Severe hypoglycemia boosts CVD risk in type 2 diabetes

Fran Lowry

August 02, 2013

Tokyo, Japan - For patients with type 2 diabetes, having episodes of severe hypoglycemia may be putting them at risk for cardiovascular disease, a review of six studies involving more than 900 000 patients suggests [1].

The meta-analysis also supports the notion that avoiding severe hypoglycemia may be important to prevent cardiovascular disease in such individuals.

The review, a joint effort by researchers in Japan, the US, and the Netherlands, is published online July 30, 2013 in BMJ.

Although severe hypoglycemia is a well-recognized side effect of glucose-lowering therapies in patients with diabetes, its potential adverse effects on vascular events have been overlooked, senior author Dr Mitsuhiko Noda (National Center for Global Health and Medicine, Tokyo, Japan) told heartwire via email.

"The results of large-scale clinical trials such as ACCORD , ADVANCE , and VADT suggested a possible association between hypoglycemia and cardiovascular disease. However, some researchers have suggested that severe hypoglycemia may be a marker of comorbid severe illness rather than the cause of cardiovascular events," Noda said.

"Therefore, the association between hypoglycemia and cardiovascular disease remains controversial; hence, we conducted the current analysis."

Relevant observational studies

The investigators analyzed observational studies found in Medline, Embase, the Cochrane Library, and Web of Science databases to February 2013, without any language restrictions.

They selected studies that reported an association between hypoglycemia and cardiovascular disease and examined the sensitivity of the association to possible uncontrolled confounding by unmeasured comorbid severe illness using a bias analysis.

The six studies included 903 510 participants and collected information on patients' age, gender, and duration of diabetes, CVD history, insulin use, body-mass index, and smoking status. Studies that were done in acute hospital settings were excluded from the analysis.

In all, from 0.6% to 5.8% of participants experienced severe hypoglycemia from one to five years of follow-up.

The team found that severe hypoglycemia was strongly associated with a higher risk for cardiovascular disease (relative risk 2.05; 95% CI 1.74-2.42; p<0.001).

The bias analysis indicated that comorbid severe illness alone may not explain the association between hypoglycemia and cardiovascular disease, Noda said.

"To explain this association, comorbid severe illness would have had to be extremely strongly associated with both severe hypoglycemia and cardiovascular disease," he said.

Severe hypoglycemia could be bad for the heart for a number of reasons, he noted.

"The sympathetic nervous response to severe hypoglycemia increases catecholamine levels, resulting in acute adverse effects on the myocardium and the vascular system. The increase in catecholamine also leads to platelet activation, leucocyte mobilization, and coagulation, which may trigger cardiovascular disease events," Noda said.

In addition, inflammation and endothelial dysfunction are also induced by acute hypoglycemia. "Both play roles in the development of atherosclerosis. Furthermore, cardiac ischemia or arrhythmia during hypoglycemia may lead to cardiovascular disease," he said.

The research team hopes that clinicians will become aware of the dangers of severe hypoglycemia in managing their type 2 diabetes patients.

"Although glycemic control is a very important part of diabetes treatment to reduce diabetic complications, physicians should consider less stringent glycemic-control targets in type 2 diabetes patients who are at risk for severe hypoglycemia, such as elderly patients and patients with renal insufficiency," Noda said.

Patient-centered approach to treatment

heart wire invited Dr Rita Kalyani (Johns Hopkins University School of Medicine, Baltimore, MD) for her views on this study.

The study has strengths, including the large number of participants, and included a rigorous systematic methodology, but the fact that it is an observational study is a limitation, she noted.

"This study investigates associations between hypoglycemia and cardiovascular disease and suggests that hypoglycemia may be a risk factor for cardiovascular disease, but it cannot provide definitive evidence of that," she said. "Also, the study did not include information as to the specific types of diabetes treatments patients were on, the dose of treatments, or the frequency of hypoglycemia in individual participants."

Kalyani added that the study points to the importance of individualized care for patients with type 2 diabetes.

"This study lends further support to adopting a patient-centered approach for treating patients with type 2 diabetes as put forth in a recent consensus statement by the American Diabetes Association and the European Association for the Study of Diabetes," she said. "But we still need further studies to better understand the causal association of hypoglycemia with cardiovascular disease."

Noda and coauthors as well as Kalyani report no relevant financial relationships.




Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.