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Long-term Efficacy and Safety of Exenatide Treatment
LETTERS TO THE EDITOR
Long-term Efficacy and Safety of Exenatide Treatment To the Editor: We read with interest the article by Wysham et al1 describing the 5-year efficacy and safety of once-weekly exenatide. Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment in the Diabetes Therapy Utilization: Research Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial. The research determined that 2 mg of exenatide injected subcutaneously once weekly could significantly reduce hemoglobin A1c levels from baseline, and 43.9% of patients achieved hemoglobin A1c levels of less than 7.0%. Fasting plasma glucose level also significantly improved. We agree with the authors that long-term once-weekly exenatide treatment produced sustained glycemic improvement. However, the study had a high dropout rate: nearly 40% of the patients did not complete the study. The result of this study may be limited to only those patients who can tolerate the adverse effects of exenatide and not to all patients who have type 2 diabetes. Nausea, vomiting, and diarrhea are common adverse effects when patients start treatment with exenatide. High rates of patients who were lost to followup could bias the results. Applying intent-to-treat analysis (as employed by the authors) is also problematic when a large proportion of participants drop out. Treatment effect could be underestimated or overestimated. Moreover, intent-to-treat analysis can also hide problems related to the way in which large dropout data are handled. We strongly agree with the authors that exenatide treatment can have continued efficacy over a long period of time. However, clinical
1304
efficacy may be limited to those patients who can tolerate exenatide treatment long term. Future research that employs a randomized controlled trial design can confirm the long-term patient acceptance, clinical benefit, and safety of exenatide treatment. Sakkarin Chirapongsathorn, MD Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN Division of Gastroenterology Department of Medicine Phramongkutklao Hospital and College of Medicine Royal Thai Army Bangkok, Thailand
Pimjai Anthanont, MD Division of Endocrinology, Mayo Clinic, Rochester, MN
1. Wysham CH, MacConell LA, Maggs DG, Zhou M, Griffin PS, Trautmann ME. Five-year efficacy and safety data of exenatide once weekly: long-term results from the DURATION-1 randomized clinical trial. Mayo Clin Proc. 2015;90(3):356-365. http://dx.doi.org/10.1016/j.mayocp.2015.06.004
In replydLong-term Efficacy and Safety of Exenatide Treatment We appreciate the interest of Drs Chirapongsathorn and Anthanont in our article on the efficacy and safety of exenatide once weekly at 5 years in patients with type 2 diabetes. They appropriately point out the withdrawal rate of approximately 40% during our long-term study. We contend that this withdrawal rate is not unexpected for a clinical trial conducted over 5 years of follow-up, and, in addition, results reported at 6 years of follow-up reveal that a large proportion of patients remained in the study even longer. During the 5-year extension phase, only 3.7% of the intent-to-treat (ITT) population discontinued the study because of adverse events (4.3% of those who entered the
open-label extension). Similar proportions of patients were lost to follow-up or withdrawn due to investigator decision. Approximately 20% of the ITT population withdrew consent during the extension phase, which again is not a surprise in a long-term study such as this. Very few patients withdrew during the open-label extension phase because of loss of glucose control, which is impressive considering the challenges in maintaining glucose control over an extended period with any medication. Although most patients added concomitant antidiabetes medications during the extension phase, the results speak to the durability of response with exenatide as part of the long-term management of the disease. The 60% completion rate at 5 years is higher than or comparable to those observed in other studies involving glucagon-like peptide-1 receptor agonists (approximately 50% completion rate at 2 years for liraglutide1 and 54%-65% at 3 years for albiglutide2-4). Drs Chirapongsathorn and Anthanont comment that patient discontinuation could bias the results, a point that we acknowledge in the “Discussion” section of our article. However, we consider the completion rate to be high relative to the length of the study, and, as we also noted in the “Discussion,” this high completion rate indicates that treatment with exenatide once weekly was well tolerated and perceived as efficacious. Regarding the suggestion that the results may be limited to only those who can tolerate the adverse effects of exenatide, the rate of discontinuation due to adverse events was low in both the initial controlled phase (5.4%6.1%) and the extension phase (3.7%), consistent with other large clinical trials of exenatide. The limitations segment of our article already points out that the “completer population may represent a subset of patients who responded well to treatment” (which would be the same as for any longer-term extension study), and notes that significant effects
Mayo Clin Proc. n September 2015;90(9):1304-1309 n http://dx.doi.org/10.1016/j.mayocp.2015.06.005 www.mayoclinicproceedings.org n ª 2015 Mayo Foundation for Medical Education and Research
Long-term Efficacy and Safety of Exenatide Treatment To the Editor: We read with interest the article by Wysham et al1 describing the 5-year efficacy and safety of once-weekly exenatide. Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment in the Diabetes Therapy Utilization: Research Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial. The research determined that 2 mg of exenatide injected subcutaneously once weekly could significantly reduce hemoglobin A1c levels from baseline, and 43.9% of patients achieved hemoglobin A1c levels of less than 7.0%. Fasting plasma glucose level also significantly improved. We agree with the authors that long-term once-weekly exenatide treatment produced sustained glycemic improvement. However, the study had a high dropout rate: nearly 40% of the patients did not complete the study. The result of this study may be limited to only those patients who can tolerate the adverse effects of exenatide and not to all patients who have type 2 diabetes. Nausea, vomiting, and diarrhea are common adverse effects when patients start treatment with exenatide. High rates of patients who were lost to followup could bias the results. Applying intent-to-treat analysis (as employed by the authors) is also problematic when a large proportion of participants drop out. Treatment effect could be underestimated or overestimated. Moreover, intent-to-treat analysis can also hide problems related to the way in which large dropout data are handled. We strongly agree with the authors that exenatide treatment can have continued efficacy over a long period of time. However, clinical
1304
efficacy may be limited to those patients who can tolerate exenatide treatment long term. Future research that employs a randomized controlled trial design can confirm the long-term patient acceptance, clinical benefit, and safety of exenatide treatment. Sakkarin Chirapongsathorn, MD Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN Division of Gastroenterology Department of Medicine Phramongkutklao Hospital and College of Medicine Royal Thai Army Bangkok, Thailand
Pimjai Anthanont, MD Division of Endocrinology, Mayo Clinic, Rochester, MN
1. Wysham CH, MacConell LA, Maggs DG, Zhou M, Griffin PS, Trautmann ME. Five-year efficacy and safety data of exenatide once weekly: long-term results from the DURATION-1 randomized clinical trial. Mayo Clin Proc. 2015;90(3):356-365. http://dx.doi.org/10.1016/j.mayocp.2015.06.004
In replydLong-term Efficacy and Safety of Exenatide Treatment We appreciate the interest of Drs Chirapongsathorn and Anthanont in our article on the efficacy and safety of exenatide once weekly at 5 years in patients with type 2 diabetes. They appropriately point out the withdrawal rate of approximately 40% during our long-term study. We contend that this withdrawal rate is not unexpected for a clinical trial conducted over 5 years of follow-up, and, in addition, results reported at 6 years of follow-up reveal that a large proportion of patients remained in the study even longer. During the 5-year extension phase, only 3.7% of the intent-to-treat (ITT) population discontinued the study because of adverse events (4.3% of those who entered the
open-label extension). Similar proportions of patients were lost to follow-up or withdrawn due to investigator decision. Approximately 20% of the ITT population withdrew consent during the extension phase, which again is not a surprise in a long-term study such as this. Very few patients withdrew during the open-label extension phase because of loss of glucose control, which is impressive considering the challenges in maintaining glucose control over an extended period with any medication. Although most patients added concomitant antidiabetes medications during the extension phase, the results speak to the durability of response with exenatide as part of the long-term management of the disease. The 60% completion rate at 5 years is higher than or comparable to those observed in other studies involving glucagon-like peptide-1 receptor agonists (approximately 50% completion rate at 2 years for liraglutide1 and 54%-65% at 3 years for albiglutide2-4). Drs Chirapongsathorn and Anthanont comment that patient discontinuation could bias the results, a point that we acknowledge in the “Discussion” section of our article. However, we consider the completion rate to be high relative to the length of the study, and, as we also noted in the “Discussion,” this high completion rate indicates that treatment with exenatide once weekly was well tolerated and perceived as efficacious. Regarding the suggestion that the results may be limited to only those who can tolerate the adverse effects of exenatide, the rate of discontinuation due to adverse events was low in both the initial controlled phase (5.4%6.1%) and the extension phase (3.7%), consistent with other large clinical trials of exenatide. The limitations segment of our article already points out that the “completer population may represent a subset of patients who responded well to treatment” (which would be the same as for any longer-term extension study), and notes that significant effects
Mayo Clin Proc. n September 2015;90(9):1304-1309 n http://dx.doi.org/10.1016/j.mayocp.2015.06.005 www.mayoclinicproceedings.org n ª 2015 Mayo Foundation for Medical Education and Research