Correspondence
The Effect of Intensive Treatment of Diabetes Mellitus
N Engl J Med 1994; 330:641-642March 3, 1994
- Article
To the Editor:
The report of the Diabetes Control and Complications Trial (Sept. 30 issue)1 provided much information about the importance of achieving strict control of blood glucose levels through intensive treatment in diabetic patients. Patients with hypertension were excluded, and base-line blood pressures were similar in the patients in the conventional-therapy and the intensive-therapy groups. We wonder whether changes in blood pressure during the study affected the outcomes, given the importance of blood pressure in the development and progression of diabetic retinopathy2 and nephropathy3 and the controversy over the effects of insulin on blood pressure4. What changes in blood pressure, if any, occurred in the patients in the two treatment groups? Did those who reached a study end point have higher blood pressures than those who did not? If hypertension developed in a patient during the study, was treatment given, and if so, what? Different antihypertensive drugs have different effects in diabetic patients. The large number of patients and the impressive percentage who completed the study (99 percent) could provide enough information for a separate study of the influence of blood pressure on outcomes.
4 ReferencesRaymond R. Townsend, M.D.
Shiv C. Kapoor, Ph.D.
University of Pennsylvania, Philadelphia, PA 191041
The Diabetes Control and Complications Trial Research Group
Full Text | Web of Science | Medline2
Knowler WC ,Bennett PH ,Ballintine EJ . Increased incidence of retinopathy in diabetics with elevated blood pressure: a six-year follow-up study in Pima Indians. N Engl J Med 1980;302:645-650
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Parving H-H ,Andersen AR ,Smidt UM ,Svendsen PA . Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1983;1:1175-1179
CrossRef | Web of Science | Medline4
Hall JE ,Coleman TG ,Mizelle HL . Does chronic hyperinsulinemia cause hypertension? Am J Hypertens 1989;2:171-173
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To the Editor:
The report of the Diabetes Control and Complications Trial contained many important data, but I have several questions and areas of concern. In presenting the results, the authors should have reported the differences in benefits and complications in the treatment groups in the same way. If the relative decrease in complications in the patients in the intensive-treatment group was 30 percent to 60 percent, then the rate of severe hypoglycemic episodes should also have been expressed as a percentage. A threefold increase in hypoglycemic episodes is a 200 percent increase.
How many patients were approached in order to enroll the 1441 patients who participated in the trial? I suspect that many patients would decline enrollment after being informed that they might have more frequent episodes of hypoglycemia.
Were the results in the patients in the intensive-therapy and the conventional-therapy groups who had the same glycosylated hemoglobin values compared? I know this is a question raised after the study design was determined, but such an analysis might indicate whether the blood glucose concentration or some other variable was responsible for the decreased incidence of complications in the intensive-treatment group.
This was a short-term study of some aspects of diabetes. The question of whether intensive treatment delays the onset of renal failure or increases survival has not been answered.
Alan Garber, M.D.
Mount Auburn Hospital, Cambridge, MA 02238To the Editor:
The Diabetes Control and Complications Trial demonstrated that intensive therapy can delay the onset and slow the progression of retinopathy, nephropathy, and neuropathy in patients with insulin-dependent diabetes mellitus (IDDM). The authors use a secondary analysis of their data (presented in their Figure 5A) to support the hypotheses that there is a continuously increasing risk of progression of retinopathy with increasing mean glycosylated hemoglobin values and that there is no specific glycosylated hemoglobin value at which the benefits of intensive therapy are maximal.
The authors have chosen to ignore the null hypothesis that there is a mean glycosylated hemoglobin value below which there is no further benefit of intensive therapy. The log regression line supports the authors' hypotheses because a single outlying point (the 10 percent of patients with the highest mean value, which was about 9.2 percent) was included. There was little difference between the mean glycosylated hemoglobin values and the rate of progression of retinopathy in the remaining 90 percent of patients, supporting the hypothesis that the benefits of intensive therapy differ little in patients with mean glycosylated hemoglobin values ranging from less than 6 to 8 percent. Do the data from the conventional-therapy group support the hypothesis that maintaining a mean glycosylated hemoglobin value of less than 8 percent confers no additional benefit in slowing the rate of progression of retinopathy? Do the data on the progression of nephropathy and neuropathy show a mean glycosylated hemoglobin value below which there is no additional benefit?
The authors' data show that the rate of severe hypoglycemia was approximately twice as high in patients with a mean glycosylated hemoglobin value of 6 percent as in patients with a mean value of 8 percent. Can the substantially increased risk of hypoglycemia, along with the resources and dedication required to maintain a mean value of 6 percent, be justified when there is so little evidence of additional benefit?
David Gerard, M.D.
333 Chestnut St., Hinsdale, IL 60521Author/Editor Response
The authors reply:
To the Editor: In response to Drs. Townsend and Kapoor: patients with IDDM who had hypertension at base line were excluded because we wanted to focus primarily on the treatment of hyperglycemia, rather than hypertension, as it affected the long-term complications of diabetes. Relatively few patients in either treatment group (77 in the intensive-treatment group and 84 in the conventional-treatment group) had hypertension (blood pressure, >140/90 mm Hg) during the follow-up period, and the rate of development of hypertension was similar in the two groups (1.8 and 1.9 episodes per 100 patient-years, respectively, in the intensive-treatment and the conventional-treatment groups). Moreover, only the mean systolic blood pressure differed between the groups at the end of the study, and the difference was small (116 mm Hg in the intensive-treatment group vs. 114 mm Hg in the conventional-treatment group, P = 0.04). Patients in whom hypertension developed were treated with dietary salt restriction and antihypertensive medications, as needed. Beta-adrenergic-antagonist drugs were avoided because of the added risk of hypoglycemia, and angiotensin-converting-enzyme inhibitors were avoided because we wished to study metabolic control rather than the putative effects of inhibition with these agents.
Drs. Garber and Gerard both question the secondary analyses that examined the association between the level of glycemia and the progression of retinopathy. We want to stress that the most valid interpretation of the trial is that intensive therapy, with the goal of achieving blood glucose concentrations as close to the nondiabetic range as possible, delays the onset and slows the progression of long-term diabetic complications. The secondary analyses support the notion that lower glycosylated hemoglobin values are associated with a lower risk of progression of retinopathy, but they do not prove that hyperglycemia in itself causes retinopathy. Even if the intensively treated patients with the highest mean glycosylated hemoglobin values are excluded, and it is not intuitively clear what would justify doing so, the risk of the progression of retinopathy increases continuously with increasing values. Finally, the adverse events associated with intensive therapy, including hypoglycemia and weight gain, were identified during the Diabetes Control and Complications Trial1,2. Patients entered the study without knowing either the risks or the benefits of intensive therapy, which the trial has now established for adolescent and adult patients with IDDM.
2 ReferencesDavid M. Nathan, M.D.
Massachusetts General Hospital, Boston, MA 02114Oscar B. Crofford, M.D.
Vanderbilt University, Nashville, TN 37232John M. Lachin, Ph.D.
George Washington University, Washington, DC 20037for the Diabetes Control and Complications Trial Research Group
1
The DCCT Research Group
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The DCCT Research Group
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