Efficacy and Safety of Multiple Doses of Exenatide Once-Monthly Suspension in Patients With Type 2 Diabetes: A Phase II Randomized Clinical Trial
OBJECTIVE This study investigated the efficacy and safety of multiple exenatide once-monthly suspension (QMS) doses of exenatide-containing microspheres in Miglyol referenced against the clinical dose of exenatide once-weekly (QW) microspheres in aqueous solution.
RESEARCH DESIGN AND METHODS In this phase II, randomized, controlled, single-blind study, 121 adults (∼30/arm) with type 2 diabetes and HbA1c 7.1–11.0% (54–97 mmol/mol) were randomized 1:1:1:1 to subcutaneous exenatide QW 2 mg (self-administered) or exenatide QMS 5, 8, or 11 mg (caregiver-administered) for 20 weeks. The primary end point was change in HbA1c.
RESULTS At baseline, mean age was 50 years, HbA1c was 8.5% (69 mmol/mol), fasting plasma glucose (FPG) was 184 mg/dL, and body weight was 98 kg. At week 20, mean ± SD HbA1c reductions were −1.54% ± 1.26% with exenatide QW and −1.29% ± 1.07%, −1.31% ± 1.66%, and −1.45% ± 0.93% with exenatide QMS 5, 8, and 11 mg, respectively (evaluable population: n = 110). There were no significant differences in HbA1c reductions among the exenatide QMS doses. FPG reductions were −34 ± 48 mg/dL with exenatide QW and −25 ± 43, −30 ± 52, and −49 ± 49 mg/dL with exenatide QMS 5, 8, and 11 mg, respectively. Weight decreased with all treatments. For exenatide QMS, nausea (16.7–23.3%) and headache (16.7–26.7%) were the most common adverse events. No major or minor hypoglycemia occurred.
CONCLUSIONS All doses of exenatide QMS resulted in efficacy and tolerability profiles consistent with exenatide QW. These results combined with pharmacokinetic and pharmacodynamic modeling could inform dose selection for further development.
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are recommended as add-on therapy for patients with type 2 diabetes after failure of oral glucose-lowering medications (1,2). GLP-1RAs target multiple pathophysiologic mechanisms, including stimulating glucose-dependent insulin secretion from pancreatic β-cells, suppressing glucose-dependent glucagon secretion from pancreatic α-cells, slowing gastric motility (more pronounced with short-acting GLP-1RAs), and promoting satiety (3–5). The GLP-1RA exenatide is available as a twice-daily (6) and once-weekly (QW) formulation (7). For exenatide QW, a fixed dose of exenatide 2.0 mg is dispersed into biodegradable poly(D,L-lactide-coglycolide) polymer microspheres, which enable gradual, long-term release of exenatide through diffusion and erosion of the polymer (8): the steady-state dose of exenatide is the sum of concomitant release processes including prior doses (9). Exenatide QW has demonstrated reductions in HbA1c and fasting plasma glucose (FPG), with additional benefits including weight loss, improvement in some cardiovascular risk markers, and better gastrointestinal tolerability than exenatide twice daily and liraglutide (5,10).
An exenatide once-monthly suspension (QMS), investigated as an extended-release formulation administered less frequently, uses a nonaqueous diluent (Miglyol 812) to improve ease of suspension of the exenatide microspheres. Miglyol 812, a mixture of medium-chain triglycerides, is approved for use in a variety of drugs, foods, and cosmetics in the U.S. and Europe. Miglyol 812 does not cause microsphere swelling, dissolution, or degradation and provides sufficient viscosity to suspend the microspheres, eliminating the need to reconstitute the microspheres with a diluent immediately before injecting. A once-monthly medication would be expected to enhance the perceived patient benefits of a QW medication, such as greater convenience, better treatment adherence, improved quality of life, and less treatment burden (11), while potentially minimizing limitations of exenatide QW, primarily the need to reconstitute the microspheres in a diluent before injection. Both formulations require a 23-gauge needle to accommodate the suspended microspheres. Given the complexity of the release process from the exenatide microspheres, estimating the monthly dose for optimal efficacy and safety is difficult.
The primary objective of this study was to examine the effects of a range of the exenatide QMS doses on HbA1c in patients with type 2 diabetes, using exenatide QW as a reference. Secondary objectives were to investigate the effects of exenatide QMS on FPG, body weight, and blood pressure, and to assess the pharmacokinetics (PK), safety, and tolerability of exenatide QMS in patients with type 2 diabetes.
Research Design and Methods
This phase II, randomized, multidose, single-blind (patients and investigators were blinded to the exenatide QMS doses), controlled, parallel, four-arm study assessed the efficacy, safety, tolerability, and PK of exenatide QMS over 20 weeks, using exenatide QW as a reference arm, and was conducted at two sites in the U.S. (ClinicalTrials.gov identifier NCT01104701) (Supplementary Fig. 1). The protocol was approved by the institutional review board at each study site. Patients provided written informed consent before participation. The study was conducted in accordance with the Declaration of Helsinki.
Patients aged ≥18 years with type 2 diabetes, HbA1c of 7.1–11.0% (54–97 mmol/mol), and FPG of <280 mg/dL were enrolled. Eligible patients were on diet and exercise alone or a stable regimen of metformin, pioglitazone, or a combination of both for ≥2 months before screening and had stable body weight.
Exclusion criteria included prior or current use of any GLP-1RA, use of a dipeptidyl peptidase 4 inhibitor, sulfonylurea, rosiglitazone, insulin, or weight-loss medication within 3 months, or use of an α-glucosidase inhibitor, meglitinide, nateglinide, pramlintide, or any investigational drug within 30 days. Also excluded were patients with two or more episodes of major hypoglycemia within 6 months, organ transplantation or major surgery within 2 months, or any other clinically significant medical condition.
Patients were randomized 1:1:1:1 to receive exenatide QW 2 mg or exenatide QMS 5, 8, or 11 mg, stratified by HbA1c value (<9.0% or ≥9.0% [75 mmol/mol]) at screening. A randomization number uniquely identified each patient and the patient’s treatment. A pharmacist at the study site used the treatment assignment schedule to ensure appropriate study medication allocation. For exenatide QW, exenatide microspheres were reconstituted in 0.65 mL of aqueous diluent using the single-dose tray and self-administered by weekly subcutaneous injections using a 23-gauge needle. The exenatide QMS doses tested were above and below the dose administered during 4 weeks of treatment with exenatide QW and targeted an exposure range known to be therapeutic based on experience with exenatide twice daily and QW. For each exenatide QMS dose, exenatide microspheres were suspended in 0.85 mL of Miglyol 812 (stored at controlled room temperature) by an unblinded pharmacist before dosing. The exenatide QMS vials were taken to the clinic, and each dose was administered by blinded personnel at the study site (at baseline and weeks 4, 8, 12, and 16) via a single subcutaneous injection through a 23-gauge needle.
The primary end point was change in HbA1c from baseline to week 20. Secondary end points included change in HbA1c by baseline HbA1c stratum (<9.0% or ≥9.0% [75 mmol/mol]), proportions of patients achieving HbA1c targets of <7.0% (<53 mmol/mol) and ≤6.5% (≤48 mmol/mol), and changes from baseline to week 20 in FPG, body weight, and seated systolic blood pressure (SBP) and diastolic blood pressure (DBP). An immunoassay was used to measure plasma exenatide concentrations.
Treatment satisfaction was assessed at baseline and at weeks 12 and 20 using the Diabetes Treatment Satisfaction Questionnaire status (DTSQs), a patient-reported measure assessing treatment satisfaction and concerns about hyperglycemia and hypoglycemia (12). At week 20, patients characterized injection-site nodules using a three-item survey assessing presence and size and providing a brief description of the nodules.
Safety assessments included physical examinations, reporting of adverse events (AEs) and concomitant medications, and routine measures of vital signs, clinical laboratory investigations, and antibodies to exenatide. Hypoglycemia was classified as major, minor, or symptomatic (Supplementary Table 1).
The intent-to-treat (ITT) population included all randomized patients receiving one or more doses of the study medication. The primary analysis population was the evaluable population, which included all ITT patients who completed the study procedures through at least week 20. Patients who received <5 planned injections (exenatide QMS groups), <16 of 20 injections (exenatide QW), or missed >2 injections between weeks 12 and 19 (exenatide QW) were excluded. The PK-evaluable population included all ITT patients who had at least half or more detectable plasma exenatide measurements (not below the lower limit of quantitation) within the evaluation time period.
Outcomes were analyzed for the exenatide QMS 5-, 8-, and 11-mg dose groups, with exenatide QW as a reference group. A sample size of ∼120 patients was chosen for randomization, with ∼30 patients per group. Assuming an early withdrawal rate of 20%, 24 patients per group were expected to complete the study through week 20. This ensured an 80% probability of observing a within-group HbA1c reduction of at least −0.9% (−9.8 mmol/mol) from baseline, assuming that the true HbA1c reduction from baseline was −1.1% (−12 mmol/mol) based on a normal distribution. Twenty-four patients per group also provided 80% power to detect a statistically significant treatment difference of 0.85% (9.3 mmol/mol) between the QMS high-dose and low-dose groups (i.e., the dose-response relationship) in HbA1c reduction at a significance level of 0.05.
Demographics and baseline characteristics were summarized descriptively. The primary end point analysis—change in HbA1c from baseline to week 20—was summarized descriptively in the evaluable population. Change in HbA1c for the dose-response relationship was evaluated using a general linear model that included factors for treatment group and baseline HbA1c stratum. Secondary outcomes were summarized descriptively. Sensitivity analyses examined changes in HbA1c, FPG, and body weight in the ITT population. Patient-reported outcomes and safety assessments were assessed in the ITT population. PK parameters were determined for the PK-evaluable population using the standard noncompartmental method and summarized descriptively.
All randomized patients received one or more doses of the study medication and were included in the ITT population (n = 121) (Supplementary Fig. 2). Seven patients discontinued during the trial because of withdrawal of consent (n = 4; 1 each in the exenatide QMS 5- and 11-mg groups, 2 in the exenatide QMS 8-mg group), investigator decision (n = 2; both exenatide QMS 5 mg), and AE (n = 1; exenatide QMS 11 mg). The evaluable population included 110 patients (exenatide QW 2 mg: n = 29; exenatide QMS 5 mg: n = 26; exenatide QMS 8 mg: n = 28; exenatide QMS 11 mg: n = 27), and the PK-evaluable population included 99 patients (exenatide QW 2 mg: n = 26; exenatide QMS 5 mg: n = 25; exenatide QMS 8 mg: n = 25; exenatide QMS 11 mg: n = 23). Demographics and baseline characteristics were generally similar across treatments, except for more men in the exenatide QMS 8-mg group (Table 1).
Primary End Point
Exenatide QW and all doses of exenatide QMS reduced HbA1c over 20 weeks (Fig. 1A). Reductions in HbA1c were generally similar across treatments. Mean ± SD changes in HbA1c were −1.54% ± 1.26% (−16.8 ± 13.8 mmol/mol) with exenatide QW and −1.29% ± 1.07% (−14.1 ± 11.7 mmol/mol), −1.31% ± 1.66% (−14.3 ± 18.1 mmol/mol), and −1.45% ± 0.93% (−15.8 ± 10.2 mmol/mol) with exenatide QMS 5, 8, and 11 mg, respectively. Sensitivity analyses in the ITT population demonstrated similar reductions in HbA1c as in the primary analysis (Supplementary Table 2). The dose-response analysis demonstrated no significant differences in HbA1c reductions among the three exenatide QMS groups (all groups: P = 0.392; 5 vs. 8 mg: P = 0.695; 8 vs. 11 mg: P = 0.209).
Secondary End Points
Patients with baseline HbA1c ≥9.0% (≥75 mmol/mol) had numerically greater mean ± SD reductions in HbA1c (−2.28% ± 0.98% [−24.9 ± 10.7 mmol/mol] with exenatide QW and −2.37% ± 0.95% [−25.9 ± 10.4 mmol/mol], −2.50% ± 1.23% [−27.3 ± 13.4 mmol/mol], and −2.05% ± 1.33% [−22.4 ± 14.5 mmol/mol] with exenatide QMS 5, 8, and 11 mg) compared with patients with baseline HbA1c <9.0% (<75 mmol/mol; −1.15% ± 1.24% [−12.6 ± 13.6 mmol/mol] with exenatide QW and −0.72% ± 0.59% [−7.9 ± 6.4 mmol/mol], −0.41% ± 1.36% [−4.5 ± 14.9 mmol/mol], and −1.20% ± 0.58% [−13.1 ± 6.3 mmol/mol] with exenatide QMS 5, 8, and 11 mg).
Similar or numerically greater proportions of patients in the exenatide QMS groups achieved HbA1c <7.0% (<53 mmol/mol) compared with exenatide QW (Fig. 1B). Proportions of patients achieving HbA1c <7.0% (<53 mmol/mol) were 48% with exenatide QW and 50%, 57%, and 70% with exenatide QMS 5, 8, and 11 mg, respectively. Proportions of patients achieving HbA1c ≤6.5% (≤48 mmol/mol) were 45% with exenatide QW and 27%, 39%, and 48% with exenatide QMS 5, 8, and 11 mg, respectively. FPG decreased with all treatments over 20 weeks (Fig. 1C). Mean ± SD changes in FPG from baseline to week 20 were −34 ± 48 mg/dL with exenatide QW and −25 ± 43, −30 ± 52, and −49 ± 49 mg/dL with exenatide QMS 5, 8, and 11 mg, respectively. Reductions in body weight at week 20 were −1.36 ± 3.45 kg with exenatide QW and −1.10 ± 3.95, −0.41 ± 2.96, and −1.14 ± 3.51 kg with exenatide QMS 5, 8, and 11 mg, respectively (Fig. 1D). Sensitivity analyses confirmed reductions in FPG and body weight in the ITT population (Supplementary Table 2). There were small decreases in blood pressure (BP) in the exenatide QW group, and the exenatide QMS groups showed variable, small changes, with no clear dose relationship. Changes in SBP were −2.9 ± 13.5 mmHg with exenatide QW and 3.2 ± 17.9, −0.3 ± 13.6, and 5.1 ± 12.3 mmHg with exenatide QMS 5, 8, and 11 mg, respectively. Changes in DBP were −1.8 ± 8.7 mmHg with exenatide QW and 2.8 ± 8.2, 1.6 ± 9.7, and 2.0 ± 8.3 mmHg with exenatide QMS 5, 8, and 11 mg, respectively. However, the variable changes in BP may have been confounded by different baseline values (Table 2) and changes in background antihypertensive medications. The final BP values were similar across the four treatment groups.
Treatment satisfaction scores for the DTSQs numerically improved with all treatments. Baseline DTSQs total scores (scale 0–36) were 26.7 ± 6.2 with exenatide QW and 26.5 ± 6.1, 28.0 ± 6.4, and 27.4 ± 5.9 with exenatide QMS 5, 8, and 11 mg, respectively. DTSQs total scores at week 20 increased and were similar across treatments (exenatide QW: 31.2 ± 4.7; exenatide QMS 5 mg: 30.2 ± 6.2; exenatide QMS 8 mg: 29.2 ± 6.2; and exenatide QMS 11 mg: 29.4 ± 7.2).
Although exenatide QW displayed initial release of exenatide within the first few hours of administration, exenatide concentrations with all exenatide QMS doses rose gradually during the first 8 h after administration (Fig. 2A). Exenatide concentrations with exenatide QMS progressively increased from baseline through ∼6 weeks, when steady-state concentrations were achieved; the PK profiles demonstrated that exenatide concentrations were not dose proportional (Fig. 2B and Supplementary Table 3). Increasing the dosing interval to once monthly resulted in greater peak-to-trough variation at steady state, with little exenatide accumulation compared with exenatide QW. Exenatide concentrations approached undetectable levels 8 weeks after the last injection with exenatide QMS, similar to the time frame of ∼10 weeks for drug elimination previously established with exenatide QW.
Safety and Tolerability
The incidence of AEs overall ranged from 64.5 to 90.0% (Table 2), most of which were mild to moderate in intensity. There were no deaths. Two serious AEs were reported—both in the QMS groups—that were both severe: acute coronary syndrome (exenatide QMS 5 mg) and acute myocardial infarction (exenatide QMS 11 mg). The patient with acute coronary syndrome remained on treatment, but the patient with the acute myocardial infarction withdrew consent and discontinued treatment. A nonserious vomiting AE of moderate intensity in a patient who received exenatide QMS 11 mg led to study withdrawal.
Patients treated with exenatide QMS 11 mg had a higher incidence of any gastrointestinal AE (60.0%) compared with exenatide QMS 5 mg (33.3%), exenatide QMS 8 mg (32.3%), and exenatide QW 2 mg (36.7%). Most gastrointestinal AEs were mild to moderate in intensity and generally resolved within a few days of onset. Although variable, incidences of diarrhea, nausea, and vomiting with exenatide QMS doses generally peaked by week 8 (Supplementary Fig. 3). Among patients receiving exenatide QMS, the most frequently observed AEs were headache and nausea, whereas headache and diarrhea were the most commonly observed AEs with exenatide QW (Table 2).
The overall incidence of injection-site–related AEs with exenatide QMS did not appear to be dose related (Table 2). The most commonly reported injection-site–related AEs were pruritus and erythema; incidences of these AEs were less with all doses of exenatide QMS compared with exenatide QW. All injection-site–related AEs were mild in intensity, and most resolved within 7 days. The total number of injection-site–related AEs was less in each exenatide QMS group (5 mg: n = 10; 8 mg: n = 3; 11 mg: n = 10) compared with exenatide QW (n = 27); none led to study discontinuation.
Patient feedback on injection-site nodules was solicited using a three-item survey to determine whether the larger volume of injectate with exenatide QMS had translated into larger nodules. Nodules were commonly reported at week 20 (83.3% [exenatide QW] and 80.8%, 79.3%, and 89.3% [exenatide QMS 5, 8, and 11 mg, respectively] of patients) and were usually <1 cm in diameter (60.0% [exenatide QW] and 76.2%, 60.9%, and 72.0% [exenatide QMS 5, 8, and 11 mg, respectively]). Patients generally described nodules as “small bumps” (20.0% [exenatide QW] and 28.6%, 30.4%, and 32.0% [exenatide QMS 5, 8, and 11 mg, respectively]), “small beads under the skin” (16.0% [exenatide QW] and 28.6%, 26.1%, and 20.0% [exenatide QMS 5, 8, and 11 mg]), and “small raised bumps under the skin” (20.0% [exenatide QW] and 23.8%, 8.7%, and 16.0% [exenatide QMS 5, 8, and 11 mg]).
Safety outcomes were generally similar with exenatide QW and all doses of exenatide QMS. No major or minor hypoglycemia AEs occurred; one patient treated with exenatide QMS 5 mg reported a mild symptom of hypoglycemia. Across all treatment groups at week 20, 10 of 114 patients (8.8%) had abnormal pancreatic amylase values and 36 of 114 (31.6%) had abnormal lipase values; incidences of each were similar among the exenatide QW group and the QMS groups (Supplementary Table 4). There was one instance of elevated calcitonin (exenatide QMS 5 mg). Heart rate increased with exenatide QW (mean 2.8 bpm) and exenatide QMS 5 and 8 mg (3.9 and 5.6 bpm, respectively), but decreased slightly with exenatide QMS 11 mg (−0.3 bpm). There were no cases of pancreatitis, altered renal function, or thyroid neoplasms.
Antibodies to exenatide with exenatide QMS were generally comparable to those with exenatide QW (Supplementary Table 5). At week 20, anti-exenatide antibodies were present in 76.7% of patients treated with exenatide QW and in 69.2%, 69.0%, and 67.9% of those treated with exenatide QMS 5, 8, and 11 mg, respectively.
Medication adherence is often an issue among patients with chronic diseases such as type 2 diabetes. A once-monthly treatment administered by caregivers may be simpler and more convenient for patients and may improve compliance—and physician knowledge of compliance—compared with once-weekly or daily medications. However, less frequent dosing may be difficult to remember for some patients. Injectable therapies for diabetes are available for daily or weekly administration. Although no therapies with less frequent dosing are currently available, once-monthly or greater than once-monthly therapies (e.g., ITCA 650 implant) (13) are under investigation. This study examined the efficacy, PK, and safety and tolerability of three doses of an exenatide QMS formulation compared with an exenatide QW reference group.
Exenatide QW and all doses of exenatide QMS improved glycemic and body weight outcomes. Each exenatide QMS dose and exenatide QW resulted in clinically meaningful reductions in HbA1c, with no significant differences among the exenatide QMS doses. Depending on the dose, an equivalent or numerically greater proportion of patients treated with exenatide QMS achieved HbA1c <7.0% (<53 mmol/mol) compared with exenatide QW. Exenatide QW and all doses of exenatide QMS reduced FPG as early as week 4, consistent with the early response reported for a pooled population of patients receiving exenatide QW (14).
Weight loss occurred with exenatide QMS, beginning at week 6, whereas exenatide QW reduced weight as early as week 2, with further reductions observed over 20 weeks. Weight loss with exenatide QMS 5 and 11 mg was similar to that with exenatide QW and comparatively lower than that with exenatide QMS 8 mg. The relationship between weight loss and PK characteristics, such as average exposure and time over a threshold value, is complex. The 4-week exposure dynamic for the exenatide QMS may have altered the effect on body weight compared with exenatide QW. Alternatively, numerical differences in weight loss may be an artifact of the small sample size.
The microspheres manufactured for the QW formulation by incorporating exenatide into biodegradable poly(D,L-lactide-coglycolide) (8) were provided in QMS doses (5, 8, and 11 mg) that were less than, equal to, or greater than four injections of exenatide QW (8 mg). Exenatide QMS doses were selected to target exenatide exposures known to be therapeutic when administered QW and feasible for injection, not to define the exposure-response curve. Dose-response studies for drugs dispersed in microspheres are complicated by the need to limit injection volume while maintaining suitable dispersion for injection. The higher microsphere mass (higher exenatide doses) needed to more fully define a dose-response curve would have been impractical owing to a high injection volume or to dispersion issues affecting injectability.
Plasma exenatide concentrations progressively increased from baseline through week 6, when steady-state concentrations were reached across exenatide QMS doses. Exenatide QMS 8 and 11 mg achieved average steady-state concentrations similar to those observed with exenatide QW and within the range previously demonstrated to improve glycemic control (15,16), whereas exenatide concentrations were slightly lower with exenatide QMS 5 mg. Although exenatide exposure over time was less consistent compared with exenatide QW, concentrations above the therapeutic threshold for glycemic effects (∼50 pg/mL) (15) were achieved and sustained with monthly dosing. Similar steady-state concentrations for the three exenatide QMS doses likely explain the flat dose-response curve and relatively flat tolerability curve observed.
Preliminary PK and pharmacodynamic analyses with exenatide QW have suggested that weight reductions occur at a higher concentration of exenatide (change in body weight half-maximal effective concentration: 184 pg/mL) compared with changes in FPG (half-maximal effective concentration: 57 pg/mL) (15). In addition, weight loss with exenatide exposure may be expected to lag behind reductions in FPG because the physiology of weight loss is more gradual than that of FPG reductions.
Overall, the tolerability profile for exenatide QMS was similar to the exenatide QW reference group and consistent with the established profile for exenatide QW (17–22). Headache and gastrointestinal AEs were the most commonly reported AEs with exenatide QW and exenatide QMS. Nausea was more common with exenatide QMS than with exenatide QW and progressively increased across exenatide QMS doses. Vomiting occurred more frequently with exenatide QMS 8 and 11 mg than with exenatide QW. The incidence of diarrhea increased progressively across exenatide QMS doses but was less than the incidence with exenatide QW. For both exenatide QW and QMS formulations, microsphere technology allows for the natural titration of exenatide over time, and the lower initial exposure of exenatide has been postulated to explain the lower rates of nausea and vomiting with exenatide QW versus exenatide twice daily (18,21). Fewer gastrointestinal AEs at early times with exenatide QMS compared with exenatide QW may have been related to less of an initial burst of exenatide release. Thus, natural titration with the exenatide QMS may also improve tolerability compared with daily GLP-1RA treatments such as exenatide twice daily. In addition, although more microspheres were injected, fewer injections appeared to lessen injection-site issues with exenatide QMS compared with exenatide QW. As reported in previous exenatide QW studies (23), anti-exenatide antibodies developed in some patients but were generally comparable among proportions of patients in the exenatide QMS and QW groups.
Changes in BP and heart rate varied across treatment groups. The variable changes in BP may have been confounded by different baseline values and changes in antihypertensive medications; in contrast, the final BP values were similar across all groups. Consistent with previous trials (24), patients receiving exenatide QW exhibited an increase in heart rate (mean 2.8 bpm); there were also increases in heart rate with exenatide QMS 5 and 8 mg (3.9 and 5.6 bpm, respectively).
Treatment satisfaction improved with exenatide QW and all exenatide QMS doses. Once-monthly dosing offers flexibility because delaying or moving up dosing by a few days is unlikely to affect efficacy and safety. Furthermore, there is the potential for improved treatment compliance and adherence, with the possibility for receiving treatments during monthly office visits. A recent retrospective cohort study based on administrative claims examined adherence to GLP-1RAs among patients with type 2 diabetes initiating exenatide QW, exenatide twice daily, or liraglutide (25). After 6 months, significantly greater proportions of patients initiating exenatide QW achieved adherence rates ≥80% and ≥90% compared with patients initiating exenatide twice daily or liraglutide. The authors hypothesized that the reduced frequency of injections with exenatide QW was associated with better adherence.
The major limitation of this study was the small sample size (n = 26–29 per treatment group), which may limit the broad applicability of the results. Furthermore, the study was not powered for exenatide QW to be used as a comparator rather than as a reference group. In addition, the identity of the study medication was not blinded, although patients and investigators were blinded to the exenatide QMS doses tested. A limited range and number of doses were tested because the dose of exenatide (microsphere mass) to be tested was modeled from previous exposure data with exenatide QW. Furthermore, progressively increased (titrated) doses to improve tolerability were beyond the scope of this study. The exenatide concentration profiles were variable, likely a result of intrinsic PK variability. No meal testing was done to examine postprandial glucose profiles or gastric emptying with extended dosing. Finally, BP assessment was not automated, and meters were not calibrated, which may have introduced variability in that end point.
In conclusion, all three doses of the exenatide QMS resulted in steady-state exenatide concentrations previously demonstrated to improve glycemic control, with resulting efficacy and tolerability profiles that appeared consistent with those observed with exenatide QW. The results of this study combined with PK and pharmacodynamic modeling could inform the dose selection for further development.
Acknowledgments. Brenda Cirincione of Bristol-Myers Squibb provided further interpretation of the PK results. Amanda L. Sheldon of inScience Communications, Springer Healthcare, provided medical writing support funded by AstraZeneca. Mary Beth DeYoung of AstraZeneca critically reviewed the manuscript.
Funding. This study was supported by Amylin Pharmaceuticals and Bristol-Myers Squibb, and the development of the manuscript was supported by AstraZeneca.
Duality of Interest. C.H.W. is a speaker and/or advisor for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. L.M. was an employee of Amylin and Bristol-Myers Squibb at the time the research was conducted. E.H. is an employee and stockholder of AstraZeneca.
Author Contributions. C.H.W. interpreted the data and reviewed and edited the manuscript. L.M. designed the study, supervised acquisition and analysis of the data, interpreted the data, and reviewed and edited the manuscript. E.H. interpreted the data and reviewed and edited the manuscript. L.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. This study was presented at the 71st Scientific Sessions of the American Diabetes Association, San Diego, CA, 24–28 June 2011, and at the 47th European Association for the Study of Diabetes Annual Meeting, Lisbon, Portugal, 12–16 September 2011.
Clinical trial reg. no. NCT01104701, clinicaltrials.gov.
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc16-0238/-/DC1
This article is featured in a podcast available at http://www.diabetesjournals.org/content/diabetes-core-update-podcasts.
L.M. is currently affiliated with Intercept Pharmaceuticals, San Diego, CA
- Received February 3, 2016.
- Accepted July 4, 2016.
- © 2016 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.