Robert Rosenson, MD: Treating Lower Extremity Arterial Disease in Diabetes

Investigators currently do not understand the role of adenosine-enhancing therapies in blood viscosity and microcirculatory blood flow in patients with lower extremity arterial disease (LEAD). What they do know is the significant association between adverse limb events or loss and blood flow impairment in patients with LEAD.

To bridge a gap between these factors, investigators from the Mount Sinai Health System recently investigated adenosine enhancers on blood viscosity in patients with LEAD and type 2 diabetes. In an interview with MD Magazine®, study author Robert Rosenson, MD, a professor of Medicine in the Division of Cardiology at the Icahn School of Medicine at Mount Sinai, provided some context and background into understanding this patient population before delving into the study’s makeup.

MD Mag: What is the currently understood pathology of lower extremity arterial disease?

Rosenson: You know that patients with diabetes have much higher rates of lower extremity arterial disease, the build-up of plaque in the arteries that supply the lower legs. Often, we can pick up these symptoms by reports of cramping of the legs, fatigue when they're walking—this is known as intermittent claudication.

However, in diabetes patients, we know that rates of lower extremity amputations are much higher than in patients without diabetes. There have been many lines of evidence that support that people with diabetes not only have greater rates of disease in the large and medium arteries, but also in the small vessels, the microcirculation. And the flow in the microcirculation, particularly in the feet, is an important determinant of infection, gangrene, and limb loss.

How could microcirculatory flow be improved in patients with LEAD?

Very little research has investigated how to improve microcirculatory flow in the feet of diabetes patients. We explored this hypothesis in a randomized, double-blind, placebo-controlled, three-arm crossover trial. This trial evaluated the effects of aspirin versus ticagrelor, versus aspirin plus ticagrelor, in patients with lower extremity arterial disease who had controlled diabetes.

Why did we pick ticagrelor? Ticagrelor is an antiplatelet agent that's often used post-coronary stent, or in the post-myocardial infarction patient, where it's been shown to reduce cardiovascular events and improve survival. But this agent also improves adenosine, and adenosine is a cellular substance within the blood cells that makes them more flexible and decreases the thrombus formation at low shear rates—mimicking what happens in the microcirculation. That was our hypothesis.

In this trial, one of the major strengths is that every study participant received the same treatment. In other words, they received aspirin, ticagrelor, and aspirin-ticagrelor. Often in mechanistic studies, one would consider a limitation is imbalance in the group, but when you have everybody receiving all the therapies in random order, that's an important strength.