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Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes mellitus. Exenatide acts by binding to and activating glucagon-like peptide-1 receptors, thereby stimulating glucose-dependent insulin secretion, suppressing glucose-dependent glucagon secretion, slowing gastric emptying, and increasing feelings of satiety. Gradual increases in drug level (“autotitration”) after the initiation of a fixed exenatide 2-mg weekly dose achieve minimal effective (~50 pg/mL) and steady-state (~300 pg/mL) concentrations by 2 weeks and 6 to 8 weeks, respectively. The purpose of this study was to examine pharmacodynamic outcomes with exenatide once weekly and to determine whether changes are secondary to weight loss and thus delayed by the sequential nature of responses.
Methods
This post hoc analysis evaluated trials in the exenatide once-weekly development program. Outcomes included glycosylated hemoglobin (HbA1c), weight, fasting serum or plasma glucose (FG), lipids, and blood pressure (BP) at weeks 2, 4, and 24. Relationships between changes from baseline in these outcomes and changes in weight were examined. The effect of nausea and vomiting (adverse events characteristic of GLP-1RAs) on weight loss was also assessed.
Findings
Pooled data were analyzed from 12 trials in which 2190 patients received exenatide once weekly. Patients had a mean HbA1c level of 8.4% and weight of 87 kg at baseline. Exenatide once weekly produced significant improvements in HbA1c, FG, weight, and systolic BP at weeks 2 and 4, with continuous improvements through week 24. There were no clinically meaningful correlations between weight loss and improvements in pharmacodynamic outcomes at weeks 2, 4, or 24. Patients had significant reductions in weight at weeks 2, 4, and 24 regardless of whether they experienced nausea and/or vomiting during the study, although patients with at least 1 nausea/vomiting event had greater weight loss at week 24 than those who did not.
Implications
Improvements in pharmacodynamic end points occurred early in treatment with exenatide once weekly, before steady-state plasma concentrations. These early effects did not seem to be secondary to weight loss and are likely the direct effects of exenatide.
Sustained metabolic control has been shown to minimize complications in type 2 diabetes mellitus (T2DM). However, reduction in hyperglycemia early after treatment initiation is reassuring to physicians and patients, providing evidence that the chosen therapy is effective. Thus, treatment is also geared toward rapid reduction in hyperglycemia and control of cardiometabolic risk factors such as lipids and blood pressure (BP).
Although long-term glycemic control is important to prevent complications of T2DM, a rapid response to therapy is also reassuring to physicians and patients. Early response helps build patients’ confidence that the medication is working, and patients’ perception that the treatment is worthwhile may help empower them to continue therapy.
However, because T2DM is a chronic disease, the use of therapies that deliver robust responses which are sustained over the long term is of greater benefit to patients than a rapid response. Moreover, having realistic expectations about the timing of anticipated therapeutic benefits is important to prevent wrong treatment decisions such as premature switching of treatment. Exenatide once weekly has demonstrated durable long-term benefits, with glucose-lowering effects sustained for several years in long-term studies.
Compared with the time course of response to thiazolidinediones and dipeptidyl peptidase-4 inhibitors, glycemic and weight responses with exenatide once weekly have been shown to occur early after treatment initiation.
Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial.
Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study.
However, because exenatide once-weekly microspheres release exenatide gradually, there has been a perception that the onset of efficacy may be too slow and that the efficacy may be dependent on weight loss. Therefore, more information is needed about the rate of onset of exenatide once-weekly therapy, and establishing whether there is a correlation between weight loss and early therapeutic outcomes is of crucial interest.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are injectable glucose-lowering medications approved as an adjunct to diet and exercise for the treatment of adults with T2DM. Agents in the GLP-1RA class bind to and activate glucagon-like peptide-1 (GLP-1) receptors, thereby producing effects similar to those of endogenous GLP-1, including stimulating glucose-dependent insulin secretion, suppressing glucose-dependent glucagon secretion, slowing gastric emptying, and increasing feelings of satiety.
Because these agents act by supplementing endogenous GLP-1 activity, treatment with high concentrations of GLP-1RAs can produce stronger effects compared with dipeptidyl peptidase-4 inhibitors, which act by inhibiting proteolytic cleavage of endogenous GLP-1 and produce only 2- to 3-fold increases in plasma GLP-1 concentrations.
Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study.
GLP-1RAs offer effective glycemic control with the added benefits of weight loss, a low risk of hypoglycemia, and positive effects on cardiovascular risk factors.
Exenatide is a GLP-1RA that is available for administration as a BID and a once-weekly formulation. In the once-weekly formulation, exenatide is encapsulated in poly-(D, L-lactide-co-glycolide) microspheres and released from these microspheres in a 3-stage process (initial release, diffusion release, and erosion release), resulting in continuous delivery of exenatide.
Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes.
Due to the long release of exenatide from the microsphere depots for up to 10 weeks, drug concentrations accumulate with subsequent injections. Exenatide once weekly achieves the minimal effective concentration (~50 pg/mL) for glucose lowering with regular once-weekly dosing in 2 weeks, and steady-state plasma concentrations (~300 pg/mL) are reached in 6 to 8 weeks.
Therefore, most GLP-1RAs are initiated at a low dose, with subsequent dose increases to improve tolerability (“titration”). With exenatide once-weekly administration, the concentration of exenatide increases with autotitration and reaches steady-state plasma levels in 6 to 8 weeks, and the risk of gastrointestinal adverse events has been found to be reduced compared with BID dosing.
Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes.
Understanding the balance between the robust and sustained effects of exenatide once weekly and tolerability during initiation of therapy is an important consideration for patients and health care providers.
In randomized controlled studies of 24 to 30 weeks and extensions up to 6 years, exenatide once weekly has been shown to improve glycemic control, reduce excess body weight, and improve cardiovascular risk markers, including BP and lipids.
However, the time courses of these changes may not be identical. Because glycemic control and cardiovascular risk markers can be improved by weight loss alone, the relationship of weight loss with efficacy outcomes is of interest.
The current post hoc analysis was designed to: (1) characterize the early therapeutic response to exenatide once weekly and thus inform patient and physician expectations for clinical practice; and (2) examine whether early improvements in pharmacodynamic outcomes are secondary to weight loss or are direct effects.
2. Patients and Methods
This post hoc analysis considered pooled data from 11 randomized, placebo- or active comparator–controlled trials and 1 single-arm study from the exenatide once-weekly development program. Pharmacodynamic outcomes were defined after 2, 4, and 24 weeks of exenatide once-weekly treatment, and the correlations between changes in these outcomes and weight loss were examined. The relationship between the occurrence of nausea and vomiting (adverse events characteristic of the GLP-1RA class) and weight loss was also assessed.
Detailed information on study designs and patient eligibility for individual trials has been published previously.
Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial.
Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study.
DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes.
Once-weekly exenatide versus once- or twice-daily insulin detemir: randomized, open-label, clinical trial of efficacy and safety in patients with type 2 diabetes treated with metformin alone or in combination with sulfonylureas.
Efficacy and safety profile of exenatide once weekly compared with insulin once daily in Japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter, noninferiority study.
Safety of exenatide once weekly in patients with type 2 diabetes mellitus treated with a thiazolidinedione alone or in combination with metformin for 2 years.
In these studies, patients with T2DM received exenatide once weekly as monotherapy or as an add-on to metformin, a sulfonylurea, or a thiazolidinedione for treatment durations of 10 to 52 weeks.
2.1 Statistical Analyses
Descriptive statistics were used to report baseline demographic characteristics and patient characteristics, with continuous variables described as mean (SD). Pharmacodynamic outcomes assessed included glycosylated hemoglobin (HbA1c), fasting glucose (FG; determined from plasma or serum), weight, lipids (total cholesterol, LDL-C, and HDL-C, and triglycerides), and BP. For each outcome, the mean (SE) change from baseline was calculated at weeks 2, 4, and 24. Ninety-five percent CIs for the mean changes from baseline at each time point were derived, and an inference on statistical significance at α = 0.05 level was made. For each outcome, the proportion of patients achieving any amount of improvement (ie, change from baseline >0 for HDL-C or <0 for other outcomes) was calculated for patients with available measurements at weeks 2, 4, and 24. Changes from baseline in body weight (mean [SE] and 95% CI) were also calculated at weeks 2, 4, and 24 for patients who experienced at least 1 nausea or vomiting event during the study period and for those who did not.
The association between change from baseline for each outcome and change from baseline in body weight was examined by using the Pearson coefficient of correlation (r) at each time point (weeks 2, 4, and 24).
3. Results
3.1 Patient Demographic and Baseline Characteristics
The pooled analysis included 2190 patients treated with exenatide once weekly in 12 clinical trials. At baseline, patients had a mean age of 55 years, and 56.7% were male (Table I). Patients had a mean HbA1c level of 8.4% and weight of 87.1 kg; the mean duration of diabetes was 7 years.
Exenatide once weekly resulted in statistically significant improvements from baseline in HbA1c, FG, weight, and systolic BP by weeks 2 and 4, and further improvements were observed at week 24.
There were modest but statistically significant reductions from baseline in HbA1c levels at weeks 2 and 4 (–0.3% and –0.4%, respectively); by week 24, the mean (SE) change from baseline in HbA1c was −1.4% (0.03%) (P < 0.05) (Figure 1A). At weeks 2 and 24, 70.8% and 91.5% of patients, respectively, had reductions in HbA1c (Figure 2).
Figure 1Mean (SE) changes from baseline in (A) glycosylated hemoglobin (HbA1c), (B) fasting glucose (FG) from plasma or serum, (C) weight, and (D) blood pressure. *P < 0.05 versus baseline. DBP = diastolic blood pressure; SBP = systolic blood pressure.
Figure 2Patients experiencing improvement in pharmacodynamic parameters. *Any amount of improvement (ie, change from baseline >0 for HDL-C or <0 for other parameters). †Calculated as percentage of patients for whom data were available for this parameter at each time point. DBP = diastolic blood pressure; FG = fasting glucose; HbA1c = glycosylated hemoglobin; SBP = systolic blood pressure; TC = total cholesterol; TG = triglycerides.
FG decreased from baseline by week 2 (mean [SE] change, −0.9 [0.1] mmol/L; P < 0.05) and continued to decrease, with a change at week 4 of −1.6 (0.1) mmol/L (P < 0.05) and a final change from baseline at week 24 of −2.1 (0.1) mmol/L (P < 0.05) (Figure 1B). At weeks 2 and 24, 75.2% and 84.3% of patients, respectively, had reductions in FG (Figure 2).
At weeks 2, 4, and 24, 55.5%, 61.5%, and 74.4% of patients, respectively, had reductions in weight (Figure 2). Initial early weight loss was −0.3 kg at week 2 and −0.6 kg at week 4; by week 24, the mean (SE) change in weight was −2.4 (0.08) kg (all, P < 0.05 vs baseline) (Figure 1C).
There were small reductions from baseline in total cholesterol and LDL-C at each time point, which were statistically significant (P < 0.05) at weeks 4 and 24 (Table II). However, there was no significant change from baseline in HDL-C or triglyceride levels at any time point. At weeks 2, 4, and 24, approximately one half of patients had improvements in lipid parameters (Figure 2).
Table IIChange from baseline in lipid levels. Data are mean (SE) unless noted otherwise.
Significant reductions in systolic BP were apparent at weeks 2 and 4, and systolic BP continued to decrease over 24 weeks (Figure 1D). There were lesser reductions in diastolic BP at each time point. At week 2, 51.1% of patients had some degree of reduction in systolic BP, with the proportion increasing slightly to 54.9% at week 24 (Figure 2).
3.3 Correlations Between Efficacy Outcomes and Weight Loss
There were no clinically meaningful correlations observed between weight loss and changes in HbA1c, FG, and systolic BP at weeks 2, 4, and 24 (r ≤ 0.1489) (Figures 3A–3C). There were also no significant correlations between weight loss and changes in diastolic BP, HDL-C, LDL-C, total cholesterol, or triglycerides at weeks 2, 4, or 24.
Figure 3At weeks 2, 4, and 24, coefficients for the correlation between change from baseline in weight and change from baseline were (A) 0.0908, 0.0411, and 0.1489, respectively, for glycosylated hemoglobin (HbA1c), (B) 0.1326, 0.0227, and 0.1429 for fasting glucose (FG), and (C) 0.0803, 0.1209, and 0.1359 for systolic blood pressure (SBP).
Nausea and vomiting events occurred in 4.0% to 7.0% and 0.7% to 2.0% of patients, respectively, during any 2-week interval between baseline and week 24. Significant reductions in weight from baseline occurred at weeks 2, 4, and 24, regardless of whether patients experienced nausea/vomiting (Figure 4). However, patients who experienced at least 1 nausea/vomiting event had greater weight loss at week 24 than those with no events (–3.1 vs –2.2 kg; P < 0.05).
Figure 4Mean (SE) change from baseline in weight in patients with and without nausea and/or vomiting events. *P < 0.05 versus baseline; †P < 0.05 versus no nausea/vomiting.
In this pooled analysis, exenatide once weekly resulted in significant improvements in HbA1c, FG, weight, and systolic BP by weeks 2 and 4, and further improvements were observed at week 24. Furthermore, approximately one half of the patients achieved improvements in lipid parameters at weeks 2, 4, and 24. The time to therapeutic response with exenatide once weekly in this analysis was comparable with those seen with pioglitazone,
Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study.
Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group.
Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study.
; for each of these agents, reductions in glycemic parameters were observed soon after treatment initiation, with the full effect achieved after 2 to 3 months with dose titrations.
Improvements in glycemic outcomes did not correlate with weight loss at the studied time points. This finding suggests that improvements were likely due to a direct effect of exenatide. Early improvements in glycemic control are consistent with the pharmacokinetics of exenatide once weekly, whereby the minimally effective concentration (~50 pg/mL) for reducing FG levels is exceeded within 2 weeks and steady-state concentrations are achieved in 6 to 8 weeks.
It has been postulated that greater weight loss is related to nausea and vomiting among some patients receiving GLP-1RA therapy. In the current analysis, patients who experienced nausea/vomiting had significantly greater weight loss than those with no nausea/vomiting at week 24. However, both groups had significant reductions in weight with exenatide once-weekly treatment at weeks 2, 4, and 24. These findings concur with those of a post hoc analysis of pooled data from 3 trials (DURATION-1 [Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly], DURATION-5, and NCT00917267) and a separate analysis of the DURATION-6 trial.
Upper and/or lower GI adverse events with long- vs short-acting GLP-1 receptor agonists: incidence, co-incidence, effects on HbA1c and weight [abstract].
In these analyses, reductions in weight after 26 weeks of treatment with exenatide once weekly occurred in patients with no gastrointestinal adverse events; however, reductions were significantly greater for patients with upper gastrointestinal events compared with patients with no gastrointestinal events.
The current results suggest that clinical efficacy, including glycemic effects, of exenatide once weekly occurs well before steady-state plasma concentrations are achieved, with effects seen from week 2 onward. Similarly, a recent post hoc analysis of the DURATION-5 trial demonstrated that improvements in HbA1c, FG, and weight occurred by week 4, before exenatide concentrations reached steady state.
Although small weight reductions were apparent early after treatment initiation (at weeks 2 and 4) in the DURATION-5 trial, weight reductions occurred more gradually than glycemic responses, consistent with the current results. The results from the current analysis are also in line with modeling analyses of exenatide once weekly, showing that weight reductions occurred at a higher exenatide plasma concentration (change in weight half-maximal effective concentration, 184 pg/mL) compared with changes in FG (change in weight half-maximal effective concentration, 57 pg/mL).
Association among weight change, glycemic control, and markers of cardiovascular risk with exenatide once weekly: a pooled analysis of patients with type 2 diabetes.
The analysis included 1830 patients treated with exenatide once weekly, in which improvements in glycemic and cardiovascular parameters were independent of changes in weight; however, the analysis found that the magnitude of improvements increased with higher degrees of weight loss. It is possible that weight loss enhances efficacy over longer durations of therapy.
Exenatide once weekly has demonstrated sustained efficacy in an extension of the DURATION-1 trial and in 3-year data from the randomized controlled DURATION-3 trial.
In the DURATION-1 trial, reductions in HbA1c levels with exenatide once weekly were maintained for up to 5 years in published studies, with recent data showing sustained reductions at 6 years (least squares mean reduction of −1.6% at both 5- and 6-year follow-up).
Compared with titrated insulin glargine, exenatide once weekly achieved and maintained significantly greater reductions in HbA1c and FG over 3 years of follow-up in the DURATION-3 trial.
Reductions in weight, lipids, and BP were also sustained after 3 years of treatment with exenatide once weekly.
Improving cardiovascular biomarkers is an important goal in managing T2DM, as controlling cardiovascular risk factors has been shown to prevent or slow cardiovascular disease in patients with T2DM.
Furthermore, long-term, intensified interventions aimed at multiple cardiovascular risk factors have been shown to reduce cardiovascular and microvascular events by ~50%.
Thus, glucose-lowering agents with the potential to improve cardiovascular risk markers provide additional benefits beyond glycemic control. In this post hoc analysis, improvements in some cardiovascular risk factors with exenatide once weekly were minimal but may contribute to the overall goal of reducing cardiovascular risk in these patients.
Overall, this study included data from a large number of patients across 12 clinical trials. Analyzing clinical trial data provides the advantage of systematically collected and measured patient data, which can be difficult to collect in a real-world setting. Improvements in glycemic control and other pharmacodynamics outcomes are also associated with weight loss, and the range of data collected in the clinical trials permitted analysis of whether any of the observed changes correlated with changes in weight from baseline. The study also carries the limitations inherent to post hoc pooled analyses in that these analyses were not specified at the time the included clinical trials were designed; thus, data were not necessarily collected for the full study population for every end point and assessment time or using uniform methods. In addition, some studies were open-label due to the different delivery of comparator agents (ie, oral vs injectable). Another limitation is the absence of data exploration for comparator treatments, which could limit the interpretation of the results. Furthermore, for most outcomes except weight and BP, the number of patients with measures at week 2 was relatively smaller, with larger numbers seen at the week 4 and week 24 analyses. Another limitation was the inclusion of nonuniform studies in the analysis. One study included only treatment-naive patients,
Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study.
DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes.
and the remainder required patients to have experience with at least 1 other glucose-lowering therapy. A limitation of the correlation analyses was that the range of changes was narrow, making it more difficult to identify a linear correlation.
5. Conclusions
This post hoc analysis showed that exenatide once-weekly treatment demonstrated early, statistically significant improvements in glycemia, weight, and systolic BP, documenting the onset of effects before steady-state plasma exenatide concentrations, and that improvements in clinical outcomes were not correlated with weight loss. These findings suggest that exenatide once weekly exerts direct actions on glycemic outcomes and systolic BP within the first 2 to 4 weeks of treatment. The multiple actions of exenatide may assist patients with T2DM in reaching the various goals recommended by international associations.
Conflicts of Interest
Dr. Trautmann has served as a consultant for AstraZeneca, Merck, and Servier and is a shareholder of Eli Lilly. Ms. Han is an employee of Pharmapace, Inc. Dr. Ruggles is an employee of AstraZeneca. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
Acknowledgments
The study and development of the manuscript were supported by AstraZeneca. Wenying Huang of Pharmapace, Inc, provided initial statistical support. Raewyn M. Poole and Amanda L. Sheldon, PhD, of inScience Communications, Springer Healthcare, provided medical writing support, which was funded by AstraZeneca. The authors thank all study patients and study teams for their participation in the clinical trials.
Drs. Trautmann and Ruggles participated in the conception and design of the study analysis plan, interpretation of the data, and drafting and critically revising of the manuscript. Ms. Han developed the statistical analysis plan, analyzed and interpreted the data, and participated in drafting and critically revising the manuscript. All authors approved the final version of the manuscript for submission.
References
Trujillo J.M.
Nuffer W.
GLP-1 receptor agonists for type 2 diabetes mellitus: recent developments and emerging agents.
Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial.
Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study.
Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study.
Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes.
DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes.
Once-weekly exenatide versus once- or twice-daily insulin detemir: randomized, open-label, clinical trial of efficacy and safety in patients with type 2 diabetes treated with metformin alone or in combination with sulfonylureas.
Efficacy and safety profile of exenatide once weekly compared with insulin once daily in Japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter, noninferiority study.
Safety of exenatide once weekly in patients with type 2 diabetes mellitus treated with a thiazolidinedione alone or in combination with metformin for 2 years.
Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group.
Upper and/or lower GI adverse events with long- vs short-acting GLP-1 receptor agonists: incidence, co-incidence, effects on HbA1c and weight [abstract].
Association among weight change, glycemic control, and markers of cardiovascular risk with exenatide once weekly: a pooled analysis of patients with type 2 diabetes.
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