March 26, 2009
The NICE-SUGAR study, published in today’s New England Journal of Medicine1, reports on mortality in 6000 critically ill hyperglycemic patients randomly assigned to either tight control of blood sugar (target blood sugar of 80-108 mg/dl with an achieved mean-weighted glucose of 115 mg/dl) or looser control of blood sugar (target blood sugar of 144-180 mg/dl with an achieved mean-weighted glucose of 144 mg/dl) while they were in the intensive care unit. This multi-center, international study’s key conclusion was that relative mortality at 90 days was actually 10% higher in the tight control group (829/3010) than in the looser control group (751/3012), with this difference primarily reflecting more cardiovascular deaths in the tight control group.
The Endocrine Society commends the NICE-SUGAR investigators for producing an important and provocative addition to the medical literature and draws the following conclusions and recommendations from their data. First, near-normalization of blood sugar does not clearly improve outcomes in all critically ill hyperglycemic ICU patients, and there is even a suggestion that such an approach may worsen outcomes. Second, looser control of hyperglycemia, i.e., target blood glucose of 144-180 mg/dl, is a reasonable, and perhaps preferable, option in this particular group of very sick patients. Third, it is essential to assess clinically meaningful outcomes, such as mortality, as well as surrogate or intermediate endpoints, such as blood sugar level, in studies of diabetes treatment as the NICE-SUGAR study has done; improvement of blood sugar control may not always translate to better clinical results.
Finally, the rush to deploy difficult and resource-intensive protocols in ICU’s may be premature until there is a better understanding of the reasons that the NICE-SUGAR results differ so markedly from those of an earlier study by Van den Berghe et al. 2, which showed that tight control of blood sugar in critically ill hyperglycemic patients seemed to improve outcomes. There are certainly differences in study design and target patient populations between these two studies, and the situation is further clouded by van den Berghe’s failure to replicate the results of her original study, which was done in surgical patients, in a subsequent study of critically ill medical patients.3
Close analysis of these study differences, including examination of the results in various sub-groups, may give rise to important questions that need to be answered by further studies. For example, are outcomes after tight glucose control the same in those with pre-existing diabetes as in those without it? Does the number or severity of hypoglycemic episodes, or some other aspect of tight glucose control, impair the future counter-regulatory and autonomic nervous system responses to hypoglycemia in this patient population? What is the temporal relationship of hypoglycemia to death? Would the use of continuous glucose monitoring improve outcomes?
Aggressive outpatient management of hyperglycemia has been the hallmark of diabetes care for almost two decades since the DCCT4 and UKPDS5 studies showed reduced microvascular complications with such an approach. Potential benefits of tight glucose control in reducing macrovascular complications and death have been more difficult to demonstrate, with recent studies (ACCORD6, ADVANCE7, and VADT8) showing that such aggressive management of hyperglycemia can be associated with substantial risks and/or few benefits.
The Endocrine Society believes that we have entered an era of more nuanced and patient-appropriate recommendations as a result of these recent large, well-done outpatient and inpatient studies. We believe physicians should individually tailor their approach to glycemic control in their ICU patients, perhaps targeting glucose values between 144-180 mg/dl, until we better understand the reasons for these somewhat counterintuitive findings.
For further information, please contact Holly Whelan, Associate Director, Health Policy, at hwhelan@endo-society.org.
References:
1. The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283-1297.
2. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359-67.
3. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461.
4. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.
5. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with Sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 21998;352:837-853.
6. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.
7. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572.
8. Duckworth, W, Abraira, C, Moritz, T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-139.
