation of exenatide in which exenatide is encapsulated in microspheres, exenatide once weekly, in patients with T2DM treated with a TZD with or without metformin in a single-arm, open-label, multicenter Phase III safety study. Changes from baseline in measures of glycemic control, including HbA1c and fasting serum glucose (FSG), and weight were also assessed.
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Twenty-six⫺week interim results have been reported previously.21
METHODS This trial was conducted in agreement with the Declaration of Helsinki, including all amendments through the Seoul revision and the International Conference on Harmonisation Guideline for Good Clinical Practice.22 The protocol was approved by local ethical review committees or institutional review boards. All participants gave written informed consent before inclusion in the study. Patients were recruited from 23 study centers in the United States, Canada, Mexico, Romania, and South Africa. Patients were at least 18 years of age, had an HbA1c level ⱕ10.0% at screening if previously treated with exenatide twice daily or an HbA1c level of 7.1% to 10.0% at screening, inclusively, if not previously treated with exenatide twice daily; a body mass index of 25 to 45 kg/m2, inclusively; and weight not varying by ⬎10% for at least 3 months before screening. Patients were on a stable TZD dosage (⬎4 mg/d rosiglitazone or ⱖ30 mg/d pioglitazone), with or without metformin, for at least 120 days before screening. Patients treated with metformin were on a stable dosage for at least 90 days before screening. Patients were included if they (1) had never received exenatide twice daily, (2) had been treated with commercially available exenatide twice daily for at least 3 months, or (3) completed a previous clinical trial involving exenatide twice daily plus a TZD within 3 months before screening. Patients recruited from a previous clinical trial that assessed the safety and efficacy of exenatide twice daily in combination with a TZD had received either placebo or exenatide twice daily.18 Exclusion criteria included treatment with medications to promote weight loss within 3 months of screening, previous treatment with other GLP-1 analogs or liraglutide, or treatment with any of the following for 2 weeks or longer within 3 months of screening: insulin, sulfonylureas, ␣-glucosidase inhibitors, meglitinides, dipeptidyl peptidase-4 inhibitors, or pramlintide acetate. After screening, patients initiated treatment with exenatide once weekly 2 mg in addition to their ongoing regimen of TZD with or without metformin. Patients treated previously with exenatide twice daily discontinued twice-daily injections upon switching to exenatide once weekly 2-mg treatment.
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Clinical Therapeutics Reported AEs were recorded beginning at screening and continuing through study termination or early discontinuation. Major hypoglycemia was defined as an episode with symptoms consistent with hypoglycemia resulting in loss of consciousness or seizure that promptly resolved upon administration of glucose or glucagon, or documented blood glucose concentrations of ⬍3.0 mmol/L requiring third-party assistance due to severe impairment in consciousness or behavior. Minor hypoglycemia was defined as a report of symptoms consistent with hypoglycemia and a concurrent blood glucose concentration of ⬍3.0 mmol/L, which resolved either independently or upon self treatment by the patient.
Study Design and Statistical Methods The study was designed to assess the long-term safety profile of exenatide once weekly in patients with T2DM treated with TZD with or without metformin during 52 weeks of treatment, with an exploratory period out to approximately 2 years. (At the time the study was terminated, patients returned for their final treatment visit at either 104 or 117 weeks, as not all patients had reached the same 3-month interval visit.) The primary end point was safety, as measured by the occurrence of reported AEs. Secondary end points included assessments of hypoglycemia, tolerability, vital signs, fasting blood lipids, HbA1c, FSG, and weight. These primary and secondary end points were also assessed at the 104 or 117-week end points. The International Conference on Harmonisation recommends that 100 patients should be treated for 1 year for the safety evaluation of a medication intended for long-term use.23 It was planned that approximately 134 patients with T2DM treated with TZD with or without metformin would be included in this study to result in a minimum of 100 patients completing at least 52 weeks of treatment. Analyses were performed for the intent-to-treat (ITT) analysis set, which was defined as all enrolled patients who received at least 1 dose of exenatide once weekly. Treatment-emergent AEs were defined as those first occurring or worsening post baseline. The incidence of minor hypoglycemia, patient vital sign measures (ie, heart rate, systolic and diastolic blood pressure), and data on antibodies to exenatide were summarized by descriptive statistics. Antibody titer levels were classified as negative (⬍25), low titer (25 to ⱕ625), and higher titer (⬎625). Although this study
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was not powered for analyses of changes from baseline in HbA1c, FSG, and weight, making these results nongeneralizable and limiting their interpretation, these measures were assessed and summarized by descriptive statistics at baseline and treatment end points (week 52 and week 104 or 117 analyzed using last observation carried forward), based on the ITT analysis set. For ITT patients, within-group change in HbA1c from baseline was assessed using a one-sample t test, conducted at a 2-sided ␣ level of 0.05. Post hoc subgroup analyses were performed on 2 subgroups of the ITT population defined based on prior exposure to exenatide (exenatide-naïve vs patients who switched from exenatide twice daily). Statistical analyses were performed using SAS Version 9.1 (SAS Institute, Inc, Cary, North Carolina).
RESULTS Patient Disposition and Baseline Characteristics Baseline characteristics for ITT patients (N ⫽ 134) are shown in Table I. Most (88%) patients were on TZD plus metformin. A total of 44 patients (17 from a previous clinical trial) were exenatide naïve; 90 patients (45 from a previous clinical trial and 45 on commercially available exenatide twice daily) switched from exenatide twice daily to exenatide once weekly. Twenty-eight patients discontinued during the course of the study; of these, 7 discontinued due to AEs (including 2 deaths), 4 were discontinued due to entry criteria not being met, 3 were lost to follow-up, 3 were withdrawn by the sponsor, 1 was withdrawn due to a protocol violation, 2 were withdrawn by the investigator, and 8 withdrew due to patient decision. Deaths and AEs leading to discontinuation are detailed in Table I. A total of 106 patients (79%) completed the final treatment visit (week 104 or week 117) of the study. Mean (SD) doses of TZD and metformin were similar at baseline and at end point (pioglitazone, 32.4 [6.3] mg/d vs 32.8 [7.3] mg/d; rosiglitazone, 6.3 [2.0] mg/d vs 6.3 [2.0] mg/d; metformin, 1811.5 [492.6] mg/d vs 1799.6 [503.7] mg/d, respectively).
Adverse Event Profile The most frequently reported treatment-emergent AEs (occurring in ⱖ5% of patients) were nausea (in 17% of patients), injection-site nodule (12%), and nasopharyngitis (12%; Table II). Overall, 80% of patients reported at least one AE. Adverse events were categorized by the investigator as mild (n ⫽ 43 [32%]),
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Table I. Patient disposition and baseline characteristics. All ITT (N ⫽ 134), no. (%)
Patient Disposition Naïve to exenatide Switched from exenatide twice daily Withdrew Withdrawal of consent Adverse event* Death† Entry criteria not met Lost to follow-up Physician decision Sponsor decision Protocol violation
44 (33) 90 (67) 28 (21) 8 (6) 5 (4) 2 (2) 4 (3) 3 (2) 2 (2) 3 (2) 1 (1) All ITT (N ⫽ 134)
Exenatide-Naïve‡ (n ⫽ 44)
Switched§ (n ⫽ 90)
55 (10)
54 (11)
56 (9)
74 (55) 60 (45)
23 (52) 21 (48)
51 (57) 39 (43)
Race, no. (%)储 American Indian/Alaska Native Asian Black or African American Multiple White
6 (5) 4 (3) 11 (8) 1 (1) 112 (84)
0 (0) 0 (0) 6 (14) 1 (2) 37 (84)
6 (7) 4 (4) 5 (6) 0 (0) 75 (83)
Weight, mean (SD), kg Body mass index, mean (SD), kg/m2 Fasting serum glucose, mean (SD), mmol/L HbA1c, mean (SD), % Duration of diabetes, mean (SD), y
98.1 (18.7) 34.1 (5.1) 8.4 (0.2) 7.2 (1.0) 6 (5)
96.3 (17.1) 33.5 (5.3) 8.4 (0.3) 7.8 (1.0) 5 (4)
99.0 (19.5) 34.3 (5.0) 8.3 (0.3) 7.0 (0.8) 7 (5)
Baseline Characteristics Age, mean (SD), y Sex, no. (%) Male Female
HbA1c⫽ glycosylated hemoglobin; ITT ⫽ intent-to-treat. *Adverse events leading to discontinuation were constipation, nausea, vomiting, injection-site nodule, and lacunar infarction. † Two deaths occurred in the study period, 1 from brain neoplasm and 1 from gastrointestinal hemorrhage. ‡ Never treated with exenatide before this study. § Switched from exenatide twice daily to exenatide once weekly. 储 Values might not add to 100% due to rounding.
moderate (n ⫽ 41 [31%]), or severe (n ⫽ 23 [17%]) in intensity. Among AEs known to be associated with TZDs, there were 4 cases of mild edema, but no reports of heart failure or myocardial infarction. Of safety
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considerations that have been raised for exenatide, there were no reports of pancreatitis or thyroid neoplasms, 1 case of mild renal failure, and 1 case of severe acute renal failure associated with gastrointestinal hemorrhage.
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Clinical Therapeutics
Table II. Treatment-emergent adverse events reported in ⱖ5% of patients.* Category and Preferred Term Patients with ⱖ1 TEAE Nausea Injection-site nodule Nasopharyngitis Upper respiratory tract infection Headache Decreased appetite Vomiting Influenza Arthralgia Back pain Constipation Diarrhea Dyspepsia Sinusitis
All ITT (N ⫽ 134), no. (%)
Exenatide-Naïve,† (n ⫽ 44), no. (%)
Switched,‡ (n ⫽ 90), no. (%)
107 (80) 23 (17) 16 (12) 16 (12) 14 (10) 13 (10) 12 (9) 11 (8) 10 (8) 9 (7) 9 (7) 9 (7) 9 (7) 8 (6) 7 (5)
36 (82) 11 (25) 7 (16) 3 (7) 4 (9) 8 (18) 7 (16) 6 (14) 2 (5) 1 (2) 1 (2) 3 (7) 2 (5) 4 (9) 0 (0)
71 (79) 12 (13) 9 (10) 13 (14) 10 (11) 5 (6) 5 (6) 5 (6) 8 (9) 8 (9) 8 (9) 6 (7) 7 (8) 4 (4) 7 (8)
ITT ⫽ intention to treat; TEAE ⫽ treatment-emergent adverse event. *Values might not add to 100% due to rounding. † Never treated with exenatide before this study. ‡ Switched from exenatide twice daily to exenatide once weekly.
Nineteen patients (14%) reported at least 1 serious treatment-emergent AE; there was no identifiable pattern among the serious AEs reported. Serious AEs listed by MedDRA system organ class are (number of reports in parentheses): vascular disorder (7), cardiac disorders (3), infections and infestations (3), injury, poisoning and procedural complications (3), gastrointestinal disorders (2), musculoskeletal and connective tissue disorders (2), neoplasms benign, malignant and unspecified (1), nervous system disorders (1), renal and urinary disorders (1), respiratory, thoracic and mediastinal disorders (1), blood and lymphatic system disorders (1), and skin and subcutaneous disorders (1). None of the events were considered by the investigators to be related to study drug, procedure, or device. Furthermore, the type of events were not unexpected given the long-term follow-up and long standing history of disease in these patients. At the time of last follow-up, all but 2 patients had recovered or were recovering. Three of the
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serious AEs led to discontinuation: lacunar infarction (diagnosed after 430 days of exposure to study drug); brain neoplasm (268 days), which was fatal; and gastrointestinal hemorrhage (459 days), which was fatal. These were the only deaths in the study period. In total, 7 (5%) patients discontinued the study due to AEs (Table I). There were no events of major hypoglycemia during the study. Five patients (4%) reported 7 total episodes of minor hypoglycemia (2 nocturnal episodes; 5 daytime episodes) during the study. At last visit, 114 patients (86%) were negative for antibodies to exenatide, 14 (11%) had low titer for antibodies to exenatide, and 5 (4%) had higher titer for antibodies to exenatide. For exenatide-naïve patients, 33 (75%) were antibody-negative, 8 (18%) had low titer, and 3 (7%) had higher titer. For patients who switched from exenatide twice daily, 81 patients (91%) were antibody negative, 6 (7%) had low titer, and 2 (2%) had higher titer antibodies.
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A
∆ in HbA1c (%)
At 52 weeks, ITT patients experienced a significant reduction in HbA1c (mean [SE], ⫺0.78% [0.07%]; P ⬍ 0.001) from a baseline mean (SE) value of 7.20% (0.08%). Reductions in HbA1c were observed in both exenatide-naïve patients (mean change [SE], ⫺1.10% [0.13%]; P ⬍ 0.001) and in patients with prior therapy with exenatide twice daily (⫺0.62% [0.08%]; P ⬍ 0.001). After 2 years of therapy with exenatide once weekly and TZD with or without metformin, patients’ HbA1c continued to be lower than at baseline (mean change [SE], ⫺0.48% [0.09%]; P ⬍ 0.001), yielding an absolute HbA1c value at end point of 6.73% (0.08%) in ITT patients (Figure). In exenatide-naïve patients at week 104 or week 117, HbA1c was lower by ⫺0.71% (0.17%) (P ⬍ 0.001) than the mean (SE) baseline of 7.67% (0.14%); in patients who switched from exenatide twice daily to exenatide once weekly, HbA1c was lower by ⫺0.36% (0.10%) (P ⬍ 0.001) than the baseline of 6.97% (0.09%) (Figure). Absolute HbA1c at the 2-year end point was similar for both groups; 6.96% (0.18%) for exenatide-naïve patients and 6.61% (0.09%) for patients who switched from exenatide twice daily. At the 52-week end point, weight was lower than at baseline in ITT patients (mean change [SE], ⫺1.5 [0.4] kg). The change in weight from baseline to week 52 was ⫺2.9 (0.6) kg for exenatide-naïve patients and ⫺0.8 (0.6) kg for patients who switched from exenatide twice daily. Weight continued to show a reduction (⫺2.7 [0.8] kg) in exenatide-naïve patients at the week 104 or week 117 end point, whereas in ITT patients and patients who switched from exenatide twice daily, weight after 2 years of treatment was similar to that at baseline (mean change [SE], ⫺0.6 [0.6] kg for ITT and 0.5 [0.7] kg for patients who switched; Figure). ITT, exenatide-naïve, and patients who switched from exenatide twice daily experienced mean (SE) reductions in FSG at end point (⫺1.10 [0.26] mmol/L, ⫺0.55 [0.50] mmol/L, and ⫺1.37 [0.30] mmol/L, respectively). No clinically relevant changes in heart rate, systolic blood pressure, or diastolic blood pressure were observed at end point in the ITT population (mean [SE] systolic blood pressure, 0.5 [1.3] mm Hg; diastolic blood pressure, ⫺0.6 [0.7] mm Hg; heart rate, 2.5 [0.8] beats/min). Changes in ITT patients from baseline (mean [SE]) in fasting lipid concentrations were as follows: total cholesterol, ⫺0.27 (0.09) mmol/L; HDL,
0.0
–0.5
–1.0
–1.5
–2.0
B
∆ in Weight (kg)
Glycemic Control, Weight, and Cardiovascular Risk Markers
12
26
40
52 65 78 Time (weeks)
91
End Point
12
26
40
52 65 78 Time (weeks)
91
End Point
2
0
–2
–4
–6
All ITT
Switched
Naïve
Figure. (A) Change from baseline in glycosylated hemoglobin (HbA1c) (P ⬍ 0.001 for changes at end point) and (B) weight in all intent-to-treat (ITT) patients, ITT patients who switched from exenatide twice daily (Switched), and ITT patients naïve to exenatide (Naïve) over 2 years of treatment with exenatide once weekly plus thiazolidinedione with or without metformin. End point was 104 or 117 weeks. End point data are presented as last observation carried forward mean (SE); other data are observed.
0.09 (0.02) mmol/L; LDL, ⫺0.25 (0.07) mmol/L; and triglycerides, ⫺0.25 (0.09) mmol/L.
DISCUSSION Combination therapy using various antihyperglycemic medications, including TZDs, to achieve optimal glucose control is common in patients with T2DM.16,17 This study was designed to assess the long-term safety profile of exenatide once weekly in combination with
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Clinical Therapeutics TZD with or without metformin in exenatide-naïve patients and patients who switched from exenatide twice daily to exenatide once weekly. Observed AEs were consistent with the known safety profile of exenatide once weekly and TZDs; exenatide once weekly has been found to be generally well tolerated with mild-to-moderate gastrointestinal events and injection-site reactions as the most commonly reported AEs.2– 6,24 In the present study, predominantly mild nausea was the most frequently reported AE and seldom led to treatment discontinuation. Injection-site nodules, another frequent AE in the present study, are an outcome anticipated with medications of sustained-release formulations using microsphere technology.25 TZD use has been associated with peripheral edema and heart failure, and meta-analyses have reported an increased risk of myocardial infarction and cardiovascular-related death associated with the TZD rosiglitazone.12,15 These observations have resulted in a decline in the use of TZDs for the treatment of T2DM.26 –28 In the present study, no cases of heart failure or myocardial infarction, and few cases of mild edema, were reported. Overall, no new AEs emerged and treatment with these 2 classes of antidiabetes medications was generally well tolerated, with no major hypoglycemia and few incidents of minor hypoglycemia, supporting the use of this combination as an option for improving glycemic control. TZDs have been associated with weight gain in T2DM patients.14 In contrast, agents in the GLP-1 receptor agonist class, such as exenatide once weekly, have been associated with weight loss,2– 6 which has helped to position them as early treatment options (after metformin) in current treatment algorithms.16,17,29 Of note, after 2 years of treatment with exenatide once weekly and a TZD in the present study, patients without prior exenatide exposure experienced net weight loss, and patients with prior exenatide exposure maintained their weight. These observations support previous findings that exenatide in combination with a TZD was associated with no changes in weight or with weight loss, and extend these findings to include the extended-release formulation of exenatide.18,19 These observations are also consistent with those observed for liraglutide, a GLP-1 receptor agonist administered once daily, in combination with TZD.30
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At both 1- and 2-year end points, clinically significant reductions in HbA1c were achieved and maintained in exenatide-naïve patients. In addition, further improvements from baseline were reported in patients having taken exenatide twice daily previously, in keeping with results from an earlier study in which patients switching to exenatide once weekly after 30 weeks of exenatide twice-daily therapy experienced additional improvements in HbA1c at 52 weeks.31 In the present study, it is notable that the observed improvements in HbA1c were achieved despite a relatively low mean baseline (7.2% for ITT patients), yielding a mean end-point value of 6.7% after 2 years of treatment and indicating that patients experienced durable improvements in glycemic control with this therapeutic combination. Limitations of this study include the lack of a control treatment arm, the open-label design of the study, and the small sample size. Another possible limitation of the study was that some patients were taking exenatide twice daily at least 3 months before the study, which might have introduced selection bias for patients who tolerate exenatide therapy. However, the studied population likely approximates the population of patients who would be prescribed exenatide once weekly after having been treated previously with common therapies for T2DM, including TZDs, metformin, and/or exenatide twice daily.16 Therefore, the AE results presented in this study are relevant to physicians treating patients on these background therapies.
CONCLUSIONS The present study is consistent with reports of the safety profile of exenatide use in combination with TZDs, and extends these findings to the extended-release formulation exenatide once weekly, in both exenatide-naïve patients and those switching from prior therapy with exenatide twice daily. Patients without prior exposure to exenatide experienced improvements in HbA1c and weight, and patients with prior exenatide therapy experienced an additional reduction from baseline in HbA1c and no further change in weight, after 2 years.
ACKNOWLEDGMENTS We thank investigators and patients who made this study possible, as well as Carole Weaver, PhD, of Amylin Pharmaceuticals, LLC, San Diego, California; Joseph Giaconia of Eli Lilly and Company, Indianapolis,
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P. Norwood et al. Indiana; and Jamie Scism-Bacon, PhD of PharmaNet/ i3, an Inventiv Health Company, Indianapolis, Indiana for writing assistance. All authors contributed equally to the study design, data collection, literature search, data analysis, data interpretation, writing, critical review, and editing of this paper.
CONFLICTS OF INTEREST Funding for this study and its publication was provided by Eli Lilly and Company and Amylin Pharmaceuticals, LLC. The study sponsors were involved in the study design and execution; in the management, analysis, and interpretation of the data; and in all aspects of the publication process. Drs. Norwood, Liutkus, and Pintilei have received payment for clinical studies and reimbursement for scientific events from Eli Lilly and Company. Mr. Haber is an employee of Pharmanet/i3, Inc. Drs. Boardman and Trautmann are or were employees of and own stock in Eli Lilly and Company. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
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18.
sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care. 2012;35:252–258. MacConell L, Brown C, Gurney K, Han J. Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials. Diabetes Metab Syndr Obes. 2012;5:29 – 41. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet. 2010;375: 2267–2277. Hernandez AV, Usmani A, Rajamanickam A, Moheet A. Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis and meta-regression analysis of placebo-controlled randomized clinical trials. Am J Cardiovasc Drugs. 2011;11:115– 128. Berlie HD, Kalus JS, Jaber LA. Thiazolidinediones and the risk of edema: a meta-analysis. Diabetes Res Clin Pract. 2007;76:279 –289. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370:1129 –1136. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003. Circulation. 2003;108:2941–2948. Phung OJ, Scholle JM, Talwar M, Coleman CI. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA. 2010;303:1410 –1418. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–2471. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364 – 1379. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/ American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15:540 –559. Zinman B, Hoogwerf BJ, Durán García S, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2007;146:477– 485.
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Clinical Therapeutics 19. Liutkus J, Rosas Guzman J, Norwood P, et al. A placebo-controlled trial of exenatide twice-daily added to thiazolidinediones alone or in combination with metformin. Diabetes Obes Metab. 2010;12:1058 – 1065. 20. Pencek R, Brunell SC, Li Y, et al. Use of concomitant glucose-lowering therapies and associated treatment results observed in clinical trials of twice-daily exenatide. Endocr Pract. 2012;18:227–237. 21. Norwood P, Pintilei E, Pop L, et al. Safety of exenatide once weekly in patients with type 2 diabetes treated with a thiazolidinedione. Diabetes. 2010;59:Abstract 715-P. 22. World Medical Association Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. JAMA. 1997;277:925–926. 23. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. The extent of population exposure to assess clinical safety for drugs intended for long-term treatment of non-lifethreatening conditions. CPMP/ICH/ 375/95. 1994. http://www.ich.org/ fileadmin/Public_Web_Site/ICH_ Products/Guidelines/Efficacy/E1/ Step4/E1_Guideline.pdf. Accessed April 3, 2012. 24. Diamant M, Van Gaal L, Stranks S, et al. Safety and efficacy of onceweekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes over 84 weeks. Diabetes Care. 2012;35:683– 689. 25. DeYoung MB, MacConell L, Sarin V, et al. Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol Ther. 2011;13:1145–1154. 26. Kung J, Henry RR. Thiazolidinedione safety. Expert Opin Drug Saf. 2012; 11:565–579.
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27. Jain R, Mullins CD, Lee H, Wong W. Use of rosiglitazone and pioglitazone immediately after the cardiovascular risk warnings. Res Social Adm Pharm. 2012; 8:47–59. 28. Hurren KM, Taylor TN, Jaber LA. Antidiabetic prescribing trends and predictors of thiazolidine discontinuation following the 2007 rosigitazone safety alert. Diabetes Res Clin Pract. 2011; 93:49 –55. 29. Vilsbøll T, Christensen M, Junker AE, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-
analyses of randomised controlled trials. BMJ. 2012;344:d7771. 30. Zinman B, Gerich J, Buse JB, et al. Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met⫹TZD). Diabetes Care. 2009;32:1224 –1230. 31. Buse JB, Drucker DJ, Taylor KL, et al. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care. 2010;33: 1255–1261.
Address correspondence to: Michael E. Trautmann, MD, Fueerbarg 16a, Hamburg, D-22393, Germany. E-mail: [email protected]
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Safety of Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus Treated With a Thiazolidinedione Alone or in Combination With Metformin for 2 Years Paul Norwood, MD, FACP1; Joanne F. Liutkus, MSW, MD, FRCP2; Harry Haber, MPH3; Ella Pintilei, MD4; Marilyn K. Boardman, PharmD5; and Michael E. Trautmann, MD5 1
University of California at San Francisco, Fresno, California; 2Cambridge Memorial Hospital, Cambridge, Ontario, Canada; 3Pharmanet/i3, Inc, Ann Arbor, Michigan; 4Consultmed SRL, Iasi, Romania; and 5Eli Lilly and Company, Indianapolis, Indiana ABSTRACT Background: Patients with type 2 diabetes mellitus are routinely treated with combinations of glucoselowering agents. The adverse event (AE) profile and effects on glycemic control have not been assessed for the glucagon-like peptide-1 receptor agonist exenatide once weekly in combination with a thiazolidinedione (TZD) with or without metformin. Objective: This study was conducted to examine the long-term safety profile and changes in glycemic control and weight for exenatide once weekly with TZD with or without metformin in patients with type 2 diabetes mellitus over 2 years. Methods: In this single-arm, open-label trial with treatment up to 104 or 117 weeks, patients received 2 mg exenatide once weekly while continuing treatment with a TZD with or without metformin. Patients were either exenatidenaïve before this study or had previously received exenatide twice daily, which was discontinued on initiating exenatide once weekly. Patients were on a stable dosage of TZD (rosiglitazone or pioglitazone) and, if applicable, metformin. Treatment-emergent AEs were defined as those first occurring or worsening post baseline. Descriptive statistics were used for absolute and change-from-baseline data, and a onesample t test for within-group change in glycosylated hemoglobin (HbA1c). Results: Of 134 patients in the intent-to-treat population (baseline mean [SD] HbA1c,7.2% [1.0%]), 44 were exenatide-naïve (baseline HbA1c, 7.8% [1.0%]) and 90 switched from exenatide twice daily (baseline HbA1c, 7.0% [0.8%]). Of intent-to-treat patients, 106 (79%) completed the final treatment visit (week 104 or week 117). The most common AEs were nausea (17% of patients) and injection-site nodule (12% of patients). Serious AEs were reported in 14% of patients and 5% withdrew because of a treatment-emergent AE. No iden-
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tifiable pattern of serious AEs was observed. There were 4 reports of edema and no reports of heart failure. No major hypoglycemia was reported; minor hypoglycemia was reported in 4% of patients. Exenatide-naïve patients experienced mean (SE) HbA1c reductions of ⫺0.7% (0.2%) and weight reductions of ⫺2.7 (0.8) kg, whereas patients with prior exposure to exenatide twice daily experienced a reduction of ⫺0.4% (0.1%) in HbA1c and no change in weight. Conclusions: Adverse events over 2 years were consistent with the reported safety profiles of exenatide once weekly and TZDs. Exenatide-naïve patients experienced improvements in HbA1c and weight, while patients with the benefit of prior exenatide therapy experienced an additional reduction from baseline in HbA1c and no additional change in weight after 2 years. ClinicalTrials.gov identifier: NCT00753896. (Clin Ther. 2012;34:2082– 2090) © 2012 Elsevier HS Journals, Inc. All rights reserved. Key words: exenatide, GLP-1 receptor agonist, metformin, glucose control, HbA1c, type 2 diabetes mellitus, TZD.
INTRODUCTION Exenatide is a glucagon-like peptide-1 receptor (GLP1R) agonist that has been approved for the treatment Earlier versions of the analyses in this article were presented in abstract and poster format at the 72nd Annual Scientific Sessions of the American Diabetes Association, Philadelphia, Pennsylvania, June 8⫺12, 2012. The abstract was published in Diabetes. 2012;61(Suppl 1):A293. Abstract: 1135-P. Accepted for publication September 10, 2012. http://dx.doi.org/10.1016/j.clinthera.2012.09.007 0149-2918/$ - see front matter © 2012 Elsevier HS Journals, Inc. All rights reserved.
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P. Norwood et al. of type 2 diabetes mellitus (T2DM) in twice-daily and once-weekly formulations. Exenatide has been shown to work through multiple mechanisms of action, including glucose-dependent enhancement of insulin secretion, inhibition of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake.1 Exenatide twice daily and exenatide once weekly have been shown to cause reductions in glycosylated hemoglobin (HbA1c) and have been associated with reductions in fasting and postprandial glucose concentrations and weight.2– 6 Both agents are generally well tolerated, with gastrointestinal events (for exenatide once weekly and twice daily) and injection-site reactions (for exenatide once weekly) being the most commonly reported adverse events (AEs).2–7 Thiazolidinediones (TZDs), which are peroxisome proliferator⫺activated receptor ␥ agonists, work through mechanisms of action that are different than, and possibly complementary to, exenatide, in that TZD therapy improves glucose disposal by reducing insulin resistance.8,9 However, TZD use has been associated with increased weight, fluid retention, heart failure, and, in the case of rosiglitazone, myocardial infarction.10 –15 Routinely, patients with T2DM are treated with combinations of glucose-lowering agents to achieve blood glucose targets. Current treatment guidelines for T2DM position GLP-1R agonists both directly after metformin and among options for dual and triple combination therapy with metformin or TZD, or both.16,17 In a previous study of patients with T2DM suboptimally controlled with a TZD (with or without metformin), treatment with exenatide twice daily for 16 weeks resulted in improved glycemic control and weight loss, with AEs consistent with the known safety profile of exenatide.18 Similar results for glycemic control and safety were observed in a 26-week study and in a post hoc pooled analysis of patients treated with exenatide twice daily and a TZD for 12 to 30 weeks.19,20 In the present study, we assessed the long-term (104 to 117 weeks) safety profile of an extended-release formulation of exenatide in which exenatide is encapsulated in microspheres, exenatide once weekly, in patients with T2DM treated with a TZD with or without metformin in a single-arm, open-label, multicenter Phase III safety study. Changes from baseline in measures of glycemic control, including HbA1c and fasting serum glucose (FSG), and weight were also assessed.
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Twenty-six⫺week interim results have been reported previously.21
METHODS This trial was conducted in agreement with the Declaration of Helsinki, including all amendments through the Seoul revision and the International Conference on Harmonisation Guideline for Good Clinical Practice.22 The protocol was approved by local ethical review committees or institutional review boards. All participants gave written informed consent before inclusion in the study. Patients were recruited from 23 study centers in the United States, Canada, Mexico, Romania, and South Africa. Patients were at least 18 years of age, had an HbA1c level ⱕ10.0% at screening if previously treated with exenatide twice daily or an HbA1c level of 7.1% to 10.0% at screening, inclusively, if not previously treated with exenatide twice daily; a body mass index of 25 to 45 kg/m2, inclusively; and weight not varying by ⬎10% for at least 3 months before screening. Patients were on a stable TZD dosage (⬎4 mg/d rosiglitazone or ⱖ30 mg/d pioglitazone), with or without metformin, for at least 120 days before screening. Patients treated with metformin were on a stable dosage for at least 90 days before screening. Patients were included if they (1) had never received exenatide twice daily, (2) had been treated with commercially available exenatide twice daily for at least 3 months, or (3) completed a previous clinical trial involving exenatide twice daily plus a TZD within 3 months before screening. Patients recruited from a previous clinical trial that assessed the safety and efficacy of exenatide twice daily in combination with a TZD had received either placebo or exenatide twice daily.18 Exclusion criteria included treatment with medications to promote weight loss within 3 months of screening, previous treatment with other GLP-1 analogs or liraglutide, or treatment with any of the following for 2 weeks or longer within 3 months of screening: insulin, sulfonylureas, ␣-glucosidase inhibitors, meglitinides, dipeptidyl peptidase-4 inhibitors, or pramlintide acetate. After screening, patients initiated treatment with exenatide once weekly 2 mg in addition to their ongoing regimen of TZD with or without metformin. Patients treated previously with exenatide twice daily discontinued twice-daily injections upon switching to exenatide once weekly 2-mg treatment.
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Clinical Therapeutics Reported AEs were recorded beginning at screening and continuing through study termination or early discontinuation. Major hypoglycemia was defined as an episode with symptoms consistent with hypoglycemia resulting in loss of consciousness or seizure that promptly resolved upon administration of glucose or glucagon, or documented blood glucose concentrations of ⬍3.0 mmol/L requiring third-party assistance due to severe impairment in consciousness or behavior. Minor hypoglycemia was defined as a report of symptoms consistent with hypoglycemia and a concurrent blood glucose concentration of ⬍3.0 mmol/L, which resolved either independently or upon self treatment by the patient.
Study Design and Statistical Methods The study was designed to assess the long-term safety profile of exenatide once weekly in patients with T2DM treated with TZD with or without metformin during 52 weeks of treatment, with an exploratory period out to approximately 2 years. (At the time the study was terminated, patients returned for their final treatment visit at either 104 or 117 weeks, as not all patients had reached the same 3-month interval visit.) The primary end point was safety, as measured by the occurrence of reported AEs. Secondary end points included assessments of hypoglycemia, tolerability, vital signs, fasting blood lipids, HbA1c, FSG, and weight. These primary and secondary end points were also assessed at the 104 or 117-week end points. The International Conference on Harmonisation recommends that 100 patients should be treated for 1 year for the safety evaluation of a medication intended for long-term use.23 It was planned that approximately 134 patients with T2DM treated with TZD with or without metformin would be included in this study to result in a minimum of 100 patients completing at least 52 weeks of treatment. Analyses were performed for the intent-to-treat (ITT) analysis set, which was defined as all enrolled patients who received at least 1 dose of exenatide once weekly. Treatment-emergent AEs were defined as those first occurring or worsening post baseline. The incidence of minor hypoglycemia, patient vital sign measures (ie, heart rate, systolic and diastolic blood pressure), and data on antibodies to exenatide were summarized by descriptive statistics. Antibody titer levels were classified as negative (⬍25), low titer (25 to ⱕ625), and higher titer (⬎625). Although this study
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was not powered for analyses of changes from baseline in HbA1c, FSG, and weight, making these results nongeneralizable and limiting their interpretation, these measures were assessed and summarized by descriptive statistics at baseline and treatment end points (week 52 and week 104 or 117 analyzed using last observation carried forward), based on the ITT analysis set. For ITT patients, within-group change in HbA1c from baseline was assessed using a one-sample t test, conducted at a 2-sided ␣ level of 0.05. Post hoc subgroup analyses were performed on 2 subgroups of the ITT population defined based on prior exposure to exenatide (exenatide-naïve vs patients who switched from exenatide twice daily). Statistical analyses were performed using SAS Version 9.1 (SAS Institute, Inc, Cary, North Carolina).
RESULTS Patient Disposition and Baseline Characteristics Baseline characteristics for ITT patients (N ⫽ 134) are shown in Table I. Most (88%) patients were on TZD plus metformin. A total of 44 patients (17 from a previous clinical trial) were exenatide naïve; 90 patients (45 from a previous clinical trial and 45 on commercially available exenatide twice daily) switched from exenatide twice daily to exenatide once weekly. Twenty-eight patients discontinued during the course of the study; of these, 7 discontinued due to AEs (including 2 deaths), 4 were discontinued due to entry criteria not being met, 3 were lost to follow-up, 3 were withdrawn by the sponsor, 1 was withdrawn due to a protocol violation, 2 were withdrawn by the investigator, and 8 withdrew due to patient decision. Deaths and AEs leading to discontinuation are detailed in Table I. A total of 106 patients (79%) completed the final treatment visit (week 104 or week 117) of the study. Mean (SD) doses of TZD and metformin were similar at baseline and at end point (pioglitazone, 32.4 [6.3] mg/d vs 32.8 [7.3] mg/d; rosiglitazone, 6.3 [2.0] mg/d vs 6.3 [2.0] mg/d; metformin, 1811.5 [492.6] mg/d vs 1799.6 [503.7] mg/d, respectively).
Adverse Event Profile The most frequently reported treatment-emergent AEs (occurring in ⱖ5% of patients) were nausea (in 17% of patients), injection-site nodule (12%), and nasopharyngitis (12%; Table II). Overall, 80% of patients reported at least one AE. Adverse events were categorized by the investigator as mild (n ⫽ 43 [32%]),
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Table I. Patient disposition and baseline characteristics. All ITT (N ⫽ 134), no. (%)
Patient Disposition Naïve to exenatide Switched from exenatide twice daily Withdrew Withdrawal of consent Adverse event* Death† Entry criteria not met Lost to follow-up Physician decision Sponsor decision Protocol violation
44 (33) 90 (67) 28 (21) 8 (6) 5 (4) 2 (2) 4 (3) 3 (2) 2 (2) 3 (2) 1 (1) All ITT (N ⫽ 134)
Exenatide-Naïve‡ (n ⫽ 44)
Switched§ (n ⫽ 90)
55 (10)
54 (11)
56 (9)
74 (55) 60 (45)
23 (52) 21 (48)
51 (57) 39 (43)
Race, no. (%)储 American Indian/Alaska Native Asian Black or African American Multiple White
6 (5) 4 (3) 11 (8) 1 (1) 112 (84)
0 (0) 0 (0) 6 (14) 1 (2) 37 (84)
6 (7) 4 (4) 5 (6) 0 (0) 75 (83)
Weight, mean (SD), kg Body mass index, mean (SD), kg/m2 Fasting serum glucose, mean (SD), mmol/L HbA1c, mean (SD), % Duration of diabetes, mean (SD), y
98.1 (18.7) 34.1 (5.1) 8.4 (0.2) 7.2 (1.0) 6 (5)
96.3 (17.1) 33.5 (5.3) 8.4 (0.3) 7.8 (1.0) 5 (4)
99.0 (19.5) 34.3 (5.0) 8.3 (0.3) 7.0 (0.8) 7 (5)
Baseline Characteristics Age, mean (SD), y Sex, no. (%) Male Female
HbA1c⫽ glycosylated hemoglobin; ITT ⫽ intent-to-treat. *Adverse events leading to discontinuation were constipation, nausea, vomiting, injection-site nodule, and lacunar infarction. † Two deaths occurred in the study period, 1 from brain neoplasm and 1 from gastrointestinal hemorrhage. ‡ Never treated with exenatide before this study. § Switched from exenatide twice daily to exenatide once weekly. 储 Values might not add to 100% due to rounding.
moderate (n ⫽ 41 [31%]), or severe (n ⫽ 23 [17%]) in intensity. Among AEs known to be associated with TZDs, there were 4 cases of mild edema, but no reports of heart failure or myocardial infarction. Of safety
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considerations that have been raised for exenatide, there were no reports of pancreatitis or thyroid neoplasms, 1 case of mild renal failure, and 1 case of severe acute renal failure associated with gastrointestinal hemorrhage.
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Table II. Treatment-emergent adverse events reported in ⱖ5% of patients.* Category and Preferred Term Patients with ⱖ1 TEAE Nausea Injection-site nodule Nasopharyngitis Upper respiratory tract infection Headache Decreased appetite Vomiting Influenza Arthralgia Back pain Constipation Diarrhea Dyspepsia Sinusitis
All ITT (N ⫽ 134), no. (%)
Exenatide-Naïve,† (n ⫽ 44), no. (%)
Switched,‡ (n ⫽ 90), no. (%)
107 (80) 23 (17) 16 (12) 16 (12) 14 (10) 13 (10) 12 (9) 11 (8) 10 (8) 9 (7) 9 (7) 9 (7) 9 (7) 8 (6) 7 (5)
36 (82) 11 (25) 7 (16) 3 (7) 4 (9) 8 (18) 7 (16) 6 (14) 2 (5) 1 (2) 1 (2) 3 (7) 2 (5) 4 (9) 0 (0)
71 (79) 12 (13) 9 (10) 13 (14) 10 (11) 5 (6) 5 (6) 5 (6) 8 (9) 8 (9) 8 (9) 6 (7) 7 (8) 4 (4) 7 (8)
ITT ⫽ intention to treat; TEAE ⫽ treatment-emergent adverse event. *Values might not add to 100% due to rounding. † Never treated with exenatide before this study. ‡ Switched from exenatide twice daily to exenatide once weekly.
Nineteen patients (14%) reported at least 1 serious treatment-emergent AE; there was no identifiable pattern among the serious AEs reported. Serious AEs listed by MedDRA system organ class are (number of reports in parentheses): vascular disorder (7), cardiac disorders (3), infections and infestations (3), injury, poisoning and procedural complications (3), gastrointestinal disorders (2), musculoskeletal and connective tissue disorders (2), neoplasms benign, malignant and unspecified (1), nervous system disorders (1), renal and urinary disorders (1), respiratory, thoracic and mediastinal disorders (1), blood and lymphatic system disorders (1), and skin and subcutaneous disorders (1). None of the events were considered by the investigators to be related to study drug, procedure, or device. Furthermore, the type of events were not unexpected given the long-term follow-up and long standing history of disease in these patients. At the time of last follow-up, all but 2 patients had recovered or were recovering. Three of the
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serious AEs led to discontinuation: lacunar infarction (diagnosed after 430 days of exposure to study drug); brain neoplasm (268 days), which was fatal; and gastrointestinal hemorrhage (459 days), which was fatal. These were the only deaths in the study period. In total, 7 (5%) patients discontinued the study due to AEs (Table I). There were no events of major hypoglycemia during the study. Five patients (4%) reported 7 total episodes of minor hypoglycemia (2 nocturnal episodes; 5 daytime episodes) during the study. At last visit, 114 patients (86%) were negative for antibodies to exenatide, 14 (11%) had low titer for antibodies to exenatide, and 5 (4%) had higher titer for antibodies to exenatide. For exenatide-naïve patients, 33 (75%) were antibody-negative, 8 (18%) had low titer, and 3 (7%) had higher titer. For patients who switched from exenatide twice daily, 81 patients (91%) were antibody negative, 6 (7%) had low titer, and 2 (2%) had higher titer antibodies.
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A
∆ in HbA1c (%)
At 52 weeks, ITT patients experienced a significant reduction in HbA1c (mean [SE], ⫺0.78% [0.07%]; P ⬍ 0.001) from a baseline mean (SE) value of 7.20% (0.08%). Reductions in HbA1c were observed in both exenatide-naïve patients (mean change [SE], ⫺1.10% [0.13%]; P ⬍ 0.001) and in patients with prior therapy with exenatide twice daily (⫺0.62% [0.08%]; P ⬍ 0.001). After 2 years of therapy with exenatide once weekly and TZD with or without metformin, patients’ HbA1c continued to be lower than at baseline (mean change [SE], ⫺0.48% [0.09%]; P ⬍ 0.001), yielding an absolute HbA1c value at end point of 6.73% (0.08%) in ITT patients (Figure). In exenatide-naïve patients at week 104 or week 117, HbA1c was lower by ⫺0.71% (0.17%) (P ⬍ 0.001) than the mean (SE) baseline of 7.67% (0.14%); in patients who switched from exenatide twice daily to exenatide once weekly, HbA1c was lower by ⫺0.36% (0.10%) (P ⬍ 0.001) than the baseline of 6.97% (0.09%) (Figure). Absolute HbA1c at the 2-year end point was similar for both groups; 6.96% (0.18%) for exenatide-naïve patients and 6.61% (0.09%) for patients who switched from exenatide twice daily. At the 52-week end point, weight was lower than at baseline in ITT patients (mean change [SE], ⫺1.5 [0.4] kg). The change in weight from baseline to week 52 was ⫺2.9 (0.6) kg for exenatide-naïve patients and ⫺0.8 (0.6) kg for patients who switched from exenatide twice daily. Weight continued to show a reduction (⫺2.7 [0.8] kg) in exenatide-naïve patients at the week 104 or week 117 end point, whereas in ITT patients and patients who switched from exenatide twice daily, weight after 2 years of treatment was similar to that at baseline (mean change [SE], ⫺0.6 [0.6] kg for ITT and 0.5 [0.7] kg for patients who switched; Figure). ITT, exenatide-naïve, and patients who switched from exenatide twice daily experienced mean (SE) reductions in FSG at end point (⫺1.10 [0.26] mmol/L, ⫺0.55 [0.50] mmol/L, and ⫺1.37 [0.30] mmol/L, respectively). No clinically relevant changes in heart rate, systolic blood pressure, or diastolic blood pressure were observed at end point in the ITT population (mean [SE] systolic blood pressure, 0.5 [1.3] mm Hg; diastolic blood pressure, ⫺0.6 [0.7] mm Hg; heart rate, 2.5 [0.8] beats/min). Changes in ITT patients from baseline (mean [SE]) in fasting lipid concentrations were as follows: total cholesterol, ⫺0.27 (0.09) mmol/L; HDL,
0.0
–0.5
–1.0
–1.5
–2.0
B
∆ in Weight (kg)
Glycemic Control, Weight, and Cardiovascular Risk Markers
12
26
40
52 65 78 Time (weeks)
91
End Point
12
26
40
52 65 78 Time (weeks)
91
End Point
2
0
–2
–4
–6
All ITT
Switched
Naïve
Figure. (A) Change from baseline in glycosylated hemoglobin (HbA1c) (P ⬍ 0.001 for changes at end point) and (B) weight in all intent-to-treat (ITT) patients, ITT patients who switched from exenatide twice daily (Switched), and ITT patients naïve to exenatide (Naïve) over 2 years of treatment with exenatide once weekly plus thiazolidinedione with or without metformin. End point was 104 or 117 weeks. End point data are presented as last observation carried forward mean (SE); other data are observed.
0.09 (0.02) mmol/L; LDL, ⫺0.25 (0.07) mmol/L; and triglycerides, ⫺0.25 (0.09) mmol/L.
DISCUSSION Combination therapy using various antihyperglycemic medications, including TZDs, to achieve optimal glucose control is common in patients with T2DM.16,17 This study was designed to assess the long-term safety profile of exenatide once weekly in combination with
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Clinical Therapeutics TZD with or without metformin in exenatide-naïve patients and patients who switched from exenatide twice daily to exenatide once weekly. Observed AEs were consistent with the known safety profile of exenatide once weekly and TZDs; exenatide once weekly has been found to be generally well tolerated with mild-to-moderate gastrointestinal events and injection-site reactions as the most commonly reported AEs.2– 6,24 In the present study, predominantly mild nausea was the most frequently reported AE and seldom led to treatment discontinuation. Injection-site nodules, another frequent AE in the present study, are an outcome anticipated with medications of sustained-release formulations using microsphere technology.25 TZD use has been associated with peripheral edema and heart failure, and meta-analyses have reported an increased risk of myocardial infarction and cardiovascular-related death associated with the TZD rosiglitazone.12,15 These observations have resulted in a decline in the use of TZDs for the treatment of T2DM.26 –28 In the present study, no cases of heart failure or myocardial infarction, and few cases of mild edema, were reported. Overall, no new AEs emerged and treatment with these 2 classes of antidiabetes medications was generally well tolerated, with no major hypoglycemia and few incidents of minor hypoglycemia, supporting the use of this combination as an option for improving glycemic control. TZDs have been associated with weight gain in T2DM patients.14 In contrast, agents in the GLP-1 receptor agonist class, such as exenatide once weekly, have been associated with weight loss,2– 6 which has helped to position them as early treatment options (after metformin) in current treatment algorithms.16,17,29 Of note, after 2 years of treatment with exenatide once weekly and a TZD in the present study, patients without prior exenatide exposure experienced net weight loss, and patients with prior exenatide exposure maintained their weight. These observations support previous findings that exenatide in combination with a TZD was associated with no changes in weight or with weight loss, and extend these findings to include the extended-release formulation of exenatide.18,19 These observations are also consistent with those observed for liraglutide, a GLP-1 receptor agonist administered once daily, in combination with TZD.30
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At both 1- and 2-year end points, clinically significant reductions in HbA1c were achieved and maintained in exenatide-naïve patients. In addition, further improvements from baseline were reported in patients having taken exenatide twice daily previously, in keeping with results from an earlier study in which patients switching to exenatide once weekly after 30 weeks of exenatide twice-daily therapy experienced additional improvements in HbA1c at 52 weeks.31 In the present study, it is notable that the observed improvements in HbA1c were achieved despite a relatively low mean baseline (7.2% for ITT patients), yielding a mean end-point value of 6.7% after 2 years of treatment and indicating that patients experienced durable improvements in glycemic control with this therapeutic combination. Limitations of this study include the lack of a control treatment arm, the open-label design of the study, and the small sample size. Another possible limitation of the study was that some patients were taking exenatide twice daily at least 3 months before the study, which might have introduced selection bias for patients who tolerate exenatide therapy. However, the studied population likely approximates the population of patients who would be prescribed exenatide once weekly after having been treated previously with common therapies for T2DM, including TZDs, metformin, and/or exenatide twice daily.16 Therefore, the AE results presented in this study are relevant to physicians treating patients on these background therapies.
CONCLUSIONS The present study is consistent with reports of the safety profile of exenatide use in combination with TZDs, and extends these findings to the extended-release formulation exenatide once weekly, in both exenatide-naïve patients and those switching from prior therapy with exenatide twice daily. Patients without prior exposure to exenatide experienced improvements in HbA1c and weight, and patients with prior exenatide therapy experienced an additional reduction from baseline in HbA1c and no further change in weight, after 2 years.
ACKNOWLEDGMENTS We thank investigators and patients who made this study possible, as well as Carole Weaver, PhD, of Amylin Pharmaceuticals, LLC, San Diego, California; Joseph Giaconia of Eli Lilly and Company, Indianapolis,
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P. Norwood et al. Indiana; and Jamie Scism-Bacon, PhD of PharmaNet/ i3, an Inventiv Health Company, Indianapolis, Indiana for writing assistance. All authors contributed equally to the study design, data collection, literature search, data analysis, data interpretation, writing, critical review, and editing of this paper.
CONFLICTS OF INTEREST Funding for this study and its publication was provided by Eli Lilly and Company and Amylin Pharmaceuticals, LLC. The study sponsors were involved in the study design and execution; in the management, analysis, and interpretation of the data; and in all aspects of the publication process. Drs. Norwood, Liutkus, and Pintilei have received payment for clinical studies and reimbursement for scientific events from Eli Lilly and Company. Mr. Haber is an employee of Pharmanet/i3, Inc. Drs. Boardman and Trautmann are or were employees of and own stock in Eli Lilly and Company. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
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Address correspondence to: Michael E. Trautmann, MD, Fueerbarg 16a, Hamburg, D-22393, Germany. E-mail: [email protected]
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