Type 2 diabetes mellitus is a complex disorder characterized by defects in the secretion and action of multiple glucoregulatory hormones, resulting in hyperglycemia. Achieving glycemic control and reduction of glycosylated hemoglobin (HbA1c) has been shown to reduce the risk of long-term microvascular and possibly macrovascular complications of diabetes (1). However, optimal treatment of diabetes must address both glycemic control and such comorbidities as obesity, hypertension, and dyslipidemia (2, 3). Although several therapies are currently approved for the treatment of type 2 diabetes, there remains a need for treatments with demonstrated effects on both hyperglycemia and associated comorbidities, with minimal risk of hypoglycemia and weight gain.
The American Diabetes Association/European Association for the Study of Diabetes treatment algorithm published in 2009 cites glucagon-like peptide-1 (GLP-1) receptor agonists as a less-validated but potential add-on therapy for the treatment of type 2 diabetes if glycemic control is not achieved after lifestyle intervention and metformin therapy (4). In addition, the 2009 consensus algorithm created by the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) for the treatment of type 2 diabetes supports combination therapy for patients who require advanced treatment. Although metformin is recommended for monotherapy and as a component of combination antidiabetes therapies, GLP-1 receptor agonists are positioned as preferred secondary agents because of their efficacy and overall safety profile, notably glucose-dependent stimulation of insulin secretion and the resultant low risk of hypoglycemia, ability to produce weight loss, and postprandial glucose-lowering characteristics (5).
An incretin hormone secreted from the gut in response to food ingestion, GLP-1 has been demonstrated to play a key role in pancreatic β-cell stimulation, insulin secretion, regulation of gastric emptying and satiety, and suppression of inappropriate glucagon secretion (6–8). GLP-1 infusion over 24 h has been demonstrated to normalize blood glucose and both basal and stimulated β-cell function (9), demonstrating the potential role of continuous GLP-1 receptor agonism in improving glycemic control in type 2 diabetes (10).
Exenatide administered twice daily (ExBID), a well-characterized GLP-1 receptor agonist approved for use as an adjunct to diet and exercise, has been shown to promote glycemic control in patients with type 2 diabetes and produce weight loss; in addition, exenatide has been reported to improve cardiovascular risk factors, such as blood pressure and lipid profiles (11). Exenatide, like GLP-1, acts to enhance glucose-dependent insulin secretion by the pancreatic β-cell, suppress inappropriately elevated glucagon secretion, reduce food intake, and slow gastric emptying (12–14).
An extended-release formulation of exenatide administered once weekly (ExQW), currently under review by regulatory authorities, provides steady-state concentrations of exenatide in the range shown to elicit effects on glycemic control within approximately 6–10 wk of initiating therapy (15, 16). As in the case of ExBID, ExQW has been demonstrated to improve glycemic control and reduce body weight (15, 16). The continuous GLP-1 receptor agonism achieved with ExQW has the potential to provide improved glycemic control with additional benefits of weight loss, blood pressure reduction, and improvement in lipid profiles. In addition, once-weekly administration has been reported to reduce patient burden by providing patients with a weekly dosing regimen (17).
Diabetes Therapy Utilization: Researching Changes in HBA1C, Weight, and Other Factors Through Intervention with Exenatide Once Weekly (DURATION)-5 was a randomized, open-label trial comparing the safety and efficacy of ExQW and ExBID, both provided in their (intended) commercial forms, over 24 wk in patients with type 2 diabetes treated with diet and exercise alone or in combination with a single or multiple oral antidiabetic agents.
Patients and Methods
Patients
Randomized patients (n = 254) were at least 18 yr of age and diagnosed with type 2 diabetes, otherwise healthy, and treated for at least 2 months with diet and exercise alone or with a stable, maximally effective regimen of metformin, sulfonylurea (SU), thiazolidinedione, or a combination of these medications. Additional entry criteria included an HbA1c of 7.1–11.0%, fasting plasma glucose (FPG) concentration less than 280 mg/dl (15.5 mmol/liter), and a body mass index of 25–45 kg/m2. Patients were to refrain from changes to oral antidiabetic, lipid-lowering, and antihypertensive medications during the study, unless instructed otherwise by the investigator. Use of concomitant weight-loss agents was not allowed; no supplementary lifestyle modification program was applied.
A common clinical protocol was approved for each site by the appropriate institutional review board, and all patients provided written informed consent before participation. The study was conducted in accordance with the principles described in the Declaration of Helsinki (1946) up to and including the Seoul revision (2008) (18).
Study design
This study was a randomized, comparator-controlled, open-label evaluation of the efficacy, safety, and tolerability of ExQW (intended commercial material) compared with ExBID. Patients were randomized 1:1 to treatment with ExBID or ExQW, with randomization performed centrally via an interactive voice or web response system. Randomization was stratified according to concomitant SU use at screening and baseline HbA1c stratum (<9.0% or ≥ 9.0%). Patients randomized to ExQW received sc 2-mg doses once weekly for 24 wk. Patients randomized to ExBID received 5 μg sc twice daily (BID) for 4 wk followed by 10 μg sc BID for 20 wk, consistent with recommended dosing for ExBID (19). Patients self-administered study medication after training by study site personnel. Sponsor personnel remained blinded to HbA1c and FPG data throughout treatment.
Study end points
The study was designed to compare the effects of ExQW and ExBID on the primary end point of change in HbA1c from baseline to wk 24. Secondary end points included body weight, FPG, proportion of subjects achieving HbA1c targets of less than 7% and 6.5% or less at wk 24, proportion of patients achieving FPG target of 126 mg/dl (7.0 mmol/liter) or less at wk 24, systolic blood pressure (SBP) and diastolic blood pressure, fasting lipid concentrations, safety, and tolerability.
Laboratory values
Blood tests, including HbA1c, were performed by Quintiles Laboratories (Smyrna, GA) using standard methods. HbA1c was measured by HPLC. Plasma concentrations of antibodies to exenatide were measured using a validated ELISA (20). Antibody titers were determined by serial 1:5 dilutions after minimal dilution of 1:25, with the titer expressed as the reciprocal of the highest dilution of sample that tested positive. Antibody to exenatide titers less than 625 were classified as low and titers of 625 or greater were classified as higher.
Statistical analysis
A sample size of approximately 250 patients (ratio of 1:1) was estimated to provide 90% power to demonstrate that ExQW was noninferior to ExBID by a 0.4% difference in the HbA1c change from baseline to wk 24, using a one-sided, two-sample t test with a significance level of 0.025 and assuming a greater (0.1%) reduction in HbA1c by ExQW compared with ExBID, a 15% withdrawal rate, and a common sd of 1.1%. Hypotheses for demonstration of both superiority and noninferiority were prespecified in the protocol. Noninferiority of ExQW to ExBID was demonstrated if the upper limit of the two-sided 95% confidence interval (CI) for the difference between treatments fell beneath 0.4%; superiority was demonstrated if the CI was below zero (21). Other tests were conducted two sided at a significance level of 0.05. Multiplicity from tests of treatment differences for the proportion of patients achieving the targets of HbA1c less than 7.0% and FPG 126 mg/dl (7.0 mmol/liter) or less at wk 24, and the change in FPG from baseline to wk 24 were adjusted using the Hochberg procedure (22) to control the overall type I error rate at a 5% level.
The changes in HbA1c and FPG between treatments were compared using general linear models, including factors for treatment group, baseline HbA1c stratum, and concomitant SU use at screening. The proportions of patients achieving HbA1c and FPG targets were compared between treatments using a Cochran-Mantel-Haenszel test, adjusted by the factors of baseline HbA1c stratum and concomitant SU use at screening. Differences in the changes in other parameters from baseline to wk 24 were assessed using general linear models, including factors for treatment group, concomitant SU use at screening, baseline HbA1c stratum, and baseline values of the parameter. The triglyceride data were analyzed after natural logarithmic transformation.
The intent-to-treat (ITT) population (n = 252) consisted of all randomized patients receiving at least one dose of randomized study medication. The evaluable population (n = 204) consisted of all ITT patients completing study procedures through at least wk 20 in compliance with the protocol and receiving adequate study medication exposure. With the exception of safety and subgroup analyses, performed for the ITT population only, all analyses were performed for both the ITT and evaluable populations. Missing postbaseline efficacy data were imputed using the last observation carried forward (LOCF) approach. As a sensitivity analysis, the change in HbA1c was evaluated using all observed postbaseline data (without imputation) in a mixed-effects model repeated-measure analysis (change in HbA1c as dependent variable; treatment, week, treatment by week interaction, concomitant SU use at screening, and baseline HbA1c stratum as fixed effects; subject as random effect). Efficacy data on mean changes from baseline were expressed as least squares (LS) means. The statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC).
Treatment-emergent adverse events were defined as adverse events that occurred or worsened after the first injection of study medication. Hypoglycemic episodes were classified as major or minor. Major hypoglycemia was defined as events that resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or iv glucose. Hypoglycemia requiring assistance because of severe impairment in consciousness or behavior accompanied by a blood glucose concentration less than 54 mg/dl (3.0 mmol/liter) before treatment was also classified as major. Minor hypoglycemia was defined as events with symptoms consistent with hypoglycemia accompanied by a blood glucose concentration less than 54 mg/dl (3.0 mmol/liter) before treatment.
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