Is There an Intrinsic Vascular Benefit to TZDs: Examining the Evidence

A CME symposium supported by an educational grant from Takeda Pharmaceuticals North America

Thomas A Buchanan, MD
William T Cefalu, MD
Robert J Chilton, DO, FACC

Reported by Joelle Escoffery, PhD

By the time patients are diagnosed with type 2 diabetes, they likely have already developed significant macrovascular disease. Cardiovascular disease (CVD) risk has been shown to be increased 15 years before the development of frank clinical diabetes. It has been documented that diabetes is considered a cardiovascular risk equivalent. Visceral adipose tissue has been shown to play an important role in impaired glucose disposal, which is one factor that makes up the metabolic syndrome, along with alterations in uric acid metabolism, dyslipidemia, hemodynamic changes, and increases in novel risk factors (eg, C-reactive protein [CRP], fibrinogen, and plasminogen activator inhibitor-1 [PAI-1]). The presence of any 3 of these is associated with a 3- to 4-fold risk of CVD, independent of the effects of hyperglycemia.

The initial damage leading to the development of atherosclerotic disease is likely to begin with changes in endothelial function that start occurring as early as the teenage years. The endothelium releases a variety of different substances, including a variety of vasodilators, vasoconstrictors, growth mediators and modulators, and inflammatory mediators and modulators. Endothelium dysfunction results in vessel constriction, as well as both prothrombotic and proinflammatory states. Endothelium-dependent vasodilation has been shown to be impaired in patients with type 2 diabetes.

Hyperglycemia also contributes to the increased risk of atherogenesis seen among patients with diabetes via the promotion of oxidative stress and endothelial dysfunction. In the STOP-NIDDM Study, treatment with acarbose was associated with a significant decrease in cardiovascular events. Elevations in novel risk factors such as CRP, PAI-1, and fibrinogen have all been associated with increased risk of CVD.

Because of the greatly elevated risk for CVD among people with diabetes, managing CVD risk factors in a high clinical priority. Studies such as the 4S and CARE have shown that lowering LDL-C is associated with significant decrease in major coronary events. Similarly, the VA-HIT Study demonstrated that treatment with gemfibrozil to lower triglycerides and increase HDL-C was associated with a 22% reduction in cardiac events. One of the biggest challenges in patients with type 2 diabetes is managing the multiple CVD risk factors associated with this condition. Studies such as the UKPDS and Steno-2 demonstrated that risk factor management can be effective.

TZDs are associated with a variety of actions that are potentially beneficial to CVD risk reduction, including: improvements in some lipid parameters, decrease in microalbumin excretion, decreases in blood pressure, decreases in endothelial cell dysfunction, increases in adiponectin, and decreases in both PAI-1 and CRP. The PROactive study tested the efficacy of pioglitazone for the secondary prevention of CVD among patients with type 2 diabetes. Although there was no significant effect of pioglitazone on all CVD endpoints, there was a 16% relative risk reduction in death, MI, or stroke, and that result was statistically significant. Several potential mediators of this effect include reductions in A1C, triglyceride improvements, elevations in LDL and HDL, and decreases in systolic blood pressure, all of which occurred in patients treated with pioglitazone. Pioglitazone has also been associated with favorable changes in intima media thickness, a subclinical measurement of atherosclerotic disease, in patients with type 2 diabetes and in patients at risk for type 2 diabetes.