LEUVEN II: Intensive Insulin Therapy in the Medical ICU (2006)

“In this randomized, controlled study, we found that intensive insulin therapy to maintain normoglycemia did not reduce in-hospital mortality among critically ill patients in the medical intensive care unit but did result in a significant increase in the risk of severe hypoglycemia.”

  • The LEUVEN II Investigators

1. Publication Details

  • Trial Title: Intensive Insulin Therapy in the Medical ICU
  • Citation: Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-461. DOI: 10.1056/NEJMoa052521
  • Published: February 2, 2006, in The New England Journal of Medicine
  • Author: Greet Van den Berghe, M.D., Ph.D.
  • Funding: The Research Foundation–Flanders, Belgium; and others.

2. Keywords

  • Intensive Insulin Therapy, Hyperglycemia, Glycemic Control, Medical ICU, Critical Illness, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients in a medical intensive care unit (ICU) (Population), does a strategy of intensive insulin therapy to maintain strict normoglycemia (Intervention) compared to a strategy of conventional glucose control (Comparison) reduce in-hospital mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The landmark LEUVEN I trial (2001) by the same investigators had shown a dramatic reduction in ICU mortality with intensive insulin therapy in a surgical ICU population. This led to the widespread adoption of “tight glycemic control” as a new standard of care.
  • Knowledge Gap: It was a critical and unanswered question whether the remarkable benefits seen in a predominantly post-cardiac surgery population would translate to the different and more heterogeneous population of patients in a medical ICU.
  • Proposed Hypothesis: The authors hypothesized that a strategy of intensive insulin therapy to maintain strict normoglycemia would be superior to a conventional glucose control strategy in reducing mortality and morbidity in critically ill medical patients.

5. Study Design and Methods

  • Design: A single-center, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: A single, large tertiary care medical ICU in Leuven, Belgium.
  • Trial Period: Enrollment ran from February 2002 to May 2005.
  • Population:
    • Inclusion Criteria: Adult patients admitted to the medical ICU who were expected to require intensive care for at least 3 days.
    • Exclusion Criteria: Included patients who were moribund (expected to die within 12 hours) or who had a history of diabetic ketoacidosis.
  • Intervention: An “intensive” insulin therapy strategy. Patients received a continuous intravenous insulin infusion, with the dose aggressively titrated to maintain a target blood glucose level between 80 and 110 mg/dL (4.4 to 6.1 mmol/L).
  • Control: A “conventional” strategy. Patients only received an insulin infusion if their blood glucose level exceeded 215 mg/dL, with a target of maintaining the glucose between 180 and 200 mg/dL.
  • Management Common to Both Groups: All patients received a standardized nutritional support regimen.
  • Power and Sample Size: The authors calculated that a sample size of 1200 patients would be required to have 80% power to detect a 7% absolute risk reduction in in-hospital mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: Overall in-hospital mortality.
    • Secondary Outcomes: Included ICU mortality, incidence of new kidney injury, duration of mechanical ventilation, and length of ICU stay.

6. Key Results

  • Enrollment and Baseline: 1200 patients were randomized (604 to the intensive group and 596 to the conventional group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in in-hospital mortality. 265 of 604 patients (43.9%) in the intensive group died, compared with 241 of 596 patients (40.4%) in the conventional group (p=0.21).
  • Secondary Outcomes: There was no significant difference in ICU mortality. However, the intensive-therapy group had a reduction in new kidney injury and a shorter duration of mechanical ventilation.
  • Adverse Events: Severe hypoglycemia (blood glucose < 40 mg/dL) was significantly more common in the intensive-therapy group (18.7% vs. 3.1%; p<0.001).

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.21 for the primary outcome of in-hospital mortality is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral for its primary outcome, ARR and NNT are not applicable.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The large, randomized, controlled design provided a high level of evidence.
  • Statistical Power: The study was large and adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The study focused on important patient-centered outcomes, including mortality and major morbidities.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The single-center design is a major limitation, as the results from this highly specialized medical ICU in Belgium may not be applicable to other centers. The nutritional strategy was also very aggressive and not typical of most ICUs.
  • Other: The very high rate of severe hypoglycemia (nearly 1 in 5 patients) in the intervention group is a major safety concern that likely counteracted any potential benefit.

10. Conclusion of the Authors

  • The authors concluded that in the medical ICU, intensive insulin therapy did not reduce mortality but did reduce morbidity (new kidney injury and duration of ventilation), at the cost of an increased risk of severe hypoglycemia.

11. To Summarize

  • Impact on Current Practice: This was a profoundly important “negative” trial. It failed to replicate the dramatic benefits seen in the surgical ICU (LEUVEN I) and provided a strong signal of harm (hypoglycemia), casting serious doubt on the universal applicability of tight glycemic control and halting its widespread adoption in medical ICUs.
  • Specific Recommendations:
    • Patient Selection: For adult patients in a medical ICU.
    • Actionable Intervention: The results do not support the routine implementation of an intensive insulin protocol to target a blood glucose of 80-110 mg/dL.
  • What This Trial Does NOT Mean: This trial does NOT mean that hyperglycemia should go untreated, only that a very strict target of 80-110 mg/dL is associated with significant harm without a clear survival benefit in this population.
  • Implementation Caveats: The key takeaway is the significant risk of severe hypoglycemia associated with this strategy.

12. Context and Related Studies

  • Building on Previous Evidence: The LEUVEN II trial (2006) was the direct follow-up to the landmark LEUVEN I trial (2001), designed to test if the findings from a surgical population would apply to a medical one.
  • Influence on Subsequent Research: The conflicting results between LEUVEN I (positive) and LEUVEN II (neutral with harm) created a state of major clinical uncertainty. This directly led to the design of the very large, multicenter NICE-SUGAR trial (2009), which ultimately provided the definitive answer, showing that tight glycemic control increased mortality in a mixed ICU population.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial left the key question of the true risk-benefit balance of tight glycemic control in a general ICU population unresolved.
  • Future Directions: The definitive NICE-SUGAR trial was the direct successor to this study, designed to resolve the conflict in the evidence and provide a clear answer for clinical practice.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, as it sought to confirm the findings of a previous, profoundly practice-changing trial in a different, larger patient population.
  • Methods: The randomized controlled design was a strength. However, the single-center, unblinded design and the unique co-interventions (high-calorie, early PN) are major methodological limitations that severely reduce the external validity of the findings.
  • Results: The study was negative for its primary outcome of in-hospital mortality and showed a significant increase in harm (severe hypoglycemia).
  • Conclusions and Applicability: The authors’ conclusion is a fair reflection of their data. The trial is a classic example of the importance of external validation. It demonstrated that the dramatic findings from a single-center study in a homogenous surgical population could not be replicated in a more heterogeneous medical population, and it served as a critical warning about the dangers of this risky therapy.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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