No Benefit of Intensive Glucose Control in Critical Patients

Intensive glucose control doesn’t reduce mortality risk in critically ill patients when compared with conventional glucose control. Instead, it increases the risk for severe hypoglycemia by threefold, according to a new meta-analysis.

Intensive glucose control “was not associated with reduced mortality or other benefits in critically ill adults,” concluded Derick Adigbli, MBBS, PhD, of the Critical Care Division at The George Institute for Global Health in Sydney, Australia, and coauthors.

The study was published online in NEJM Evidence.

Previous Conflicting Results

Hyperglycemia is associated with poorer outcomes in critically ill patients, but randomized controlled trials (RCTs) investigating intensive insulin therapy targeting normoglycemia have yielded conflicting results regarding whether this approach reduces mortality in such patients. Trial-level meta-analyses published in the wake of these studies did not support the use of intensive insulin therapy targeting normoglycemia.

This has carried over to current clinical practice guidelines, which recommend initiating insulin therapy for persistent hyperglycemia only in those with blood glucose ≥ 18src mg/dL checked on two occasions and targeting a glucose range of 14src-18src mg/dL.

Researchers chose to perform a meta-analysis of individual patient data, as it “allows patients to be allocated to subgroups even when those subgroups were not explored in the individual trials,” they wrote.

The researchers therefore meta-analyzed individual patient data in RCTs of intensive glucose control in critically ill adults, not only to estimate its effect on mortality overall but also in prespecified subgroups.

Study Design

To be included, a trial had to focus on critically ill adults (≥ 18 years) and compare outcomes between those randomized to intravenous insulin administration targeting a blood glucose concentration of ≤ 12src mg/dL and those assigned to a higher blood glucose target, and where the target was maintained for the duration of the full intensive care unit stay or ≥ 7 days.

The primary outcome was in-hospital mortality (censored at 9src days), with secondary outcomes including survival to 9src days post-randomization, proportion of patients treated with mechanical ventilation, vasoactive agents, new renal replacement therapy, and the time to alive cessation of those treatments.

Severe hypoglycemia (blood glucose concentration <4src mg/dL) was a safety outcome.

Subgroup analyses, performed only for the primary outcome, looked at operative vs nonoperative patients, prior diagnosis of diabetes or sepsis at baseline, acute brain injury, and illness severity.

Intensive Glucose Control: Comparable Mortality, Greater Hypoglycemia

Of 14,726 reports, the researchers chose 2src trials (n=14,171; mean age, 59 years; 36% women; mean body mass index, 27) that met inclusion criteria, with publication dates ranging from 2srcsrc1 to 2src23.

For the primary outcome analysis, data were available for 7src59 and 7src49 participants allotted to intensive and conventional glucose control, respectively. Of these, 27.3% and 26.8%, respectively, died (risk ratio [RR], 1.src2; 95% CI, src.96-1.src7; P=.52). There were also no significant differences in secondary outcomes.

Of the trials, 14 had only aggregated data. These yielded a pooled RR for in-hospital death of src.94 (95% CI, src.74-1.2src; I², 71.4%).

The researchers found no evidence of publication bias and no apparent heterogeneity of the treatment effect in any of the subgroups.

There were, however, notable differences between the groups in severe hypoglycemia experienced by 13.3% vs 3.9% of patients in the intensive vs the conventional glucose groups, respectively (RR, 3.38; 95% CI, 2.99-3.83; P <.srcsrcsrc1).

The authors noted their study had several potential limitations. Its main weakness was not obtaining patient-level data from all eligible trials. As they limited the study to critically ill adults, they were also unable to comment on the possible benefits or harms of intensive glucose control in critically ill children. Additionally, the analysis depended on the internal and external validity of data generated over a 2src-year period.

Follow Guideline Recommendations

An editorial by Shohinee Sarma, MD, MPH, of the Division of Endocrinology, Diabetes, and Metabolism at Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, published on July 23 in NEJM Evidence, noted that the meta-analysis didn’t capture the full risk for severe hypoglycemia in hospitalized patients, including coma and cardiovascular events. Moreover, Sarma added that critically ill patients “may not be able to vocalize hypoglycemic symptoms and may already be experiencing pain and discomfort.”

The findings of this meta-analyses “remind clinicians to continue targeting glucose at 14src-18src mg/dL among critically ill patients to reduce the risk of hypoglycemia,” Sarma concluded.

The analysis was funded by the National Health and Medical Research Council of Australia, the Canadian Institutes of Health Research, a grant to one of the authors from the National Health and Medical Research Council of Australia, and funding to one of the authors from the French Ministry of Health. Adigbli reported no relevant financial relationships. The other authors’ disclosures are available in the original paper. Sarma received grants from the University of Toronto Clinician Scientist Training Program, the Clinician Investigator Program (Ministry of Health and Long-Term Care Ontario and University of Toronto), the Canadian Society of Endocrinology and Metabolism, and the Women’s Research Institute. Sarma also received a speaker’s honorarium from the American Diabetes Association.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape Medical News and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).