07.30.2013
by Crystal Phend
Senior Staff Writer, MedPage Today

Action Points

Results of a new meta-analysis suggest that both high and low concentrations of serum glucose are damaging to the heart.

Low glucose levels requiring outside assistance or medical treatment were associated with a 2.05-fold elevated relative risk of cardiovascular disease (95% CI 1.74 to 2.42), Mitsuhiko Noda, MD, PhD, of the National Center for Global Health and Medicine in Tokyo, and colleagues found.

Severe comorbid illness didn’t appear to explain the link, the researchers reported online in BMJ.

“Because intensive glucose control increases the risk of severe hypoglycemia, the findings of this study add to the evidence supporting individualized glycemic targets in people with type 2 diabetes,” they wrote.

That might mean using a less stringent glycated hemoglobin (HbA1c) target for individuals at high risk of hypoglycemia, they explained.

The findings would also tend to support use of metformin and other glucose-lowering agents with a low propensity toward hypoglycemia as well as good self-care in terms of glucose monitoring and attention to food intake, particularly for individuals on insulin, the group added.

A link between hypoglycemic events and cardiovascular health is plausible, they argued, citing acute effects on sympathoadrenal activation, inflammation, and endothelial function and the possibility of cardiac ischemia or arrhythmia during hypoglycemia.

The review included six cohort studies that looked at the association between severe hypoglycemia and cardiovascular events in a total of 903,510 participants with type 2 diabetes.

The ACCORD trial, in which subanalyses had suggested a correlation between mortality and severe hypoglycemia that wasn’t stronger with tight glucose control, was not included in the meta-analysis due to lack of a hazard ratio for cardiovascular disease. Studies in acute hospital settings were also excluded.

During follow-up ranging from 1 to 5.6 years, 0.6% to 5.8% of the patients had severe hypoglycemia.

Severe hypoglycemia was defined by a healthcare diagnostic code in most of the studies, but one study defined it by assistance from someone other than the patient, and another defined it by episodes that were life-threatening or fatal or that caused disability, incapacity, hospital admission, or medical intervention.

Regardless, all of the included studies individually showed a correlation between hypoglycemia and cardiovascular disease, with relative risks ranging from 1.60 to 3.45.

Assuming that the association of severe hypoglycemia and cardiovascular disease was causal, 1.56% of cardiovascular disease in the population would be attributable to severe hypoglycemia (95% CI 1.32% to 1.81%), the researchers estimated.

All of the studies adjusted for age, sex, history of cardiovascular disease, history of microvascular complications or a surrogate, baseline health status, and use of diabetes medication.

While factors like race, dyslipidemia, smoking, and body mass index weren’t consistently adjusted for, analyses stratified by adjustment for those factors didn’t suggest different results.

A bias analysis indicated that comorbid severe illness alone was unlikely to entirely explain the association of hypoglycemia with cardiovascular disease.

“For example, to account for the association, comorbid severe illness would have needed to be 10 times more prevalent in patients with severe hypoglycemia than in those without severe hypoglycemia, and would have to have had a relative risk of 10,” Noda’s group pointed out, which they called “unrealistically high.”

Limitations were lack of individual patient data, exclusion of unpublished studies, and the possibility of selection bias in the studies included that extracted data from medical records or claims or primary care databases.

Also the results might not generalize to type 1 diabetes because cardiovascular events are relatively rare in young people with type 1 diabetes, Noda and colleagues noted.

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

last updated 07.31.2013