The link between poor diabetes control and lower extremity disease — the term that covers an array of conditions including peripheral artery disease and peripheral neuropathy — has long been clear. But which patients will develop this serious diabetes complication has not, says Caitlin Hicks, a vascular surgeon in Johns Hopkins’ Multidisciplinary Diabetic Foot and Wound Service.

“Lower extremity disease can cause substantial harm, including foot ulcers, amputation and even death,” she says. “But the literature is mixed about what markers of diabetes control we can use to assess patients’ risk of having these complications.”

Searching for biomarkers that can accurately predict lower extremity disease, Hicks and her colleagues used data gathered from the 1999–2004 National Health and Nutrition Examination Survey, a long-running study designed to assess the health and nutritional status of thousands of volunteers in the U.S. based on physical exams and interviews. A diabetes diagnosis is typically recorded as part of this annual study, as are the results of a hemoglobin A1C test, which is a biomarker that reflects blood sugar control over three months. Hicks and her colleagues used stored blood samples from participants to measure glycated albumin, a newer biomarker that reflects blood-sugar control over two to three weeks, a shorter time than the hemoglobin A1C test. Glycated albumin is not commonly used in the U.S., and has never before been associated with lower extremity disease.

In addition, the volunteers underwent ankle-brachial index measurements (a test that measures the difference in blood flow between the arms and legs to diagnose peripheral artery disease) and monofilament testing (an exam in which the foot is gently probed by a nylon pointer to assess sensation to diagnose peripheral neuropathy).

Using data from 5,785 volunteers — 5,092 without diabetes and 693 with the disease — the researchers compared their measures of hemoglobin A1C and glycated albumin with diagnoses of peripheral artery disease and peripheral neuropathy. They found that both tests were associated with lower extremity disease in people with diabetes but not in people without diabetes. Moreover, the higher the blood sugar reflected in these tests, the higher the risk of having peripheral artery disease and peripheral neuropathy. According to senior author Elizabeth Selvin, a professor at the Johns Hopkins Bloomberg School of Public Health, “This study adds to the growing evidence that controlling blood sugar is very important to prevent lower extremity disease.”

Hicks notes that these findings have bidirectional implications: If patients with diabetes have elevated hemoglobin A1C and/or glycated albumin results, doctors should consider testing them for lower extremity disease. And if patients are diagnosed with lower extremity disease, these blood sugar tests should be the next step in their workup to look for underlying diabetes.

“A lot of what we see as vascular surgeons is a lack of awareness in the community. A patient might come to see us with a foot wound, but they haven’t been checked yet for diabetes. Or if they have diabetes, their blood sugar control has not been recently assessed and may be poorly controlled,” Hicks says. “By identifying factors related to lower extremity disease, we can help patients avoid further complications.”