CD3-Antibody Therapy in New-Onset Type 1 Diabetes Mellitus
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《新英格兰医药杂志》
To the Editor: We urge caution regarding the conclusion of Keymeulen et al. (June 23 issue)1 in reporting their study of CD3-antibody therapy for new-onset type 1 diabetes mellitus that treatment with ChAglyCD3 preserves residual beta-cell function. Differences in C-peptide levels between the study groups at six months suggest a benefit of treatment. However, increases in C-peptide levels in treated patients at 6 months, with decreases in C-peptide levels in controls, appear to account for most of the improvement in the treated group at 18 months. After six months, the rate of C-peptide loss is almost identical in both groups. The decrease in C-peptide levels in controls with new-onset diabetes is at odds with the results of multiple studies demonstrating a "honeymoon phase" of increased levels of C peptide three to six months after diagnosis.2,3,4 Furthermore, older patients with new-onset type 1 diabetes (mean age, 26 years in the study by Keymeulen et al.) typically have a slower loss of C peptide than do younger patients.5
Although we applaud efforts to investigate new therapies for type 1 diabetes, the unexpected decrease in C-peptide levels among the controls at six months may lead to an overinterpretation of the results of this well-conducted but small study, which is possibly confounded by the heterogeneity of subjects.
Michael J. Haller, M.D.
Desmond A. Schatz, M.D.
University of Florida
Gainesville, FL 32610
hallemj@peds.ufl.edu
References
Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005;352:2598-2608.
Assan R, Feutren G, Sirmai J, et al. Plasma C-peptide levels and clinical remissions in recent-onset type I diabetic patients treated with cyclosporin A and insulin. Diabetes 1990;39:768-774.
Shah SC, Malone JI, Simpson NE. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989;320:550-554.
Silverstein J, Maclaren N, Riley W, Spillar R, Radjenovic D, Johnson S. Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N Engl J Med 1988;319:599-604.
Schiffrin A, Suissa S, Weitzner G, Poussier P, Lalla D. Factors predicting course of beta-cell function in IDDM. Diabetes Care 1992;15:997-1001.
To the Editor: The description of the study design by Keymeulen et al. states that patients received "intensive insulin therapy (i.e., at least three injections per day)." In clinical practice, intensive insulin therapy delivered by means of multiple daily injections (rather than with an insulin pump) connotes the use of a basal–bolus insulin plan, with long-acting insulin as the basal component and then "bolusing" at meals with rapid-acting insulin at a dose based on calorie consumption (e.g., "carbohydrate counting"). A regimen of three daily injections does not necessarily equal intensive insulin therapy.
In addition, total daily insulin requirements, expressed in international units (IU) per kilogram of body weight, were used in the data analysis. This approach does not gauge insulin needs effectively when conditions are not strictly controlled. The flexibility or variability of individual meal planning and subsequent insulin dosing is part of intensive insulin therapy. If a meal is skipped, no bolus insulin is administered; a feast will require much more insulin. I propose that analysis of required basal insulin relative to body weight is a more meaningful measure for the comparison and assessment of interventional insulin requirements for patients receiving intensive insulin therapy.
I. David Schwartz, M.D.
University of South Carolina School of Medicine
Columbia, SC 29203
dschwartz@richmed.medpark.sc.edu
The authors reply: Drs. Haller and Schatz regard as unexpected the decrease in glucose-clamp–induced C-peptide release that occurred between diagnosis and month 6 in our placebo group. However, our findings concur with those of a study by Assan et al.1 (cited by Haller and Schatz), which also evaluated patients by means of intravenous glucose-tolerance tests. Both groups observed a rise in C-peptide levels either when glucagon was added (in our study and in that of Assan et al.) or when a meal test was conducted (in Assan et al.). In our study, the decline in glucose-clamp–induced C-peptide levels was accounted for by the subpopulation with the higher residual beta-cell function at the start of the study (50th percentile); the decline was not detected in the subgroup with lower function (<50th percentile). These findings resemble those from control groups in other studies cited by Haller and Schatz, as indicated by the high mean levels of glycosylated hemoglobin (range, 10.4 to 18.2 percent) and insulin doses (range, 0.7 to 0.9 IU per kilogram of body weight) cited by Assan et al.,1 Shah et al.,2 and Silverstein et al.3 Patients in the studies by Shah et al. and Silverstein et al. were younger (between 10 and 14 years of age) than were patients in our study, and they were included after a shorter duration of insulin treatment, which could explain the differences between our data and theirs. These and other variables need to be investigated in a larger patient population to assess any potential influence on the outcome of intervention with anti-CD3 antibodies. Our study was not designed for such stratification, which is not a reason to consider our patient recruitment as heterogeneous. A closer examination of our inclusion criteria would demonstrate this point.
In response to Dr. Schwartz: we would like to clarify that all patients in our study were receiving basal long-acting insulin therapy (one or two daily injections) and bolus insulin therapy (two to four injections). Basal insulin therapy was not a predefined end point in our study or in other such studies. Median basal insulin therapy at baseline was 35 percent (interquartile range, 25 to 40 percent) of the daily dose. Similar conclusions are reached when basal insulin doses are assessed, rather than total doses. At 18 months, the mean basal insulin dose had increased among patients receiving placebo (from 0.13 to 0.25 IU per kilogram per day) but not among patients treated with ChAglyCD3 (from 0.15 to 0.18 IU per kilogram per day). The effect of ChAglyCD3 was most pronounced among patients with higher initial residual beta-cell function (50th percentile). For these patients, the mean basal insulin dose at 18 months was 0.09 IU per kilogram per day, as compared with 0.28 IU per kilogram per day in the corresponding placebo subgroup (P<0.001).
Bart Keymeulen, M.D., Ph.D.
Daniel Pipeleers, M.D., Ph.D.
Brussels Free University
B-1090 Brussels, Belgium
Lucienne Chatenoud, M.D., Ph.D.
Institut Fédératif de Recherche Necker–Enfants Malades
75015 Paris, France
References
Assan R, Feutren G, Sirmai J, et al. Plasma C-peptide levels and clinical remissions in recent-onset type I diabetic patients treated with cyclosporin A and insulin. Diabetes 1990;39:768-774.
Shah SC, Malone JI, Simpson NE. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989;320:550-554.
Silverstein J, Maclaren N, Riley W, Spillar R, Radjenovic D, Johnson S. Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N Engl J Med 1988;319:599-604.
Although we applaud efforts to investigate new therapies for type 1 diabetes, the unexpected decrease in C-peptide levels among the controls at six months may lead to an overinterpretation of the results of this well-conducted but small study, which is possibly confounded by the heterogeneity of subjects.
Michael J. Haller, M.D.
Desmond A. Schatz, M.D.
University of Florida
Gainesville, FL 32610
hallemj@peds.ufl.edu
References
Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005;352:2598-2608.
Assan R, Feutren G, Sirmai J, et al. Plasma C-peptide levels and clinical remissions in recent-onset type I diabetic patients treated with cyclosporin A and insulin. Diabetes 1990;39:768-774.
Shah SC, Malone JI, Simpson NE. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989;320:550-554.
Silverstein J, Maclaren N, Riley W, Spillar R, Radjenovic D, Johnson S. Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N Engl J Med 1988;319:599-604.
Schiffrin A, Suissa S, Weitzner G, Poussier P, Lalla D. Factors predicting course of beta-cell function in IDDM. Diabetes Care 1992;15:997-1001.
To the Editor: The description of the study design by Keymeulen et al. states that patients received "intensive insulin therapy (i.e., at least three injections per day)." In clinical practice, intensive insulin therapy delivered by means of multiple daily injections (rather than with an insulin pump) connotes the use of a basal–bolus insulin plan, with long-acting insulin as the basal component and then "bolusing" at meals with rapid-acting insulin at a dose based on calorie consumption (e.g., "carbohydrate counting"). A regimen of three daily injections does not necessarily equal intensive insulin therapy.
In addition, total daily insulin requirements, expressed in international units (IU) per kilogram of body weight, were used in the data analysis. This approach does not gauge insulin needs effectively when conditions are not strictly controlled. The flexibility or variability of individual meal planning and subsequent insulin dosing is part of intensive insulin therapy. If a meal is skipped, no bolus insulin is administered; a feast will require much more insulin. I propose that analysis of required basal insulin relative to body weight is a more meaningful measure for the comparison and assessment of interventional insulin requirements for patients receiving intensive insulin therapy.
I. David Schwartz, M.D.
University of South Carolina School of Medicine
Columbia, SC 29203
dschwartz@richmed.medpark.sc.edu
The authors reply: Drs. Haller and Schatz regard as unexpected the decrease in glucose-clamp–induced C-peptide release that occurred between diagnosis and month 6 in our placebo group. However, our findings concur with those of a study by Assan et al.1 (cited by Haller and Schatz), which also evaluated patients by means of intravenous glucose-tolerance tests. Both groups observed a rise in C-peptide levels either when glucagon was added (in our study and in that of Assan et al.) or when a meal test was conducted (in Assan et al.). In our study, the decline in glucose-clamp–induced C-peptide levels was accounted for by the subpopulation with the higher residual beta-cell function at the start of the study (50th percentile); the decline was not detected in the subgroup with lower function (<50th percentile). These findings resemble those from control groups in other studies cited by Haller and Schatz, as indicated by the high mean levels of glycosylated hemoglobin (range, 10.4 to 18.2 percent) and insulin doses (range, 0.7 to 0.9 IU per kilogram of body weight) cited by Assan et al.,1 Shah et al.,2 and Silverstein et al.3 Patients in the studies by Shah et al. and Silverstein et al. were younger (between 10 and 14 years of age) than were patients in our study, and they were included after a shorter duration of insulin treatment, which could explain the differences between our data and theirs. These and other variables need to be investigated in a larger patient population to assess any potential influence on the outcome of intervention with anti-CD3 antibodies. Our study was not designed for such stratification, which is not a reason to consider our patient recruitment as heterogeneous. A closer examination of our inclusion criteria would demonstrate this point.
In response to Dr. Schwartz: we would like to clarify that all patients in our study were receiving basal long-acting insulin therapy (one or two daily injections) and bolus insulin therapy (two to four injections). Basal insulin therapy was not a predefined end point in our study or in other such studies. Median basal insulin therapy at baseline was 35 percent (interquartile range, 25 to 40 percent) of the daily dose. Similar conclusions are reached when basal insulin doses are assessed, rather than total doses. At 18 months, the mean basal insulin dose had increased among patients receiving placebo (from 0.13 to 0.25 IU per kilogram per day) but not among patients treated with ChAglyCD3 (from 0.15 to 0.18 IU per kilogram per day). The effect of ChAglyCD3 was most pronounced among patients with higher initial residual beta-cell function (50th percentile). For these patients, the mean basal insulin dose at 18 months was 0.09 IU per kilogram per day, as compared with 0.28 IU per kilogram per day in the corresponding placebo subgroup (P<0.001).
Bart Keymeulen, M.D., Ph.D.
Daniel Pipeleers, M.D., Ph.D.
Brussels Free University
B-1090 Brussels, Belgium
Lucienne Chatenoud, M.D., Ph.D.
Institut Fédératif de Recherche Necker–Enfants Malades
75015 Paris, France
References
Assan R, Feutren G, Sirmai J, et al. Plasma C-peptide levels and clinical remissions in recent-onset type I diabetic patients treated with cyclosporin A and insulin. Diabetes 1990;39:768-774.
Shah SC, Malone JI, Simpson NE. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989;320:550-554.
Silverstein J, Maclaren N, Riley W, Spillar R, Radjenovic D, Johnson S. Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N Engl J Med 1988;319:599-604.