Hospital Patients Twice as Likely to Die With Hypoglycemia

Liam Davenport

December 07, 2016

Hospitalized patients who experience low blood glucose levels are at substantially increased risk of death, both over the short term and after discharge, compared with those who don't have hypoglycemia, regardless of their diabetes status, new results from a large-scale study indicate.

The findings show that, in hospitalized patients with spontaneous and insulin-related hypoglycemia, the mortality risk is more than doubled, rising to an approximately fourfold increased risk of death in patients with severe hypoglycemia (compared with those without hypoglycemia).

The research, which was published online recently in the Journal of Clinical Endocrinology & Metabolism, coincides with the publication of a series of recommendations to tackle the threat of hypoglycemia to diabetes patients.

Noting that hypoglycemia is common among hospitalized patients, regardless of diabetes status, lead researcher Amit Akirov, MD, Institute of Endocrinology, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel, said: "These data are a timely reminder that hypoglycemia of any cause carries the association with increased mortality."

And Dr Akirov told Medscape Medical News that the finding that death rates are higher with severe vs moderate hypoglycemia "indicates a possible dose-dependent effect — a decrease in blood glucose levels is associated with an increase in mortality rates."

However, although he and his coauthors put forward several potential explanations as to why hypoglycemia may be associated with increased mortality risk, there remain a number of unanswered questions.

He said: "There is some controversy regarding the importance of blood glucose levels, as some claim this is a real cause for increased mortality, while others believe this is a marker of the general status of the patient. Further research is needed to try to find the answer to this question."

As most hospitalized patients get routine blood tests, and these usually include glucose levels, "there is probably no need for a specific recommendation" to do this, he said, but stressed that it's important to have this information on admission.

Implications of Hypoglycemia Are Unclear

Although it is known that spontaneous and insulin-related hypoglycemia are common in hospitalized patients, both with and without diabetes, the definition of hypoglycemia in hospitalized patients is inconsistent, and so the true prevalence and prognostic implications remain unclear.

To examine the association between hypoglycemia and mortality in hospitalized patients, Dr Akirov and colleagues defined hypoglycemia as a blood glucose level < 70 mg/dL (3.9 mmol/L), which was stratified into moderate hypoglycemia (40–70 mg/dL, 2.2–3.9 mmol/L) and severe hypoglycemia (< 40 mg/dL, < 2.2 mmol/L).

His team gathered data on all first admissions to an Israeli 1300-bed tertiary medical center with 10 medical wards between January 2011 and December 2013. Mortality data were obtained to June 2015, with the medical database used to collate self-reported data on alcohol use, smoking, and body mass index, as well as the presence of comorbidities.

Diabetes was defined as a previous diagnosis of diabetes in medical records or use of any oral hypoglycemic agent, glucagonlike peptide 1 (GLP-1) agonist, or insulin at admission.

Patients were therefore divided into: non–insulin-treated controls (NITC) and insulin-treated controls (ITC), non–insulin-related hypoglycemia (NIH) and non–insulin-related severe hypoglycemia (NISH), and insulin-related hypoglycemia (IH) and insulin-related severe hypoglycemia (ISH).

From an overall cohort of 33,675 patients, 2947 (9%) were identified to have at least one blood glucose value < 70 mg/dL. Of these, 2605 had moderate hypoglycemia, with 1011 cases being insulin-related, and 342 had severe hypoglycemia, with 201 cases being insulin-related.

Of interest, almost half of the patients with hypoglycemia during hospitalization did not have preexisting diabetes (49%), although most of the patients with severe hypoglycemia did have preexisting diabetes (69%). Most of those with moderate hypoglycemia were not treated with insulin during the hospitalization (61%), while the majority of those with severe hypoglycemia were treated with insulin (59%).

Cause of Admission Doesn't Affect Link Between Hypoglycemia and Mortality

The overall in-hospital mortality rate was 6.3%, with the highest death rate during hospitalization seen among non–insulin-treated patients with severe hypoglycemia.

The median follow-up period was 1022 days, and the overall mortality rate at the end of follow-up was 31.9%, with the highest death rate again seen among non–insulin-treated patients with severe hypoglycemia, although the rate was almost as high among insulin-treated patients with severe hypoglycemia.

Outcomes of In-Hospital and Overall Mortality by Group

In-hospital mortality rate (%) 4.7 11.0 13.9 41.8 12.9 24.9
Overall mortality rate at follow-up (%) 28.0 42.9 50.7 70.9 55.3 69.1
Adjusted HR for mortalitya 1.0b 1.8c 2.1c 3.2 c 2.4c 3.6c
a. Adjusted for age, gender, smoking, alcohol, diabetes status, hypertension, malignancy, ischemic heart disease, congestive heart failure, cerebrovascular disease, and chronic renal failure
b. Reference
c. All P < .001 compared with non–insulin-treated controls
NITC=Non–insulin-treated controls
ITC=insulin-treated controls
NIH=non–insulin-related hypoglycemia
NISH=severe non–insulin-related hypoglycemia
IH=insulin-related hypoglycemia
ISH=insulin-related severe hypoglycemia

When analyzing the impact of diabetes on mortality risk, the team found that adjusted hazard ratios for NIH and NISH patients without diabetes, compared with NITCs, were 2.3 and 3.9, respectively (P < .001 for both).

For patients with diabetes, the adjusted hazard ratios for NIH and NISH patients vs NITCs were 1.6 and 2.7, respectively (P < .001 for both).

The most common admission diagnoses were infectious diseases (29%), diseases of the circulatory system (15%), and diseases of the digestive system (8%). Infectious diseases and circulatory diseases were also the most common admission diagnoses in patients with insulin-related and non–insulin-related hypoglycemia.

However, the researchers found that cause of admission did not have a significant influence on the association between hypoglycemia and mortality.

Blueprint to Reduce Hypoglycemia in Diabetes Patients is "Starting Point"

Separately, the Endocrine Society has partnered with a coalition of medical-specialty societies, payers, industry, patient advocates, diabetes educators, and research organizations involved in diabetes to produce a Hypoglycemia Quality Collaborative (HQC) blueprint.

The aim of this is to raise awareness of hypoglycemia in diabetes patients and to encourage initiatives to reduce its incidence, says the Endocrine Society, which publishes the Journal of Clinical Endocrinology & Metabolism.

The recommendations tackle areas such as gaps in care, research, and the quality of care provided to diabetes patients who experience hypoglycemia, which are much needed because "despite the availability of evidence-based prevention and management techniques, policy mechanisms, and digital health tools, hypoglycemia outcomes in individuals with diabetes remain poor, and the incidence and effects of long-term and recurrent hypoglycemia are not fully understood," the organizations state.

The HQC Strategic Blueprint has just been published and sets out a framework for reducing the incidence of hypoglycemia, divided into six domains:

  • Defining and describing hypoglycemia to support standards of care.

  • Advancing hypoglycemia evidence to reduce gaps in care.

  • Measuring and improving the quality of care for patients who experience hypoglycemia.

  • Advocating for an increased focus on hypoglycemia.

  • Delivering hypoglycemia prevention and management education.

  • Recognizing hypoglycemia as a public-health issue.

Each of these domains is further subdivided into three strategic areas, which contain a series of recommendations. For example, the first domain, to define and describe hypoglycemia, contains these strategic areas: creating a new definition; implementing the definition; and maintaining the definition.

In terms of the second domain — advancing the hypoglycemia evidence to reduce care gaps — the blueprint stresses the need to identify areas for research, recommendations for how that research should be conducted, and how best practices should be adopted from research.

For the third — measuring and improving of the quality of care in hypoglycemia — the blueprint discusses the need for current quality measures to be reviewed and updated, if necessary, and calls for the development of new quality measures that support the surveillance of individuals at risk of hypoglycemia across care settings.

Summarizing, the HQC states: "Success in increasing awareness and reducing incidence will require the ability of the entire healthcare, medical, and patient community to elevate the issue of hypoglycemia into the national consciousness and work together to design, implement, and evaluate initiatives to improve the prevention and management of hypoglycemia.

"This blueprint provides a starting point."

No external funding was received for the study. The authors report no relevant financial relationships. The Endocrine Society thanks Merck for its generous support of the HQC Blueprint. The HQC is spearheaded by the Endocrine Society, in conjunction with Abbott Diabetes Care, Aetna, American Association of Clinical Endocrinologists, American Association of Diabetes Educators, American College of Physicians, American Diabetes Association, AstraZeneca, Close Concerns, Dexcom, Lilly, JDRF, Johnson & Johnson, Joslin Diabetes Center, Medtronic Diabetes, Merck, Novo Nordisk, PQA Alliance, and T1D Exchange.

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J Clin Endocrinol Metab. Published online November 17, 2016. Abstract

Endocrine Society. Hypoglycemia Quality Collaborative Strategic Blueprint. Statement


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