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


Intensified insulin increased the risk for serious hypoglycemia and neuroglycopenia in IDDM

ACP J Club. 1991 May-June;114:84. doi:10.7326/ACPJC-1991-114-3-084

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Source Citation

Reichard P, Berglund A, Britz A, Levander S, Rosenqvist U. Hypoglycaemic episodes during intensified insulin treatment: increased frequency but no effect on cognitive function. J Intern Med. 1991;229:9-16.



To study the neuropsychologic effects of episodic hypoglycemia occurring in diabetic patients receiving intensified insulin treatment.


Secondary analysis of a randomized trial of 3 years duration.


Stockholm Diabetes Intervention Study (SDIS).


102 patients with insulin-dependent diabetes mellitus (IDDM), nonproliferative retinopathy, normal serum creatinine levels, and unsatisfactory blood glucose control were included. 97 patients (mean age 31y; duration of diabetes 17 y) were followed for 3 years.


Treatment was intended to reduce glycosylated hemoglobin levels (HbA1c, normal range 3.9% to 5.7%). Patients were assigned to intensified conventional treatment (ICT) ( n = 44) or to regular treatment (RT) , (n = 53). ICT included education, change to multiple insulin injections, self-blood-glucose monitoring, and easy access to a physician.

Main outcome measures

Number of serious hypoglycemic episodes (requiring assistance) and nature of hypoglycemic symptoms. Change in performance on neuropsychologic tests of auditory and visual reaction time; short-term memory and concentration (digit span); visuospatial intelligence (perceptual maze test); frontal-lobe functions (Necker cube test). Autonomic nerve function was tested by respiratory sinus arrhythmia, Valsalva ratio, dive reflex heart rate, arm blood flow during contralateral isometric handgrip, and changes in blood pressure when tilted.

Main results

HbA1c fell in both treatment groups — from 9.5% to 7.4% in the ICT group and from 9.4% to 9.0% in the RT group (P < 0.001 for the difference between groups). More patients in theICT group (57%, 95% CI 44% to 73%) had serious episodes of hypoglycemia than did patients in the RT group (23%, CI 11% to 34%, P < 0.001) {This absolute risk difference of 34% means that 1 additional serious episode of hypoglycemia occurred for every 3 patients who received ICT (rather than RT), 95% CI 2 to 7; the relative risk increase was 151%, CI 47% to 344%}.* More serious hypoglycemic episodes occurred in the period from 18 months to 3 years in the ICT group (102 episodes) than in the RT group (28 episodes), and emergency hospital visits were also more common (11 vs 3 visits). 18 of 32 patients in the ICT group noted a change from mainly adrenergic symptoms during hypoglycemia to mainly neuroglycopenic symptoms (56%, CI 39% to 73%) compared with 8 of 38 patients in the RT group (21%, CI 8% to 39%, P for difference < 0.01). The groups did not differ on neuropsychologic tests.


Intensified insulin therapy increased the risk for serious episodes of hypoglycemia and neuroglycopenia but did not change neuropsychologic functioning overall in patients with insulin-dependent diabetes mellitus.

Sources of funding: NOVO-Nordisk Inc.; Boehringer Mannheim Scand. Inc.; the Swedish Medical Research Council.

Address for article reprint: Dr P. Reichard, Medical Clinic II, Södersjukhuset, S-10064 Stockholm, Sweden.

*Numbers calculated from data in article.


This small, but well-designed, open study patients with IDDM supports previous observations that an intensified insulin regimen both improves glycemic control and increases risk for severe hypoglycemia. It also shows that hypoglycemic symptoms may shift from adrenergic to neuroglycopenic with intensified therapy.

This change in the frequency and nature of hypoglycemia could not be explained on the basis of differences in autonomic function before initiating intensified therapy. The mechanism for the change in symptoms of hypoglycemia therefore remains unclear, but may be related to a decrease in the glycemic threshold for hormonal counter-regulation that occurs with intensified insulin therapy (1). The finding that serious hypoglycemic episodes were more frequent in the second 18 months of the study indicates that the effect of intensified therapy on hypoglycemia is not transient.

Although it is reassuring that cognitive function did not deteriorate in the group of patients on intensified therapy, the risks for chronic hypoglycemia in certain patients may be substantial. For example, patients who have frequent episodes of hypoglycemic coma or seizures (not generally experienced in the patients in this study) may constitute a high-risk group for chronic cognitive dysfunction. Moreover, acute consequences of frequent hypoglycemia (for example, the risk of mishap during a hypoglycemic episode) should not be underestimated. They should be weighed against potential benefits when clinical judgments are made with respect to intensifying insulin therapy and warrant close follow-up of all intensively treated patients with diabetes.

Hertzel C. Gerstein, MD, MSc
McMaster UniversityHamilton, Ontario, Canada


1. Amiel SA, Tamborlane WV, Simonson DC, Sherwin RS. Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus. N Engl J Med. 1987;316:1376-83.