Current issues of ACP Journal Club are published in Annals of Internal Medicine


Intensive diabetes therapy did not affect neuropsychological functioning

ACP J Club. 1996 May-June;124:69. doi:10.7326/ACPJC-1996-124-3-069

Source Citation

The Diabetes Control and Complications Trial Research Group. Effects of intensive diabetes therapy on neuropsychological function in adults in the Diabetes Control and Complications Trial. Ann Intern Med. 1996 Feb 15; 124:379-88. [PubMed ID: 8554246]



To assess the effect of intensive diabetes therapy on neuropsychological functioning in patients with insulin-dependent diabetes mellitus.


9-year randomized controlled trial with mean 6.5-year follow-up.


29 centers in North America.


1441 patients who were between 13 and 39 years of age (mean age 27 y, 52% men) and had had insulin-dependent diabetes mellitus for 1 to 15 years. Patients were excluded if they had advanced retinopathy, nephropathy, or neuropathy; history of drug or alcohol abuse; psychotic episodes; eating disorders; or recurrent episodes of ketoacidosis, coma, or seizures caused by hypoglycemia. Follow-up data were available for 99% of patients.


Patients were allocated to intensive therapy (n = 711) or conventional therapy (n = 730). Intensive therapy consisted of ≥ 3 injections/d or continuous pump infusion of insulin. Blood glucose levels were measured ≥ 4 times/d, and insulin doses were adjusted to maintain normoglycemia. Conventional therapy consisted of 1 to 2 insulin injections/d to prevent hyperglycemic symptoms and hypoglycemia.

Main Outcome Measures

Neuropsychological assessments (25 individual test scores, grouped into 8 cognitive domains) at 0, 2, 5, and 7 years and at study end. The relation between severe hypoglycemia and the degree of neuropsychological impairment was also assessed.

Main Results

The groups did not differ for clinically rated neuropsychological worsening. Cumulatively, at 5 years, 9 patients (1.3%) who received intensive therapy and 14 patients (1.9%) who received conventional therapy were rated as significantly worsened {P = 0.32}*. In 1 cognitive domain, intensive therapy was associated with improved neuropsychological function (motor speed, P = 0.004). For the domain of immediate memory, there was a trend toward improved function with intensive therapy (P = 0.06), and for the other 6 domains, groups did not differ (P > 0.2). The mean rate of severe hypoglycemia in patients with neuropsychological worsening was no higher than in patients without worsening.


Intensive diabetes therapy was not associated with significant cognitive impairment in patients with insulin-dependent diabetes mellitus. Severe hypoglycemia was not more common in patients with neuropsychological impairment.

Sources of funding: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung and Blood Institute; National Eye Institute; National Center for Research Resources.

For article reprint: DCCT Research Group, Box NDIC/DCCT, Bethesda, MD 20892, USA. FAX 617-726-6781.

*Numbers calculated from data in article.


In rats, hypoglycemia that causes unconsciousness and an isoelectric electroencephalogram results in brain damage (1). Cross-sectional studies in humans have shown signs of cognitive impairment in patients with insulin-dependent diabetes and repeated episodes of hypoglycemic coma (2); however, these studies do not prove that cognitive impairment was caused by the hypoglycemic episodes. This proof can only come from randomized studies in which similar patients are randomly allocated to different treatment regimens.

2 long-term studies that compared intensified insulin treatment to achieve near-normoglycemia with conventional therapy are now complete: the Stockholm Diabetes Intervention Study (SDIS) and the Diabetes Control and Complications Trial (DCCT). In both studies, severe hypoglycemia that required outside help was 3 times more common in intensively treated patients. This increase in hypoglycemia made it possible to prospectively study the neuropsychological effects of an increased frequency of hypoglycemia. In the SDIS, a computerized test battery did not show any deleterious effects of intensified treatment after 7.5 years (3).

The DCCT confirmed that intensified insulin treatment did not cause cognitive impairment. The neuropsychological study methods used are well established, rigorous statistical procedures were applicable, and many patients were investigated, which made a false-negative result unlikely.

Despite these reassuring results, hypoglycemia is still an unpleasant and dangerous complication of diabetes therapy. Minimization of its frequency and severity requires a willing patient and teamwork by dedicated physicians and nurses with expertise in intensified insulin treatment of diabetes.

Per Reichard, MD, PhD
Södersjukhuset Medicinska KlinikenStockholm, Sweden


1. Auer RN, Olsson Y, Siesjö B. Hypoglycemic brain injury in the rat. Correlation of density of brain damage with the EEG isoelectric time: a quantitative study. Diabetes. 1984;33:1090-8.

2. Deary IJ, Crawford JR, Hepburn DA, et al. Severe hypoglycemia and intelligence in adult patients with insulin-treated diabetes. Diabetes. 1993;42:341-4.

3. Reichard P, Pihl M. Mortality and treatment side-effects during long-term intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study. Diabetes. 1994;43: 313-7.