Correspondence
Diabetic Gastroparesis
N Engl J Med 2007; 357:418-420July 26, 2007
- Article
To the Editor:
In his review of diabetic gastroparesis, Camilleri (Feb. 22 issue)1 states that in our clinical trial of exenatide,2 nausea and vomiting led to the “cessation of treatment in about one third of patients.” This information is incorrect. Of 282 patients randomly assigned to receive exenatide, 54 withdrew from the study (27 withdrew because of an adverse event, 10 because of protocol violations, 7 because of the patient's decision, 4 because of loss of glucose control, and 1 because of the physician's decision, and 5 were lost to follow-up). As stated in our article, 18 of these patients withdrew from the study because of nausea or other gastrointestinal symptoms. This rate is in line with the dropout rates in other recent clinical trials, which range from 1.8 to 5.1%.3-5 Mild-to-moderate nausea is the most common adverse event in patients receiving exenatide. However, the development of tolerance to these adverse gastrointestinal effects of exenatide has been suggested in our trial as well as in other long-term phase 3 trials of the drug that have been reported.3-5
5 ReferencesRobert J. Heine, M.D., Ph.D.
VU University Medical Center, 1007 MB Amsterdam, the NetherlandsRobert Brodows, M.D.
Lilly Research Laboratories, Indianapolis, IN 462851
Camilleri M . Diabetic gastroparesis. N Engl J Med 2007;356:820-829
Full Text | Web of Science | Medline2
Heine RJ ,Van Gaal LF ,Johns D , et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005;143:559-569
Web of Science | Medline3
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;28:1092-1100
CrossRef | Web of Science | Medline4
Kendall DM ,Riddle MC ,Rosenstock J , et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005;28:1083-1091
CrossRef | Web of Science | Medline5
Nauck MA ,Duran S ,Kim D , et al. A comparison of twice daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia 2007;50:259-267
CrossRef | Web of Science | Medline
To the Editor:
In Table 2 of his article, Camilleri lists the motilin-receptor agonists erythromycin, clarithromycin, and azithromycin as recommended agents for the treatment of diabetic gastroparesis. I agree with the recommendation regarding erythromycin. However, clarithromycin, azithromycin, and other more acid-stable macrolides and azalides are likely to be poor alternatives. Erythromycin A in an acidic medium such as gastric juice is degraded into its anhydrous hemiketal and spiroketal forms.1 Both forms are inactive microbiologically, but they have motilin-like activity that is several times greater than that of erythromycin A.1,2 It is mostly because of this characteristic that erythromycin has a low oral bioavailability of the microbiologically active drug and considerable gastrointestinal adverse effects. Clarithromycin and azithromycin have modified chemical structures that are more acid-stable and do not form the highly active motilin mimics2,3; consequently, neither drug is likely to be as useful as erythromycin for the treatment of motilin-responsive disorders. Both clarithromycin and azithromycin are also more expensive than erythromycin.
3 ReferencesEufronio G. Maderazo, M.D.
William W. Backus Hospital, Norwich, CT 063601
Weymouth-Wilson AC . The role of carbohydrates in biologically active natural products. Nat Prod Rep 1997;14:99-110
CrossRef | Web of Science | Medline2
Tsuzuki K ,Sunazuka T ,Marui S , et al. Motilides, macrolides with gastrointestinal motor stimulating activity. I. O-substituted and tertiary N-substituted derivatives of 8,9-anhydroerythromycin A 6,9-hemiacetal. Chem Pharm Bull (Tokyo) 1989;37:2687-2700
CrossRef | Web of Science | Medline3
Gill CJ ,Abruzzo GK ,Flattery AM , et al. In vivo evaluation of three acid-stable azalide compounds, L-701,677, L-708,299 and L-708,365 compared to erythromycin, azithromycin and clarithromycin. J Antibiot (Tokyo) 1995;48:1141-1147
Web of Science | Medline
To the Editor:
Camilleri compares gastrointestinal prokinetic agents with regard to their efficacy and side effects. For metoclopramide, neurologic side effects are reported from one 4-week trial. Tardive dyskinesia and other extrapyramidal effects are not mentioned in the text and are cited only briefly in Table 2 of the article. Since clinical trials of metoclopramide have been short-term trials, this review understates the risk of tardive dyskinesia among patients treated with metoclopramide on a long-term basis.
Metoclopramide is a dopamine-receptor antagonist that causes parkinsonism, acute dystonia, akathisia, and tardive dyskinesia. The risk of tardive dyskinesia after long-term treatment with antipsychotic drugs that are dopamine-receptor antagonists is 5% per year of drug exposure.1 Although prospective data for metoclopramide are unavailable, the prevalence and severity of tardive dyskinesia are increased after long-term treatment.2,3 Diabetes is associated with an increased frequency and severity of tardive dyskinesia.2,4 The risk of tardive dyskinesia is underrecognized by physicians who use metoclopramide for long-term treatment3; this is especially important in view of the increased use of metoclopramide since the withdrawal of cisapride in 2000.5
5 ReferencesDaniel Tarsy, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
dtarsy@bidmc.harvard. edu 1
Tarsy D ,Baldessarini RJ . Epidemiology of tardive dyskinesia: is risk declining with modern antipsychotics? Mov Disord 2006;21:589-598
CrossRef | Web of Science | Medline2
Ganzini L ,Heintz RT ,Hoffman WF ,Casey DE . The prevalence of tardive dyskinesia in neuroleptic-treated diabetics: a controlled study. Arch Gen Psychiatry 1991;48:259-263
CrossRef | Web of Science | Medline3
Pasricha PJ ,Pehlivanov N ,Sugumar A ,Jankovic J . Drug insight: from disturbed motility to disordered movement -- a review of the clinical benefits and medicolegal risks of metoclopramide. Nat Clin Pract Gastroenterol Hepatol 2006;3:138-148
CrossRef | Web of Science | Medline4
Woerner MG ,Saltz BL ,Kane JM ,Lieberman JA ,Alvir JM . Diabetes and development of tardive dyskinesia. Am J Psychiatry 1993;150:966-968
Web of Science | Medline5
Shaffer D ,Butterfield M ,Pamer C ,Mackey AC . Tardive dyskinesia risks and metoclopramide use before and after U.S. market withdrawal of cisapride. J Am Pharm Assoc ( 2003;44:661-665
CrossRef
Author/Editor Response
Heine and Brodows correctly point out that the withdrawal rate attributed to nausea in their clinical trial was overstated in my article. However, in trials involving longer-term treatment that may better reflect clinical experience,1-4 as well as in the study by Nauck et al. cited by Heine and Brodows, there is a high prevalence of nausea (average prevalence, approximately 33%). The all-cause withdrawal rate in these randomized, controlled, or open-label treatment trials involving exenatide ranged from 21 to 45%. Approximately 4% of these withdrawals were attributed to a loss of glucose control and 7% were attributed to adverse events. It is unclear whether the withdrawal of consent by approximately 11% of patients and withdrawals because of protocol violations by approximately 10% of patients were due to nausea, which was by far the most frequent adverse event (57% in the article by Heine et al. cited by Heine and Brodows). Nausea and vomiting in patients with diabetes may be wrongly attributed to gastroparesis rather than to iatrogenic disease, which may be reversible.
I agree with Maderazo's statement regarding the different potencies of macrolides in the stimulation of gastric emptying. I included clarithromycin and azithromycin in Table 2 because this table reflects national society guidelines, as noted in one of the table footnotes.
The potential for tardive dyskinesia during treatment with metoclopramide is important. However, as indicated in the article by Shaffer et al. (to which Tarsy refers in his letter), well-described risk factors are common in reports of metoclopramide-associated tardive dyskinesia. Moreover, Ganzini et al.5 calculated that the relative risk of tardive dyskinesia was not significantly elevated with use of metoclopramide (relative risk, 1.67; 95% confidence interval, 0.93 to 2.97), although the risk appeared to be higher among patients with diabetes.
Michael Camilleri, M.D.
Mayo Clinic College of Medicine, Rochester, MN 55905
camilleri.michael@mayo. edu Since publication of his article, Dr. Camilleri reports having received research support from Novartis.
5 References1
Riddle MC ,Henry RR ,Poon TH , et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev 2006;22:483-491
CrossRef | Web of Science | Medline2
Blonde L ,Klein EJ ,Han J , et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab 2006;8:436-447
CrossRef | Web of Science | Medline3
Ratner RE ,Maggs D ,Nielsen LL , et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab 2006;8:419-428
CrossRef | Web of Science | Medline4
Buse JB ,Klonoff DC ,Nielsen LL , et al. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther 2007;29:139-153
CrossRef | Web of Science | Medline5
Ganzini L ,Casey DE ,Hoffman WF ,McCall AL . The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med 1993;153:1469-1475
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Uazman Alam, Omar Asghar, Rayaz Ahmed Malik. (2010) Diabetic gastroparesis: Therapeutic options. Diabetes Therapy 1:1, 32-43
CrossRef2
Uazman Alam, Omar Asghar, Rayaz Ahmed Malik. (2010) Diabetic gastroparesis: Therapeutic options. Diabetes Therapy 1:1, 32
CrossRef3
Pavan Chepyala, Kevin W. Olden. (2008) Nausea and vomiting. Current Treatment Options in Gastroenterology 11:2, 135-144
CrossRef
