- Email: [email protected]
Five-Year Efficacy and Safety Data of Exenatide Once Weekly
ORIGINAL ARTICLE
Five-Year Efficacy and Safety Data of Exenatide Once Weekly: Long-term Results From the DURATION-1 Randomized Clinical Trial Carol H. Wysham, MD; Leigh A. MacConell, PhD; David G. Maggs, MD; Ming Zhou, PhD; Peter S. Griffin, BA; and Michael E. Trautmann, MD Abstract Objective: To evaluate the 5-year efficacy and safety of once weekly exenatide. Patients and Methods: The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial consisted of a 30-week controlled phase (2 mg of exenatide once weekly vs 10 mg of exenatide twice daily) with an open-ended uncontrolled extension (once weekly exenatide only) in patients with type 2 diabetes mellitus on background glucose-lowering therapies (April 15, 2006, through February 21, 2012). At week 30, patients initially receiving 10 mg of exenatide twice daily switched to 2 mg of exenatide once weekly. Study end points included changes from baseline in hemoglobin A1c, fasting plasma glucose, weight, lipids, and blood pressure. Long-term safety data included adverse events, liver and renal function, and heart rate. Results: Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment. Hemoglobin A1c levels were significantly and durably reduced from baseline (least-squares mean, e1.6%; 95% CI, e1.8% to e1.4%; vs e1.9% for exenatide once weekly at week 30), and 65 (43.9%) of 148 patients achieved hemoglobin A1c levels of less than 7.0%. Significant improvements in fasting plasma glucose level (e28.8 mg/dL; 95% CI, 36.2 to 21.5 mg/dL), weight (e3.0 kg; 95% CI, e4.6 to e1.3 kg), lipids, and diastolic blood pressure were observed, with minimal heart rate increase. Frequencies of nausea and injection-site reactions or nodules were decreased vs the initial 30-week controlled phase. Minor hypoglycemia occurred predominantly with sulfonylurea use, and no major hypoglycemia or new safety signals were observed. Conclusion: Long-term once weekly exenatide treatment was generally well tolerated with sustained glycemic improvement, weight reduction, and improved markers of cardiovascular risk in patients with type 2 diabetes. Trial Registration: clinicaltrials.gov Identifier: NCT00308139 ª 2015 Mayo Foundation for Medical Education and Research
From the Rockwood Clinic, Spokane, WA (C.H.W.); Amylin Pharmaceuticals/Bristol-Myers Squibb, San Diego, CA (L.A.M.); Amylin Pharmaceuticals, San Diego, CA (D.G.M., P.S.G.); BristolMyers Squibb, Hopewell, NJ (M.Z.); and Diabetes Research, Hamburg, Germany (M.E.T.). Dr MacConell is now with Intercept Pharmaceuticals, San Diego, CA, and Dr Maggs is now with GI Dynamics, San Diego, CA.
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ype 2 diabetes mellitus (T2DM) is a progressive disease characterized by declining b-cell function, insulin resistance, and an attenuated incretin effect.1 As a result, patients exhibit uncontrolled hyperglycemia if inadequately treated, along with an associated increased risk of myocardial infarction, stroke, microvascular events, and premature death.2,3 Treatment is aimed at lowering hemoglobin A1c (HbA1c) levels and normalizing elevated fasting plasma glucose (FPG) and postprandial glucose levels, with patients generally requiring long-term therapy for the remainder of their lives. Moreover, the progressive nature of the disease often necessitates increasingly
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intensive treatment regimens to maintain glycemic control.4,5 Initial pharmacotherapy for T2DM involves the use of single or multiple oral agents. Despite the availability of a number of oral agent classes, the progressive nature of the disease prevails and hyperglycemia becomes increasingly difficult to control.6,7 A common next step is to add basal insulin to background oral agents. Despite being efficacious for many patients, a large meta-analysis of trials of 16 to 134 weeks’ duration found that almost 60% of patients with T2DM did not achieve an HbA1c level less than 7% with basal insulinebased regimens (with or without other antidiabetes agents), and a basal-bolus regimen failed in
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EXENATIDE ONCE WEEKLY FOR 5 YEARS
nearly 50%.8 Furthermore, hypoglycemia risk increases with more intensive insulin regimens and longer duration of insulin therapy. In a post hoc analysis of 2251 patients with T2DM enrolled in 11 prospective randomized clinical trials of insulin glargine, severe hypoglycemia occurred in 1.5% of patients,9 whereas a clinical trial comparing basal bolus to prandial premixed insulin revealed incidences of 2.1% and 3.2%, respectively.10 A retrospective study of 215 patients with T2DM found increased incidence of hypoglycemia with increased insulin treatment duration (1-5 years, 10%; 6-10 years, 15%; >10 years, 35%).11 Weight gain is another issue associated with insulin therapy. In a metaanalysis of 46 randomized studies, patients with T2DM following a basal insulin regimen gained 3.6 kg in 1 year, whereas those following a prandial insulin regimen (with or without basal insulin) gained 6.4 kg.12 Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapy is an alternative injectable therapy option to insulin in the management of T2DM.6,7 Because these agents act in a glucose-dependent manner, the risk of hypoglycemia is low with monotherapy or when combined with other nonhypoglycemic treatments.13-16 In addition, GLP-1RAs suppress inadequately elevated glucagon levels, delay gastric emptying, and reduce appetite and food intake at mealtimes, with this last effect likely to be associated with the reduction in body weight also observed in GLP-1RAe treated patients with T2DM.17,18 Exenatide, the first US Food and Drug Administrationeapproved GLP-1RA for use in patients with T2DM as an adjunct to diet and exercise, was first available for administration as a twice daily subcutaneous injection before the morning and evening meals (or the 2 main meals).19 A sustained-release exenatide formulation was later approved by the US Food and Drug Administration for once weekly administration.13 The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial was designed to compare twice daily and once weekly exenatide.20-22 The study consisted of 2 phases: a 30-week, controlled, open-label phase and an uncontrolled, open-ended, Mayo Clin Proc. n March 2015;90(3):356-365 www.mayoclinicproceedings.org
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extension phase. In the controlled period, once weekly exenatide exhibited a greater reduction from baseline in HbA1c levels compared with twice daily exenatide (e1.9% vs e1.5%, P¼.002) and a significantly greater achievement of the HbA1c target of 7.0% or less (77% vs 61%, P¼.004).21 The 1-, 2-, and 3-year results of once weekly exenatide treatment in the open-ended extension have been previously published.20,22,23 The current analysis expands on these results by examining the safety and efficacy of once weekly exenatide treatment over 5 years, to our knowledge, the longest assessment of a GLP1RA reported to date. METHODS Study Design and Patients In the initial randomized, comparatorcontrolled, open-label study (April 15, 2006, through February 21, 2012), patients with T2DM were randomized to 2 mg of exenatide once weekly or 10 mg of exenatide twice daily (5 mg twice daily for the first 28 days) and followed for 30 weeks.21 At week 30, patients who initially received exenatide twice daily were switched to exenatide once weekly; all patients received exenatide once weekly throughout the open-ended extension.20,22 Those patients who switched from twice daily to once weekly exenatide and were concomitantly receiving a sulfonylurea were required to have their sulfonylurea dose reduced to the minimum recommended dose until week 40, after which time their sulfonylurea dose was uptitrated based on daily glucose measurements (target FPG 110 mg/dL [to convert to mmol/L, multiply by 0.0555]). Patients maintained on exenatide once weekly did not change their sulfonylurea treatment regimen after the controlled phase. Concomitant lipid-lowering, antihypertensive, and nonsulfonylurea glucose-lowering therapies during the 30-week controlled phase and open-ended extension generally remained stable, with changes allowed at the discretion of the study investigator or primary care physician. Only patients who completed the 30week controlled phase were permitted to enter the open-ended extension. The initial study protocol was approved by an institutional review board at each site, and
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patients provided written informed consent before participation. Inclusion criteria were published previously (Supplemental Appendix 1, available online at http://www.mayoclinic proceedings.org).21 Outcome Measures Efficacy end points included change from baseline in HbA1c level, FPG level, body weight, lipid profile (total cholesterol, lowdensity lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDLC], and triglyceride levels), and seated blood pressure (BP) for the 5-year completer and intent-to-treat (ITT) populations. The measurements of HbA1c and BP were described previously.20,21 Safety data were reported for the ITT population, with adverse events reported as the overall incidence and event rate. Treatment-emergent adverse events were those events reported during or after the first injection of randomized medication. Serious adverse events were those events that resulted in death, a life-threatening situation, inpatient hospitalization or prolongation of inpatient hospitalization, incapacity or substantial disruption to the ability to conduct normal life functions, congenital anomaly or birth defect, or an important medical event that may have jeopardized the patient and required medical or surgical intervention to prevent one of the previously mentioned outcomes. Liver and renal function and heart rate were also evaluated and are presented in 5year completers. Definitions of major and minor hypoglycemia appear in Supplemental Appendix 2 (available online at http://www. mayoclinicproceedings.org). Statistical Analyses The ITT population consisted of all randomized patients who received 1 or more doses of study medication during the 30-week controlled phase. The 5-year completer population consisted of patients from the ITT population who received exenatide treatment for 260 weeks or longer. Descriptive statistics were applied for demographic data, analysis of primary glycemic end points, body weight, and fasting lipid concentrations. The HbA1c analyses were based on a general linear model (analysis of variance), which included the original treatment assignment, baseline HbA1c 358
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stratum, and concomitant sulfonylurea use at screening. Baseline FPG level, body weight, and BP were added in the model (analysis of covariance) for FPG, body weight, and BP, respectively. The results for all efficacy end points are presented as least-squares (LS) means with SEs and 95% CIs. The last observation carried forward approach was applied to estimate missing values for weeks 2 to 260. All statistical analyses were performed using SAS statistical software, version 9.2 (SAS Institute Inc). RESULTS Patient Disposition and Baseline Characteristics The original ITT population consisted of 295 patients. Of the 258 patients who entered the extension phase, 153 (59.3%) completed 5 years of treatment (Figure 1). The most common reasons for discontinuation during the open-ended extension (weeks 30-260) were withdrawal of consent (57 [19.3%]), adverse event (11 [3.7%]), investigator decision (10 [3.4%]), and loss to follow-up (10 [3.4%]). The baseline and demographic characteristics of the 5-year completer and ITT populations were similar (Supplemental Table, available online at http://www.mayoclinicproceedings. org). Patients had a mean duration of diabetes of 7 years, mean HbA1c levels of 8.1% to 8.3%, mean FPG levels of 163.9 to 169.4 mg/dL, and mean body weight of 100.7 to 101.8 kg across the 2 populations. At screening, 59 (38.6%) of the 153 patients who completed the 5-year treatment and 109 (36.9%) of the 295 ITT patients were receiving sulfonylurea-based therapy. Effects on Glycemic Control and Body Weight A significant reduction in HbA1c from baseline in the controlled phase was maintained during 5 years with once weekly exenatide treatment. In the 5-year completer population, the mean SD baseline HbA1c level was 8.1%0.9%. At 5 years, the mean SE HbA1c level was 7.0%0.1%, with a significant LS mean reduction from baseline of 1.6%0.1% (95% CI, 1.8% to 1.4%) (Figure 2, A). By comparison, in the ITT population, the mean SE HbA1c level
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303 Randomized 8 Withdrew before lead-in 295 ITT population
Controlled phase
148 Receiving 2 mg of exenatide once weekly
Withdrew before week 30:
147 Receiving 10 μg of exenatide twice daily
No.
(%)a
No.
(%)a
20
(13.5)
17
(11.6)
Adverse event
9
(6.1)
Adverse event
8
(5.4)
Lost to follow-up
5
(3.4)
Lost to follow-up
4
(2.7)
Withdrew consent
5
(3.4)
Withdrew consent
2
(1.4)
Investigator decision
1
(0.7)
Investigator decision
2
(1.4)
Protocol violation
0
Protocol violation
1
(0.7)
Withdrew before week 30:
258 (87.5%) Receiving 2 mg of exenatide once weekly (ITT)b
No.
(%)b
(%)c
99
(33.6)
(38.4)
57
(19.3)
(22.1)
Adverse event
11
(3.7)
(4.3)
Lost to follow-up
10
(3.4)
(3.9)
Investigator decision
10
(3.4)
(3.9)
Loss of glucose control
8
(2.7)
(3.1)
Administrative
2
(0.7)
(0.8)
1
(0.3)
(0.4)
Withdrew prior to weeks 30 and 260: Withdrew consent Open-ended extension phase
Protocol violation
6 Removed from final analysisd
153 (59.3%) Completer populationc
FIGURE 1. Patient disposition. aPercentages represent the proportion of the treatment arm. bPercentages represent the proportion of the intent-to-treat (ITT) population (N¼295). cPercentages represent the proportion of ITT patients entering the open-ended extension (n¼258). dSix patients were not included in the completer population analysis because their individual drug exposure was less than 260 weeks.
was 7.3%0.1% at 5 years, with an LS mean SE change from baseline of 1.2%0.1% (95% CI, 1.4% to 1.0%). The HbA1c targets of 6.5% or less and less than 7% were achieved by 50 (32.7%) of 153 patients Mayo Clin Proc. n March 2015;90(3):356-365 www.mayoclinicproceedings.org
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and 65 (43.9%) of 148 patients with nonmissing HbA1c values, respectively, who did not meet the target at baseline in the 5year completer population (Figure 2, B) and 79 (28.4%) of 278 patients and 106
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Mean (SE) HbA1c (%)
8.5 8 7.5 7 6.9
6.8
6.5
7.0
6.9
6.5 6 0
1
2
3
4
5
Year
A 100
[48.4%]), thiazolidinediones (20 [13.1%]), oral blood glucoseelowering drug (not specified; 5 [3.3%]), fast-acting insulins (15 [9.8%]), intermediate-acting insulins (2 [1.3%]), long-acting insulins (19 [12.4%]), other insulins (not specified; 1 [0.7%]), and drug used in diabetes (not specified; 1 [0.7%]). Reductions in body weight observed during the controlled phase were mostly maintained in 5-year completers (Figure 3, B). At 5 years, the observed mean SE body weight was 97.21.5 kg, with a significant LS mean SE change from baseline of e3.00.9 kg (95% CI, e4.6 to e1.3 kg).
90
Proportion of patients (%)
80 70 60 50 40
43.9 32.7
30 20 10 0 ≤6.5%
B
<7.0% HbA1c targets
FIGURE 2. Hemoglobin A1c (HbA1c) values over time (A) and percentage of patients who achieved HbA1c targets (B) in the 5-year completer population (n¼153; last observation carried forward). The baseline HbA1c level was 8.1%. Dashed line represents the recommended goal of 7.0%.
(39.1%) of 271 patients, respectively, in the ITT population. Similar to HbA1c, a significant reduction from baseline in FPG levels observed during the initial controlled phase was maintained through the extension phase in 5-year completers (Figure 3, A). The LS mean SE change from baseline at 5 years was e28.83.7 mg/dL (95% CI, 36.2 to 21.5 mg/dL). New concomitant antidiabetes medications added by the 153 patients in the completer population over 5 years included biguanides (54 [35.3%]), sulfonylureas (74 360
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Effects on Lipids and BP Total cholesterol and LDL-C values were significantly reduced from baseline in the 5-year completer population, whereas HDL-C values were significantly increased (Figure 4, A). At 5 years, the LS mean SE changes were e11.53.4 mg/dL (95% CI, 18.2 to 4.8 mg/dL) for fasting total cholesterol, 9.12.8 mg/dL (95% CI, 14.5 to 3.6 mg/dL) for LDL-C, and 2.00.9 mg/dL (95% CI, 0.2 to 3.7 mg/dL) for HDL-C (to convert cholesterol values to mmol/L, multiply by 0.0259). Triglycerides also decreased significantly from baseline (geometric LS mean SE change, e12%4%; 95% CI, e20% to e4%). Lipids in the ITT population were significantly reduced for total cholesterol (LS mean SE, 10.8 2.2 mg/ dL; 95% CI, 15.2 to 6.5 mg/dL), LDL-C (7.21.9 mg/dL; 95% CI, 10.9 to 3.5), and triglycerides (9% 3%; 95% CI, 14% to 4%); the HDL-C level was unchanged (0.20.6 mg/dL; 95% CI, 1.1 to 1.4 mg/ dL). A total of 113 (73.9%) of 153 patients initiated 1 or more lipid-lowering agents during the 5 years of the study, including b-hydroxy-bmethylglutarylecoenzyme A reductase inhibitors (statins: 101 [66.0%]), other (eg, fish oil, omega-3 fatty acids, and ezetimibe) (23 [15.0%]), nicotinic acid or a derivative (14 [9.2%]), fibrates (11 [7.2%]), bile acid sequestrants (3 [2.0%]), and serum lipid-reducing agents (not specified; 1 [0.7%]). No clinically meaningful change at 5 years was observed in seated systolic BP. The LS mean SE change in systolic BP for the 5-year completer population was e0.41.6 mm Hg (95% CI, e3.4 to 2.8 mm Hg), with 82
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0 –10 LS mean (SE) change in FPG (mg/dL)
(53.6%) of 153 patients exhibiting a systolic BP of less than 130 mm Hg. Diastolic BP decreased significantly at 5 years, with an LS mean SE change of e2.00.8 mm Hg (95% CI, e3.67 to e0.36 mm Hg). During the 5 years of follow-up, 100 (65.4%) of 153 patients started taking 1 or more antihypertensive medications, including renin-angiotensin system inhibitors (79 [51.6%]), diuretics (32 [20.9%]), b-blockers (31 [20.3%]), calcium channel blockers (23 [15.0%]), organic nitrates (15 [9.8%]), and other antihypertensives (6 [3.9%]).
–20 –30
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−36.7a a
−44.1
–50 −48.3a –60 0
A
1
2
3
4
−1.8a
−1.8a
5
Year 0 –1
LS mean (SE) change in body weight (kg)
Safety and Tolerability No new safety signals for once weekly exenatide were detected during the open-ended extension in the ITT population. Treatmentemergent adverse events leading to withdrawal from week 30 to year 5 were infrequent (11 [3.7%] of 295), with no apparent pattern in the type of events that led to discontinuation. Serious adverse events occurred in 13 (4.4%) of 293 patients during the initial 30-week assessment and in 57 (22.1%) of 258 patients during the open-ended extension. The most common serious adverse events by system organ class during the open-ended extension were cardiac disorders (14 [5.4%]), infections and infestations (14 [5.4%]), and musculoskeletal and connective tissue disorders (9 [3.5%]). The most common adverse events in the ITT population during the open-ended extension were upper respiratory tract infection (106 [41.1%]), nasopharyngitis (73 [28.3%]), diarrhea (66 [25.6%]), sinusitis (55 [21.3%]), back pain (51 [19.8%]), and arthralgia (47 [18.2%]). Exposure-adjusted event rates for nausea with once weekly exenatide decreased from 84.6 events per 100 patient-years during the initial 30-week assessment to 8.0 events per 100 patient-years during the open-ended extension (Table); exposure-adjusted event rates of injection-site pruritus (from 51.0 to 1.6 events per 100 patient-years) and injection-site erythema (from 13.7 to 1.2 events per 100 patient-years) also decreased. Injection-site nodules were infrequent during the controlled phase (3.7 events per 100 patient-years) and were not observed in the open-ended extension. One case (0.4%) of pancreatitis, 1 case (0.4%) of pancreatic carcinoma, and 3 cases (1.2%) of acute renal failure
−28.8a
−32.6a
–40
–2 –3 −2.6a –4
−3.0a
–5 −4.5a –6 0
B
1
2
3
4
5
Year
FIGURE 3. Change in fasting plasma glucose (FPG) (A) and body weight (B) over time in the 5-year completer population (n¼153; last observation carried forward). The baseline FPG level was 163.9 mg/dL (to convert to mmol/L, multiply by 0.0555), and the baseline body weight was 100.7 kg. LS ¼ least-squares. aP<.05 for change from baseline.
were reported during the 5-year treatment period, with exposure-adjusted event rates of 1.0 event per 1000 patient-years for pancreatitis and pancreatic carcinoma and 3.0 events per 1000 patient-years for acute renal failure. Most adverse events were mild. Liver function changes from baseline with once weekly exenatide were minimal during the long-term open-ended extension. In the completer population, the mean SE changes from baseline to year 5 in alanine aminotransferase and aspartate aminotransferase were e4.41.4 U/L (95% CI, e7.3 to e1.6 U/L) and e3.20.9 U/L (95% CI, e4.9 to e1.4 U/L), respectively (to convert to mkat/L, multiply by 0.0167). There were no clinically meaningful changes in renal function in the completer population. The mean SE baseline estimated glomerular filtration rate was 80.61.6 mL/min/1.73 m2, and the end
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Baseline (mg/dL):
Total cholesterol
HDL-C
LDL-C
172.5
45.8
92.3
point estimated glomerular filtration rate was 71.11.6 mL/min/1.73 m2, representing a change of e9.61.3 mL/min/1.73 m2 (95% CI, e12.0 to e7.1 mL/min/1.73 m2). In 5-year completers, the mean SE baseline heart rate was 73.90.8 beats/min, and the end point heart rate was 75.30.8 beats/min, representing an increase of þ1.50.9 beats/min. This small increase in heart rate after 5 years of exenatide treatment was consistent with observed changes at week 30 (1.10.7 beats/ min) and at 1 year (2.80.7 beats/min).21 No cases of major hypoglycemia were reported during the 5 years of the study in the ITT population. Treatment-emergent minor hypoglycemia was observed in 38 (14.7%) of 258 patients and was mainly observed in those taking a concomitant sulfonylurea at baseline (25 [25.3%] of 99 vs 13 [8.2%] of 159 nonsulfonylurea users).
2.0a
4 LS mean (SE) change in cholesterol (mg/dL)
2 0 –2 –4 –6 –8 –10 –12
–9.1a
–14 –16
A Baseline (mg/dL):
–11.5a
154.4 4 2 0
Geometric LS mean (SE) change in triglycerides (%)
–2 –4 –6 –8 –10 –12 –14 –16 –12a
B
–18
FIGURE 4. Change from baseline in cholesterol (A) (to convert to mmol/L, multiply by 0.0259) and triglycerides (B) (to convert to mmol/L, multiply by 0.0113) in the 5-year completer population (n¼153; last observation carried forward). The baseline levels were 172.5, 45.8, and 92.3 mg/dL for total cholesterol; HDL-C, and LDL-C cholesterol, respectively, and the baseline triglyceride level was 154.4 mg/dL. HDL-C ¼ high-density lipoprotein cholesterol; LDL-C ¼ low-density lipoprotein cholesterol; LS ¼ least-squares. aP<.05 for change from baseline.
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DISCUSSION This is the longest study of a GLP-1RA to date, and the findings indicate that once weekly exenatide can elicit durable efficacy and an acceptable tolerability profile during 5 years. More than 50% of patients continued once weekly treatment with exenatide for the full 5 years. This compares favorably with long-term extension studies of other antidiabetes medications. In a study of liraglutide, another GLP-1RA, approximately 50% of patients remained in the study at year 2,24 whereas for the present study, more than 73% completed 2 years.22 In 3 studies of albiglutide added to background metformin (with or without glimepiride or pioglitazone), 54% to 65% of patients completed 3 years of treatment, and 40% to 52% required rescue medication, including insulin.25-27 Because selection bias is an issue in extension trials (in which patients who do not do well in the initial trial usually do not enter the extension trial),28,29 the high 5-year completer rate in the present study is an indirect indicator that once weekly exenatide was well tolerated, perceived as efficacious, or both. For 5-year completers, long-term treatment with once weekly exenatide was associated with sustained improvement in glycemic control compared with baseline, with more than 40% of patients reaching an HbA1c goal of less than 7%. The results were similar between the completer and ITT populations,
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providing further confidence in the validity of the conclusions. Although the FPG level appeared to increase slightly between years 1 and 5, the decrease from baseline remained clinically meaningful, with patients maintaining levels near the recommended goal of less than 130 mg/dL.7 More than half of patients added one or more antidiabetes medications, which likely contributed to the benefits observed at 5 years. However, this could also be considered a reflection of real-world clinical experience, where patients often require incremental pharmacologic intervention because of progression of T2DM. Patients also maintained body weight loss during 5 years. Studies have found that even a modest decrease in body weight (5%-10%) in overweight and obese people can elicit improvement in glycemic control and mitigate risk factors for cardiovascular disease.30,31 In contrast, long-term treatment with insulin with or without oral glucose-lowering medications has produced weight gain rather than sustained weight loss.32,33 The sustained body weight loss with exenatide is particularly impressive because durable weight loss, in general, is not often achieved despite intensive lifestyle modification, with patients typically regaining 30% to 40% of the weight initially lost after a year.34 No unexpected safety signals were detected in the longstanding study of this cohort. In fact, the incidence of nausea and injection-site events diminished over time compared with the initial 30-week study.21 Consistent with earlier reports,20-23 no cases of major hypoglycemia were reported during the 5 years of follow-up, and minor hypoglycemia was mainly observed in those taking a concomitant sulfonylurea at baseline. Because hypoglycemia risk increases with increased duration of insulin use,11,35,36 the observations of no cases of major hypoglycemia and the low rate of minor hypoglycemia with once weekly exenatide treatment throughout the 5 years further underscore the advantage that GLP-1RA therapy has over insulin with this safety consideration in mind. This should also give physicians confidence in the safety of treatment when considering longer-term therapy options. After 5 years, risk factors for cardiovascular disease were improved compared with baseline, with even greater decreases in total cholesterol and LDL-C and a greater increase Mayo Clin Proc. n March 2015;90(3):356-365 www.mayoclinicproceedings.org
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TABLE. Annual Event Rates for Treatment-Emergent Adverse Events With a 10% or Greater Incidence During the Controlled and Open-Ended Extension Phases in the Intent-to-Treat Populationa Controlled phase (weeks 0-30)
Adverse event
Exenatide twice daily (n¼145)b
Nausea Vomiting Upper respiratory tract infection Diarrhea Urinary tract infection Sinusitis Nasopharyngitis Gastroenteritis, viral Headache Back pain Arthralgia Bronchitis Hypertension Pain in extremity Cough Musculoskeletal pain
92.0 47.3 35.8 34.5 14.1 12.8 11.5 11.5 10.2 7.7 7.7 7.7 5.1 2.6 2.6 0
Exenatide Open-ended extension phase (weeks 30-260) of once exenatide once weekly weekly (n¼258) (n¼148) 84.6 36.1 16.2 37.3 22.4 8.7 18.7 16.2 26.1 8.7 12.4 5.0 6.2 2.5 6.2 2.5
8.0 7.1 17.4 10.3 7.8 10.5 16.3 3.4 3.6 6.2 7.1 4.8 4.5 5.0 3.2 4.2
a
Annual event rates are presented as events per 100 patient-years. Two patients withdrew during the lead-in to the initial 30-week controlled phase.
b
in HDL-C than that observed at years 2 and 3.22,23 However, this observation is likely confounded by the fact that a large proportion of patients started taking an antilipid medication (such as a statin) during the study. Also of note, there was no clinically meaningful change in BP at year 5 despite a large percentage of patients starting use of an antihypertensive medication. This finding is not unexpected because adequate BP control is difficult to achieve in clinical practice. In a 1-year study of 78 patients with T2DM, less than half of the patients achieved a BP of 130/80 mm Hg or less despite intensification of lifestyle changes and the addition of pharmacotherapeutic agents.37 One limitation of this analysis is that an open-label study design may create bias and affect patient expectations.29 Another limitation is that the completer population may represent a subset of patients who responded well to treatment.28 However, levels of HbA1c, total cholesterol, LDL-C, and triglycerides were significantly improved from baseline in the ITT population (which includes patients who dropped
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out during the open-ended extension as nonresponders), similar to findings in the 5-year completer population (ITT data for FPG, body weight, and seated BP were not available for comparison), supporting the validity of the outcomes of the completer analyses. A further study limitation is that the lack of a control group limits comparisons with other treatment modalities and the contribution of advancing disease severity. However, 3-year extension data from an open-label, 26-week study of once weekly exenatide vs insulin glargine in patients in whom existing glucose-lowering therapy failed revealed the superior longterm efficacy of once weekly exenatide with respect to HbA1c, body weight reduction, and low rate of hypoglycemia.38 CONCLUSION Treatment with once weekly exenatide during 5 years was well tolerated and associated with sustained improvement in glycemic control, body weight, and markers of cardiovascular risk. Because patients with diabetes generally require lifelong treatment, having confidence that a chosen treatment modality will be well tolerated and effective in the long term is important. These results provide the longest follow-up of a GLP-1RA to date and will help physicians make therapy decisions for their patients. ACKNOWLEDGMENTS Meredith Rogers, MS, former employee of BristolMyers Squibb, and Robert Schupp, PharmD, of inScience Communications, Springer Healthcare, provided writing and editorial assistance with funding provided by AstraZeneca. SUPPLEMENTAL ONLINE MATERIAL Supplemental material can be found online at http://www.mayoclinicproceedings.org. Abbreviations and Acronyms: BP = blood pressure; FPG = fasting plasma glucose; GLP-1RA = glucagon-like peptide 1 receptor agonist; HbA1c = hemoglobin A1c; HDLC = high-density lipoprotein cholesterol; ITT = intent to treat; LDL-C = low-density lipoprotein cholesterol; LS = least-squares; T2DM = type 2 diabetes mellitus Grant Support: The design and conduct of the study were supported by Amylin Pharmaceuticals and Eli Lilly and Company. Development of the manuscript was supported by AstraZeneca.
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Potential Competing Interests: Dr Wysham is a speaker and/or adviser for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Janssen, Novo Nordisk, and Sanofi-Aventis. Dr MacConell was an employee of Amylin Pharmaceuticals/Bristol-Myers Squibb at the time the research was conducted and is currently vice president of clinical development at Intercept Pharmaceuticals. Dr Maggs was an employee of Amylin Pharmaceuticals at the time the research was conducted and is currently chief medical officer at GI Dynamics. Dr Zhou is an employee of Bristol-Myers Squibb. Mr Griffin was an employee of Amylin Pharmaceuticals at the time the research was conducted. Dr Trautmann was an employee of Eli Lilly and Company at the time of the research was conducted and is a stockholder of Eli Lilly and Company. He was a consultant to Amylin Pharmaceuticals, BristolMyers Squibb, and AstraZeneca. Correspondence: Address to Carol H. Wysham, MD, Rockwood Clinic, 400 E Fifth Ave, Spokane, WA 99202 ([email protected]).
REFERENCES 1. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795. 2. Fonseca VA. Defining and characterizing the progression of type 2 diabetes. Diabetes Care. 2009;32(suppl 2):S151-S156. 3. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-412. 4. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427-2443. 5. Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC; UK Prospective Diabetes Study (UKPDS) Group. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years. Diabet Med. 1998;15(4):297-303. 6. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013; 19(2):327-336. 7. 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(6): 1364-1379. 8. Giugliano D, Maiorino MI, Bellastella G, Chiodini P, Esposito K. Multiple HbA1c targets and insulin analogues in type 2 diabetes: a systematic review. J Diabetes Complications. 2011;25(4):275-281. 9. Karl DM, Gill J, Zhou R, Riddle MC. Clinical predictors of risk of hypoglycaemia during addition and titration of insulin glargine for type 2 diabetes mellitus. Diabetes Obes Metab. 2013; 15(7):622-628. 10. Rosenstock J, Ahmann AJ, Colon G, Scism-Bacon J, Jiang H, Martin S. Advancing insulin therapy in type 2 diabetes previously treated with glargine plus oral agents: prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy. Diabetes Care. 2008;31(1):20-25. 11. Henderson JN, Allen KV, Deary IJ, Frier BM. Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness. Diabet Med. 2003;20(12):1016-1021. 12. Pontiroli AE, Miele L, Morabito A. Increase of body weight during the first year of intensive insulin treatment in type 2 diabetes: systematic review and meta-analysis. Diabetes Obes Metab. 2011;13(11):1008-1019.
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13. AstraZeneca. Bydureon Prescribing Information. 2014. http: //www.azpicentral.com/bydureon/pi_bydureon.pdf#page¼1. Accessed October 10, 2014. 14. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092-1100. 15. Diamant M, Van Gaal L, Stranks S, et al. Safety and efficacy of once-weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes over 84 weeks. Diabetes Care. 2012;35(4):683-689. 16. Goke R, Fehmann HC, Linn T, et al. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulinsecreting beta-cells. J Biol Chem. 1993;268(26):19650-19655. 17. Gentilella R, Bianchi C, Rossi A, Rotella CM. Exenatide: a review from pharmacology to clinical practice. Diabetes Obes Metab. 2009;11(6):544-556. 18. Madsbad S, Kielgast U, Asmar M, Deacon CF, Torekov SS, Holst JJ. An overview of once-weekly glucagon-like peptide-1 receptor agonistseavailable efficacy and safety data and perspectives for the future. Diabetes Obes Metab. 2011;13(5):394-407. 19. AstraZeneca. Byetta Prescribing Information. 2014. http:// www.azpicentral.com/byetta/pi_byetta.pdf#page¼1. Accessed October 10, 2014. 20. 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(6):1255-1261. 21. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008; 372(9645):1240-1250. 22. Taylor K, Gurney K, Han J, Pencek R, Walsh B, Trautmann M. Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years. BMC Endocr Disord. 2011;11:9. 23. Macconell L, Pencek R, Li Y, Maggs D, Porter L. Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years. Diabetes Metab Syndr Obes. 2013;6:31-41. 24. Nauck M, Frid A, Hermansen K, et al. Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study. Diabetes Obes Metab. 2013;15(3): 204-212. 25. Home P, Stewart M, Mallory J, et al, eds. Harmony 5 year 3 results: albiglutide vs. placebo and vs. pioglitazone in triple therapy (background metformin and glimepiride) in people with type 2 diabetes. Poster presented at: American Diabetes
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26.
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29. 30.
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Association 74th Scientific Sessions; June 13-17, 2014; San Francisco, CA. Poster 963-P. Weissman P, Stewart M, Cirkel D, Ye J, Ambery P, eds. Harmony 4: 3-year efficacy of albiglutide (albi) vs. insulin glargine (glar) in patients with T2DM. Poster presented at: American Diabetes Association 74th Scientific Sessions; June 13-17, 2014; San Francisco, CA. Poster 961-P. Bode BW, Stewart M, Cirkel D, et al, eds. Harmony 1 year 3 results: albiglutide vs. placebo in patients with type 2 diabetes mellitus not controlled on pioglitazone (pio) metformin (met). Poster presented at: American Diabetes Association 74th Scientific Sessions; June 13-17, 2014; San Francisco, CA. Poster 960-P. Hemming K, Hutton JL, Maguire MJ, Marson AG. Open label extension studies and patient selection biases. J Eval Clin Pract. 2008;14(1):141-144. Taylor GJ, Wainwright P. Open label extension studies: research or marketing? BMJ. 2005;331(7516):572-574. Ajala O, English P, Pinkney J. Systematic review and metaanalysis of different dietary approaches to the management of type 2 diabetes. Am J Clin Nutr. 2013;97(3):505-516. Diabetes Prevention Program Outcomes Study Research Group, Orchard TJ, Temprosa M, Barrett-Connor E, et al. Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. Diabet Med. 2013;30(1):46-55. Hanefeld M, Bramlage P. Insulin use early in the course of type 2 diabetes mellitus: the ORIGIN trial. Curr Diab Rep. 2013; 13(3):342-349. Reaney M, Mathieu C, Ostenson CG, et al. Patient-reported outcomes among patients using exenatide twice daily or insulin in clinical practice in six European countries: the CHOICE prospective observational study. Health Qual Life Outcomes. 2013; 11:217. Wadden TA, Webb VL, Moran CH, Bailer BA. Lifestyle modification for obesity: new developments in diet, physical activity, and behavior therapy. Circulation. 2012;125(9):1157-1170. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50(6):1140-1147. Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care. 2005;28(12):2948-2961. Viana LV, Leitao CB, Grillo MF, et al. Hypertension management algorithm for type 2 diabetic patients applied in primary care. Diabetol Metab Syndr. 2013;5(1):52. Diamant M, Van Gaal L, Guerci B, et al. Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial. Lancet Diabetes Endocrinol. 2014;2(6):464-473.
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Five-Year Efficacy and Safety Data of Exenatide Once Weekly: Long-term Results From the DURATION-1 Randomized Clinical Trial Carol H. Wysham, MD; Leigh A. MacConell, PhD; David G. Maggs, MD; Ming Zhou, PhD; Peter S. Griffin, BA; and Michael E. Trautmann, MD Abstract Objective: To evaluate the 5-year efficacy and safety of once weekly exenatide. Patients and Methods: The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial consisted of a 30-week controlled phase (2 mg of exenatide once weekly vs 10 mg of exenatide twice daily) with an open-ended uncontrolled extension (once weekly exenatide only) in patients with type 2 diabetes mellitus on background glucose-lowering therapies (April 15, 2006, through February 21, 2012). At week 30, patients initially receiving 10 mg of exenatide twice daily switched to 2 mg of exenatide once weekly. Study end points included changes from baseline in hemoglobin A1c, fasting plasma glucose, weight, lipids, and blood pressure. Long-term safety data included adverse events, liver and renal function, and heart rate. Results: Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment. Hemoglobin A1c levels were significantly and durably reduced from baseline (least-squares mean, e1.6%; 95% CI, e1.8% to e1.4%; vs e1.9% for exenatide once weekly at week 30), and 65 (43.9%) of 148 patients achieved hemoglobin A1c levels of less than 7.0%. Significant improvements in fasting plasma glucose level (e28.8 mg/dL; 95% CI, 36.2 to 21.5 mg/dL), weight (e3.0 kg; 95% CI, e4.6 to e1.3 kg), lipids, and diastolic blood pressure were observed, with minimal heart rate increase. Frequencies of nausea and injection-site reactions or nodules were decreased vs the initial 30-week controlled phase. Minor hypoglycemia occurred predominantly with sulfonylurea use, and no major hypoglycemia or new safety signals were observed. Conclusion: Long-term once weekly exenatide treatment was generally well tolerated with sustained glycemic improvement, weight reduction, and improved markers of cardiovascular risk in patients with type 2 diabetes. Trial Registration: clinicaltrials.gov Identifier: NCT00308139 ª 2015 Mayo Foundation for Medical Education and Research
From the Rockwood Clinic, Spokane, WA (C.H.W.); Amylin Pharmaceuticals/Bristol-Myers Squibb, San Diego, CA (L.A.M.); Amylin Pharmaceuticals, San Diego, CA (D.G.M., P.S.G.); BristolMyers Squibb, Hopewell, NJ (M.Z.); and Diabetes Research, Hamburg, Germany (M.E.T.). Dr MacConell is now with Intercept Pharmaceuticals, San Diego, CA, and Dr Maggs is now with GI Dynamics, San Diego, CA.
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ype 2 diabetes mellitus (T2DM) is a progressive disease characterized by declining b-cell function, insulin resistance, and an attenuated incretin effect.1 As a result, patients exhibit uncontrolled hyperglycemia if inadequately treated, along with an associated increased risk of myocardial infarction, stroke, microvascular events, and premature death.2,3 Treatment is aimed at lowering hemoglobin A1c (HbA1c) levels and normalizing elevated fasting plasma glucose (FPG) and postprandial glucose levels, with patients generally requiring long-term therapy for the remainder of their lives. Moreover, the progressive nature of the disease often necessitates increasingly
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intensive treatment regimens to maintain glycemic control.4,5 Initial pharmacotherapy for T2DM involves the use of single or multiple oral agents. Despite the availability of a number of oral agent classes, the progressive nature of the disease prevails and hyperglycemia becomes increasingly difficult to control.6,7 A common next step is to add basal insulin to background oral agents. Despite being efficacious for many patients, a large meta-analysis of trials of 16 to 134 weeks’ duration found that almost 60% of patients with T2DM did not achieve an HbA1c level less than 7% with basal insulinebased regimens (with or without other antidiabetes agents), and a basal-bolus regimen failed in
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nearly 50%.8 Furthermore, hypoglycemia risk increases with more intensive insulin regimens and longer duration of insulin therapy. In a post hoc analysis of 2251 patients with T2DM enrolled in 11 prospective randomized clinical trials of insulin glargine, severe hypoglycemia occurred in 1.5% of patients,9 whereas a clinical trial comparing basal bolus to prandial premixed insulin revealed incidences of 2.1% and 3.2%, respectively.10 A retrospective study of 215 patients with T2DM found increased incidence of hypoglycemia with increased insulin treatment duration (1-5 years, 10%; 6-10 years, 15%; >10 years, 35%).11 Weight gain is another issue associated with insulin therapy. In a metaanalysis of 46 randomized studies, patients with T2DM following a basal insulin regimen gained 3.6 kg in 1 year, whereas those following a prandial insulin regimen (with or without basal insulin) gained 6.4 kg.12 Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapy is an alternative injectable therapy option to insulin in the management of T2DM.6,7 Because these agents act in a glucose-dependent manner, the risk of hypoglycemia is low with monotherapy or when combined with other nonhypoglycemic treatments.13-16 In addition, GLP-1RAs suppress inadequately elevated glucagon levels, delay gastric emptying, and reduce appetite and food intake at mealtimes, with this last effect likely to be associated with the reduction in body weight also observed in GLP-1RAe treated patients with T2DM.17,18 Exenatide, the first US Food and Drug Administrationeapproved GLP-1RA for use in patients with T2DM as an adjunct to diet and exercise, was first available for administration as a twice daily subcutaneous injection before the morning and evening meals (or the 2 main meals).19 A sustained-release exenatide formulation was later approved by the US Food and Drug Administration for once weekly administration.13 The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial was designed to compare twice daily and once weekly exenatide.20-22 The study consisted of 2 phases: a 30-week, controlled, open-label phase and an uncontrolled, open-ended, Mayo Clin Proc. n March 2015;90(3):356-365 www.mayoclinicproceedings.org
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extension phase. In the controlled period, once weekly exenatide exhibited a greater reduction from baseline in HbA1c levels compared with twice daily exenatide (e1.9% vs e1.5%, P¼.002) and a significantly greater achievement of the HbA1c target of 7.0% or less (77% vs 61%, P¼.004).21 The 1-, 2-, and 3-year results of once weekly exenatide treatment in the open-ended extension have been previously published.20,22,23 The current analysis expands on these results by examining the safety and efficacy of once weekly exenatide treatment over 5 years, to our knowledge, the longest assessment of a GLP1RA reported to date. METHODS Study Design and Patients In the initial randomized, comparatorcontrolled, open-label study (April 15, 2006, through February 21, 2012), patients with T2DM were randomized to 2 mg of exenatide once weekly or 10 mg of exenatide twice daily (5 mg twice daily for the first 28 days) and followed for 30 weeks.21 At week 30, patients who initially received exenatide twice daily were switched to exenatide once weekly; all patients received exenatide once weekly throughout the open-ended extension.20,22 Those patients who switched from twice daily to once weekly exenatide and were concomitantly receiving a sulfonylurea were required to have their sulfonylurea dose reduced to the minimum recommended dose until week 40, after which time their sulfonylurea dose was uptitrated based on daily glucose measurements (target FPG 110 mg/dL [to convert to mmol/L, multiply by 0.0555]). Patients maintained on exenatide once weekly did not change their sulfonylurea treatment regimen after the controlled phase. Concomitant lipid-lowering, antihypertensive, and nonsulfonylurea glucose-lowering therapies during the 30-week controlled phase and open-ended extension generally remained stable, with changes allowed at the discretion of the study investigator or primary care physician. Only patients who completed the 30week controlled phase were permitted to enter the open-ended extension. The initial study protocol was approved by an institutional review board at each site, and
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patients provided written informed consent before participation. Inclusion criteria were published previously (Supplemental Appendix 1, available online at http://www.mayoclinic proceedings.org).21 Outcome Measures Efficacy end points included change from baseline in HbA1c level, FPG level, body weight, lipid profile (total cholesterol, lowdensity lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDLC], and triglyceride levels), and seated blood pressure (BP) for the 5-year completer and intent-to-treat (ITT) populations. The measurements of HbA1c and BP were described previously.20,21 Safety data were reported for the ITT population, with adverse events reported as the overall incidence and event rate. Treatment-emergent adverse events were those events reported during or after the first injection of randomized medication. Serious adverse events were those events that resulted in death, a life-threatening situation, inpatient hospitalization or prolongation of inpatient hospitalization, incapacity or substantial disruption to the ability to conduct normal life functions, congenital anomaly or birth defect, or an important medical event that may have jeopardized the patient and required medical or surgical intervention to prevent one of the previously mentioned outcomes. Liver and renal function and heart rate were also evaluated and are presented in 5year completers. Definitions of major and minor hypoglycemia appear in Supplemental Appendix 2 (available online at http://www. mayoclinicproceedings.org). Statistical Analyses The ITT population consisted of all randomized patients who received 1 or more doses of study medication during the 30-week controlled phase. The 5-year completer population consisted of patients from the ITT population who received exenatide treatment for 260 weeks or longer. Descriptive statistics were applied for demographic data, analysis of primary glycemic end points, body weight, and fasting lipid concentrations. The HbA1c analyses were based on a general linear model (analysis of variance), which included the original treatment assignment, baseline HbA1c 358
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stratum, and concomitant sulfonylurea use at screening. Baseline FPG level, body weight, and BP were added in the model (analysis of covariance) for FPG, body weight, and BP, respectively. The results for all efficacy end points are presented as least-squares (LS) means with SEs and 95% CIs. The last observation carried forward approach was applied to estimate missing values for weeks 2 to 260. All statistical analyses were performed using SAS statistical software, version 9.2 (SAS Institute Inc). RESULTS Patient Disposition and Baseline Characteristics The original ITT population consisted of 295 patients. Of the 258 patients who entered the extension phase, 153 (59.3%) completed 5 years of treatment (Figure 1). The most common reasons for discontinuation during the open-ended extension (weeks 30-260) were withdrawal of consent (57 [19.3%]), adverse event (11 [3.7%]), investigator decision (10 [3.4%]), and loss to follow-up (10 [3.4%]). The baseline and demographic characteristics of the 5-year completer and ITT populations were similar (Supplemental Table, available online at http://www.mayoclinicproceedings. org). Patients had a mean duration of diabetes of 7 years, mean HbA1c levels of 8.1% to 8.3%, mean FPG levels of 163.9 to 169.4 mg/dL, and mean body weight of 100.7 to 101.8 kg across the 2 populations. At screening, 59 (38.6%) of the 153 patients who completed the 5-year treatment and 109 (36.9%) of the 295 ITT patients were receiving sulfonylurea-based therapy. Effects on Glycemic Control and Body Weight A significant reduction in HbA1c from baseline in the controlled phase was maintained during 5 years with once weekly exenatide treatment. In the 5-year completer population, the mean SD baseline HbA1c level was 8.1%0.9%. At 5 years, the mean SE HbA1c level was 7.0%0.1%, with a significant LS mean reduction from baseline of 1.6%0.1% (95% CI, 1.8% to 1.4%) (Figure 2, A). By comparison, in the ITT population, the mean SE HbA1c level
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303 Randomized 8 Withdrew before lead-in 295 ITT population
Controlled phase
148 Receiving 2 mg of exenatide once weekly
Withdrew before week 30:
147 Receiving 10 μg of exenatide twice daily
No.
(%)a
No.
(%)a
20
(13.5)
17
(11.6)
Adverse event
9
(6.1)
Adverse event
8
(5.4)
Lost to follow-up
5
(3.4)
Lost to follow-up
4
(2.7)
Withdrew consent
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(3.4)
Withdrew consent
2
(1.4)
Investigator decision
1
(0.7)
Investigator decision
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(1.4)
Protocol violation
0
Protocol violation
1
(0.7)
Withdrew before week 30:
258 (87.5%) Receiving 2 mg of exenatide once weekly (ITT)b
No.
(%)b
(%)c
99
(33.6)
(38.4)
57
(19.3)
(22.1)
Adverse event
11
(3.7)
(4.3)
Lost to follow-up
10
(3.4)
(3.9)
Investigator decision
10
(3.4)
(3.9)
Loss of glucose control
8
(2.7)
(3.1)
Administrative
2
(0.7)
(0.8)
1
(0.3)
(0.4)
Withdrew prior to weeks 30 and 260: Withdrew consent Open-ended extension phase
Protocol violation
6 Removed from final analysisd
153 (59.3%) Completer populationc
FIGURE 1. Patient disposition. aPercentages represent the proportion of the treatment arm. bPercentages represent the proportion of the intent-to-treat (ITT) population (N¼295). cPercentages represent the proportion of ITT patients entering the open-ended extension (n¼258). dSix patients were not included in the completer population analysis because their individual drug exposure was less than 260 weeks.
was 7.3%0.1% at 5 years, with an LS mean SE change from baseline of 1.2%0.1% (95% CI, 1.4% to 1.0%). The HbA1c targets of 6.5% or less and less than 7% were achieved by 50 (32.7%) of 153 patients Mayo Clin Proc. n March 2015;90(3):356-365 www.mayoclinicproceedings.org
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and 65 (43.9%) of 148 patients with nonmissing HbA1c values, respectively, who did not meet the target at baseline in the 5year completer population (Figure 2, B) and 79 (28.4%) of 278 patients and 106
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Mean (SE) HbA1c (%)
8.5 8 7.5 7 6.9
6.8
6.5
7.0
6.9
6.5 6 0
1
2
3
4
5
Year
A 100
[48.4%]), thiazolidinediones (20 [13.1%]), oral blood glucoseelowering drug (not specified; 5 [3.3%]), fast-acting insulins (15 [9.8%]), intermediate-acting insulins (2 [1.3%]), long-acting insulins (19 [12.4%]), other insulins (not specified; 1 [0.7%]), and drug used in diabetes (not specified; 1 [0.7%]). Reductions in body weight observed during the controlled phase were mostly maintained in 5-year completers (Figure 3, B). At 5 years, the observed mean SE body weight was 97.21.5 kg, with a significant LS mean SE change from baseline of e3.00.9 kg (95% CI, e4.6 to e1.3 kg).
90
Proportion of patients (%)
80 70 60 50 40
43.9 32.7
30 20 10 0 ≤6.5%
B
<7.0% HbA1c targets
FIGURE 2. Hemoglobin A1c (HbA1c) values over time (A) and percentage of patients who achieved HbA1c targets (B) in the 5-year completer population (n¼153; last observation carried forward). The baseline HbA1c level was 8.1%. Dashed line represents the recommended goal of 7.0%.
(39.1%) of 271 patients, respectively, in the ITT population. Similar to HbA1c, a significant reduction from baseline in FPG levels observed during the initial controlled phase was maintained through the extension phase in 5-year completers (Figure 3, A). The LS mean SE change from baseline at 5 years was e28.83.7 mg/dL (95% CI, 36.2 to 21.5 mg/dL). New concomitant antidiabetes medications added by the 153 patients in the completer population over 5 years included biguanides (54 [35.3%]), sulfonylureas (74 360
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Effects on Lipids and BP Total cholesterol and LDL-C values were significantly reduced from baseline in the 5-year completer population, whereas HDL-C values were significantly increased (Figure 4, A). At 5 years, the LS mean SE changes were e11.53.4 mg/dL (95% CI, 18.2 to 4.8 mg/dL) for fasting total cholesterol, 9.12.8 mg/dL (95% CI, 14.5 to 3.6 mg/dL) for LDL-C, and 2.00.9 mg/dL (95% CI, 0.2 to 3.7 mg/dL) for HDL-C (to convert cholesterol values to mmol/L, multiply by 0.0259). Triglycerides also decreased significantly from baseline (geometric LS mean SE change, e12%4%; 95% CI, e20% to e4%). Lipids in the ITT population were significantly reduced for total cholesterol (LS mean SE, 10.8 2.2 mg/ dL; 95% CI, 15.2 to 6.5 mg/dL), LDL-C (7.21.9 mg/dL; 95% CI, 10.9 to 3.5), and triglycerides (9% 3%; 95% CI, 14% to 4%); the HDL-C level was unchanged (0.20.6 mg/dL; 95% CI, 1.1 to 1.4 mg/ dL). A total of 113 (73.9%) of 153 patients initiated 1 or more lipid-lowering agents during the 5 years of the study, including b-hydroxy-bmethylglutarylecoenzyme A reductase inhibitors (statins: 101 [66.0%]), other (eg, fish oil, omega-3 fatty acids, and ezetimibe) (23 [15.0%]), nicotinic acid or a derivative (14 [9.2%]), fibrates (11 [7.2%]), bile acid sequestrants (3 [2.0%]), and serum lipid-reducing agents (not specified; 1 [0.7%]). No clinically meaningful change at 5 years was observed in seated systolic BP. The LS mean SE change in systolic BP for the 5-year completer population was e0.41.6 mm Hg (95% CI, e3.4 to 2.8 mm Hg), with 82
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0 –10 LS mean (SE) change in FPG (mg/dL)
(53.6%) of 153 patients exhibiting a systolic BP of less than 130 mm Hg. Diastolic BP decreased significantly at 5 years, with an LS mean SE change of e2.00.8 mm Hg (95% CI, e3.67 to e0.36 mm Hg). During the 5 years of follow-up, 100 (65.4%) of 153 patients started taking 1 or more antihypertensive medications, including renin-angiotensin system inhibitors (79 [51.6%]), diuretics (32 [20.9%]), b-blockers (31 [20.3%]), calcium channel blockers (23 [15.0%]), organic nitrates (15 [9.8%]), and other antihypertensives (6 [3.9%]).
–20 –30
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Safety and Tolerability No new safety signals for once weekly exenatide were detected during the open-ended extension in the ITT population. Treatmentemergent adverse events leading to withdrawal from week 30 to year 5 were infrequent (11 [3.7%] of 295), with no apparent pattern in the type of events that led to discontinuation. Serious adverse events occurred in 13 (4.4%) of 293 patients during the initial 30-week assessment and in 57 (22.1%) of 258 patients during the open-ended extension. The most common serious adverse events by system organ class during the open-ended extension were cardiac disorders (14 [5.4%]), infections and infestations (14 [5.4%]), and musculoskeletal and connective tissue disorders (9 [3.5%]). The most common adverse events in the ITT population during the open-ended extension were upper respiratory tract infection (106 [41.1%]), nasopharyngitis (73 [28.3%]), diarrhea (66 [25.6%]), sinusitis (55 [21.3%]), back pain (51 [19.8%]), and arthralgia (47 [18.2%]). Exposure-adjusted event rates for nausea with once weekly exenatide decreased from 84.6 events per 100 patient-years during the initial 30-week assessment to 8.0 events per 100 patient-years during the open-ended extension (Table); exposure-adjusted event rates of injection-site pruritus (from 51.0 to 1.6 events per 100 patient-years) and injection-site erythema (from 13.7 to 1.2 events per 100 patient-years) also decreased. Injection-site nodules were infrequent during the controlled phase (3.7 events per 100 patient-years) and were not observed in the open-ended extension. One case (0.4%) of pancreatitis, 1 case (0.4%) of pancreatic carcinoma, and 3 cases (1.2%) of acute renal failure
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FIGURE 3. Change in fasting plasma glucose (FPG) (A) and body weight (B) over time in the 5-year completer population (n¼153; last observation carried forward). The baseline FPG level was 163.9 mg/dL (to convert to mmol/L, multiply by 0.0555), and the baseline body weight was 100.7 kg. LS ¼ least-squares. aP<.05 for change from baseline.
were reported during the 5-year treatment period, with exposure-adjusted event rates of 1.0 event per 1000 patient-years for pancreatitis and pancreatic carcinoma and 3.0 events per 1000 patient-years for acute renal failure. Most adverse events were mild. Liver function changes from baseline with once weekly exenatide were minimal during the long-term open-ended extension. In the completer population, the mean SE changes from baseline to year 5 in alanine aminotransferase and aspartate aminotransferase were e4.41.4 U/L (95% CI, e7.3 to e1.6 U/L) and e3.20.9 U/L (95% CI, e4.9 to e1.4 U/L), respectively (to convert to mkat/L, multiply by 0.0167). There were no clinically meaningful changes in renal function in the completer population. The mean SE baseline estimated glomerular filtration rate was 80.61.6 mL/min/1.73 m2, and the end
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Baseline (mg/dL):
Total cholesterol
HDL-C
LDL-C
172.5
45.8
92.3
point estimated glomerular filtration rate was 71.11.6 mL/min/1.73 m2, representing a change of e9.61.3 mL/min/1.73 m2 (95% CI, e12.0 to e7.1 mL/min/1.73 m2). In 5-year completers, the mean SE baseline heart rate was 73.90.8 beats/min, and the end point heart rate was 75.30.8 beats/min, representing an increase of þ1.50.9 beats/min. This small increase in heart rate after 5 years of exenatide treatment was consistent with observed changes at week 30 (1.10.7 beats/ min) and at 1 year (2.80.7 beats/min).21 No cases of major hypoglycemia were reported during the 5 years of the study in the ITT population. Treatment-emergent minor hypoglycemia was observed in 38 (14.7%) of 258 patients and was mainly observed in those taking a concomitant sulfonylurea at baseline (25 [25.3%] of 99 vs 13 [8.2%] of 159 nonsulfonylurea users).
2.0a
4 LS mean (SE) change in cholesterol (mg/dL)
2 0 –2 –4 –6 –8 –10 –12
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A Baseline (mg/dL):
–11.5a
154.4 4 2 0
Geometric LS mean (SE) change in triglycerides (%)
–2 –4 –6 –8 –10 –12 –14 –16 –12a
B
–18
FIGURE 4. Change from baseline in cholesterol (A) (to convert to mmol/L, multiply by 0.0259) and triglycerides (B) (to convert to mmol/L, multiply by 0.0113) in the 5-year completer population (n¼153; last observation carried forward). The baseline levels were 172.5, 45.8, and 92.3 mg/dL for total cholesterol; HDL-C, and LDL-C cholesterol, respectively, and the baseline triglyceride level was 154.4 mg/dL. HDL-C ¼ high-density lipoprotein cholesterol; LDL-C ¼ low-density lipoprotein cholesterol; LS ¼ least-squares. aP<.05 for change from baseline.
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DISCUSSION This is the longest study of a GLP-1RA to date, and the findings indicate that once weekly exenatide can elicit durable efficacy and an acceptable tolerability profile during 5 years. More than 50% of patients continued once weekly treatment with exenatide for the full 5 years. This compares favorably with long-term extension studies of other antidiabetes medications. In a study of liraglutide, another GLP-1RA, approximately 50% of patients remained in the study at year 2,24 whereas for the present study, more than 73% completed 2 years.22 In 3 studies of albiglutide added to background metformin (with or without glimepiride or pioglitazone), 54% to 65% of patients completed 3 years of treatment, and 40% to 52% required rescue medication, including insulin.25-27 Because selection bias is an issue in extension trials (in which patients who do not do well in the initial trial usually do not enter the extension trial),28,29 the high 5-year completer rate in the present study is an indirect indicator that once weekly exenatide was well tolerated, perceived as efficacious, or both. For 5-year completers, long-term treatment with once weekly exenatide was associated with sustained improvement in glycemic control compared with baseline, with more than 40% of patients reaching an HbA1c goal of less than 7%. The results were similar between the completer and ITT populations,
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providing further confidence in the validity of the conclusions. Although the FPG level appeared to increase slightly between years 1 and 5, the decrease from baseline remained clinically meaningful, with patients maintaining levels near the recommended goal of less than 130 mg/dL.7 More than half of patients added one or more antidiabetes medications, which likely contributed to the benefits observed at 5 years. However, this could also be considered a reflection of real-world clinical experience, where patients often require incremental pharmacologic intervention because of progression of T2DM. Patients also maintained body weight loss during 5 years. Studies have found that even a modest decrease in body weight (5%-10%) in overweight and obese people can elicit improvement in glycemic control and mitigate risk factors for cardiovascular disease.30,31 In contrast, long-term treatment with insulin with or without oral glucose-lowering medications has produced weight gain rather than sustained weight loss.32,33 The sustained body weight loss with exenatide is particularly impressive because durable weight loss, in general, is not often achieved despite intensive lifestyle modification, with patients typically regaining 30% to 40% of the weight initially lost after a year.34 No unexpected safety signals were detected in the longstanding study of this cohort. In fact, the incidence of nausea and injection-site events diminished over time compared with the initial 30-week study.21 Consistent with earlier reports,20-23 no cases of major hypoglycemia were reported during the 5 years of follow-up, and minor hypoglycemia was mainly observed in those taking a concomitant sulfonylurea at baseline. Because hypoglycemia risk increases with increased duration of insulin use,11,35,36 the observations of no cases of major hypoglycemia and the low rate of minor hypoglycemia with once weekly exenatide treatment throughout the 5 years further underscore the advantage that GLP-1RA therapy has over insulin with this safety consideration in mind. This should also give physicians confidence in the safety of treatment when considering longer-term therapy options. After 5 years, risk factors for cardiovascular disease were improved compared with baseline, with even greater decreases in total cholesterol and LDL-C and a greater increase Mayo Clin Proc. n March 2015;90(3):356-365 www.mayoclinicproceedings.org
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TABLE. Annual Event Rates for Treatment-Emergent Adverse Events With a 10% or Greater Incidence During the Controlled and Open-Ended Extension Phases in the Intent-to-Treat Populationa Controlled phase (weeks 0-30)
Adverse event
Exenatide twice daily (n¼145)b
Nausea Vomiting Upper respiratory tract infection Diarrhea Urinary tract infection Sinusitis Nasopharyngitis Gastroenteritis, viral Headache Back pain Arthralgia Bronchitis Hypertension Pain in extremity Cough Musculoskeletal pain
92.0 47.3 35.8 34.5 14.1 12.8 11.5 11.5 10.2 7.7 7.7 7.7 5.1 2.6 2.6 0
Exenatide Open-ended extension phase (weeks 30-260) of once exenatide once weekly weekly (n¼258) (n¼148) 84.6 36.1 16.2 37.3 22.4 8.7 18.7 16.2 26.1 8.7 12.4 5.0 6.2 2.5 6.2 2.5
8.0 7.1 17.4 10.3 7.8 10.5 16.3 3.4 3.6 6.2 7.1 4.8 4.5 5.0 3.2 4.2
a
Annual event rates are presented as events per 100 patient-years. Two patients withdrew during the lead-in to the initial 30-week controlled phase.
b
in HDL-C than that observed at years 2 and 3.22,23 However, this observation is likely confounded by the fact that a large proportion of patients started taking an antilipid medication (such as a statin) during the study. Also of note, there was no clinically meaningful change in BP at year 5 despite a large percentage of patients starting use of an antihypertensive medication. This finding is not unexpected because adequate BP control is difficult to achieve in clinical practice. In a 1-year study of 78 patients with T2DM, less than half of the patients achieved a BP of 130/80 mm Hg or less despite intensification of lifestyle changes and the addition of pharmacotherapeutic agents.37 One limitation of this analysis is that an open-label study design may create bias and affect patient expectations.29 Another limitation is that the completer population may represent a subset of patients who responded well to treatment.28 However, levels of HbA1c, total cholesterol, LDL-C, and triglycerides were significantly improved from baseline in the ITT population (which includes patients who dropped
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out during the open-ended extension as nonresponders), similar to findings in the 5-year completer population (ITT data for FPG, body weight, and seated BP were not available for comparison), supporting the validity of the outcomes of the completer analyses. A further study limitation is that the lack of a control group limits comparisons with other treatment modalities and the contribution of advancing disease severity. However, 3-year extension data from an open-label, 26-week study of once weekly exenatide vs insulin glargine in patients in whom existing glucose-lowering therapy failed revealed the superior longterm efficacy of once weekly exenatide with respect to HbA1c, body weight reduction, and low rate of hypoglycemia.38 CONCLUSION Treatment with once weekly exenatide during 5 years was well tolerated and associated with sustained improvement in glycemic control, body weight, and markers of cardiovascular risk. Because patients with diabetes generally require lifelong treatment, having confidence that a chosen treatment modality will be well tolerated and effective in the long term is important. These results provide the longest follow-up of a GLP-1RA to date and will help physicians make therapy decisions for their patients. ACKNOWLEDGMENTS Meredith Rogers, MS, former employee of BristolMyers Squibb, and Robert Schupp, PharmD, of inScience Communications, Springer Healthcare, provided writing and editorial assistance with funding provided by AstraZeneca. SUPPLEMENTAL ONLINE MATERIAL Supplemental material can be found online at http://www.mayoclinicproceedings.org. Abbreviations and Acronyms: BP = blood pressure; FPG = fasting plasma glucose; GLP-1RA = glucagon-like peptide 1 receptor agonist; HbA1c = hemoglobin A1c; HDLC = high-density lipoprotein cholesterol; ITT = intent to treat; LDL-C = low-density lipoprotein cholesterol; LS = least-squares; T2DM = type 2 diabetes mellitus Grant Support: The design and conduct of the study were supported by Amylin Pharmaceuticals and Eli Lilly and Company. Development of the manuscript was supported by AstraZeneca.
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Potential Competing Interests: Dr Wysham is a speaker and/or adviser for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Janssen, Novo Nordisk, and Sanofi-Aventis. Dr MacConell was an employee of Amylin Pharmaceuticals/Bristol-Myers Squibb at the time the research was conducted and is currently vice president of clinical development at Intercept Pharmaceuticals. Dr Maggs was an employee of Amylin Pharmaceuticals at the time the research was conducted and is currently chief medical officer at GI Dynamics. Dr Zhou is an employee of Bristol-Myers Squibb. Mr Griffin was an employee of Amylin Pharmaceuticals at the time the research was conducted. Dr Trautmann was an employee of Eli Lilly and Company at the time of the research was conducted and is a stockholder of Eli Lilly and Company. He was a consultant to Amylin Pharmaceuticals, BristolMyers Squibb, and AstraZeneca. Correspondence: Address to Carol H. Wysham, MD, Rockwood Clinic, 400 E Fifth Ave, Spokane, WA 99202 ([email protected]).
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