NICE-SUGAR: Intensive vs. Conventional Glucose Control in Critical Illness (2009)

“In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU.”

  • The NICE-SUGAR Study Investigators

1. Publication Details

  • Trial Title: Intensive versus Conventional Glucose Control in Critically Ill Patients
  • Citation: The NICE-SUGAR Study Investigators. Intensive versus Conventional Glucose Control in Critically Ill Patients. N Engl J Med. 2009;360(13):1283-1297. DOI: 10.1056/NEJMoa0810625
  • Published: March 26, 2009, in The New England Journal of Medicine
  • Author: The NICE-SUGAR Study Investigators
  • Funding: The Australian and New Zealand National Health and Medical Research Council; Health Research Council of New Zealand; and others.

2. Keywords

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

3. The Clinical Question

  • In a mixed population of critically ill adult patients expected to require ICU care for 3 or more days (Population), does a strategy of intensive glucose control (Intervention) compared to a strategy of conventional glucose control (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The landmark single-center LEUVEN I trial (2001) had shown a dramatic mortality benefit with “tight” glycemic control (target 80-110 mg/dL) in a surgical ICU population. This led to the widespread adoption of this practice. However, a subsequent trial by the same group in a medical ICU population (LEUVEN II, 2006) failed to show a survival benefit and revealed a high risk of severe hypoglycemia.
  • Knowledge Gap: There was major clinical uncertainty and controversy regarding the true risk-benefit balance of tight glycemic control in a general, mixed population of critically ill patients. A large, definitive, multicenter trial was urgently needed to resolve this conflict.
  • Proposed Hypothesis: The authors hypothesized that intensive glucose control would be superior to conventional glucose control in reducing 90-day mortality.

5. Study Design and Methods

  • Design: A very large, international, multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 42 intensive care units (ICUs) in Australia, New Zealand, and Canada.
  • Trial Period: Enrollment ran from December 2004 to August 2008.
  • Population:
    • Inclusion Criteria: Adult patients admitted to the ICU who were expected to require ICU care for 3 or more consecutive days.
    • Exclusion Criteria: Included patients with a contraindication to tight glucose control, those not expected to survive, and those with 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 81 and 108 mg/dL (4.5 to 6.0 mmol/L).
  • Control: A “conventional” strategy. Patients only received an insulin infusion if their blood glucose level exceeded 180 mg/dL (10.0 mmol/L), with a target of maintaining the glucose below this level.
  • Management Common to Both Groups: All other aspects of ICU care, including nutritional support, were at the discretion of the treating clinicians according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 6100 patients would provide 90% power to detect a 3.8% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included cause-specific mortality, duration of organ support, and the incidence of severe hypoglycemia.

6. Key Results

  • Enrollment and Baseline: 6104 patients were randomized (3054 to the intensive group and 3050 to the conventional group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: 90-day mortality was significantly higher in the intensive-control group: 829 of 3014 patients (27.5%) died, compared with 751 of 3012 patients (24.9%) in the conventional-control group (p=0.02).
  • Secondary Outcomes: The increased mortality in the intensive-control group was primarily due to an increase in deaths from cardiovascular causes. There were no significant differences in the duration of mechanical ventilation or renal-replacement therapy.
  • Adverse Events: Severe hypoglycemia (blood glucose ≤ 40 mg/dL) was significantly more common in the intensive-control group (6.8% vs. 0.5%; 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: Odds Ratio (OR) for death at 90 days: 1.14 (95% CI, 1.02 to 1.28; P-value: 0.02).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Death in Intervention Group) / (Odds of Death in Control Group).
      • Calculation: The paper reports the result as 1.14.
      • Clinical Meaning: An OR of 1.14 means that patients in the intensive-control group had a 14% higher odds of dying at 90 days compared to the conventional-control group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 1.02 to 1.28.
      • Clinical Meaning: Since this entire range is above the line of no effect (1.0), it confirms that the result is statistically significant and demonstrates a clear signal of harm.
    • P-value: The p-value of 0.02 is below the 0.05 threshold, indicating the result is statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 27.5% – 24.9% = 2.6%.
      • Clinical Meaning: For every 100 critically ill patients treated with intensive glucose control, about 2-3 additional deaths occurred.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.026 = 38.
      • Clinical Meaning: You would only need to treat 38 patients with intensive glucose control to cause one additional death.
  • Subgroup Analyses: The finding of harm was consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized, controlled design provided a massive amount of high-quality data and minimized bias.
  • Generalizability: The pragmatic design and inclusion of a very large, heterogeneous population of medical and surgical ICU patients make the findings highly generalizable to real-world practice.
  • Statistical Power: The enormous sample size provided definitive power to confidently rule out a benefit and to detect a small but clinically important harm.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are highly generalizable to the broad population of critically ill patients.
  • Other: The study was not placebo-controlled, as it was considered unethical to not treat significant hyperglycemia in the control group.

10. Conclusion of the Authors

  • The authors concluded that in a large, international cohort of critically ill adults, intensive glucose control increased mortality at 90 days.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided definitive evidence that the widespread practice of “tight glycemic control” was not just ineffective, but actively harmful. It led to the immediate and universal de-adoption of this practice.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients.
    • Actionable Intervention: Do not target strict normoglycemia (81-108 mg/dL). A more moderate target (e.g., <180 mg/dL) is safer and associated with better survival.
    • Expected Benefit: Avoiding tight glycemic control prevents one additional death for every 38 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that hyperglycemia should go untreated. It only argues against a very strict and aggressive target.
  • Implementation Caveats: The key takeaway is the critical importance of avoiding severe hypoglycemia, which was a major driver of harm in the intensive-control group.

12. Context and Related Studies

  • Building on Previous Evidence: The NICE-SUGAR trial (2009) was designed to definitively resolve the major clinical controversy created by the conflicting results of the single-center LEUVEN I (2001) and LEUVEN II (2006) trials.
  • Influence on Subsequent Research: The definitive finding of harm in this trial has been the cornerstone of all subsequent international critical care and diabetes guidelines, which now universally recommend a more conservative approach to glucose control in the ICU.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear finding of harm.
  • Future Directions: The results of this trial have shifted the focus of research in this area towards understanding the optimal management of hyperglycemia in specific subgroups and the long-term consequences of glycemic variability.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, seeking to provide a definitive answer to one of the most significant controversies in critical care at the time.
  • Methods: The very large, multicenter, pragmatic RCT design was of the highest quality and was essential for providing a generalizable and definitive answer. The main methodological weakness is the open-label design, but the primary outcome of mortality is objective and unlikely to be biased.
  • Results: The study reported a statistically significant and clinically important increase in harm (NNH of 38) for its primary outcome. The finding of a dramatic increase in severe hypoglycemia provided a plausible mechanism for this harm.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in evidence-based medicine, serving as a powerful example of how a large, high-quality trial is essential for validating the findings of smaller, single-center studies before a risky intervention is widely adopted. Its findings are broadly applicable and have become the global standard of care.

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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