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What do type 2 diabetes and atherosclerosis have in common? More than you may realize, according to researchers. In fact, recent evidence indicates that inflammation may be a risk factor in the development and complications of both diseases. These were among some of the issues raised by presenters at the American Diabetes Association's (ADA) 54th Annual Advanced Postgraduate Course, February 23–25 in New York.
A high fraction of cardiovascular events cannot be attributed to traditional and modifiable risk factors such as dyslipidemia, hypertension and smoking, notes Vivian A. Fonseca, MD, FRCP, professor of medicine and chief of the endocrinology section at Tulane University in New Orleans.
This finding prompted researchers to consider several emerging risk factors, including circulatory inflammatory markers seen in the origins of atherosclerosis. "As you add more risk factors, you tend to have more inflammation," says Fonseca.
"We're rediscovering old things," he says, citing a study that appeared in last year's Journal of Clinical Investigation. In the study, researcher Steven E. Shoelson, MD, PhD, of Joslin Diabetes Center in Boston, states that "clues to the involvement of inflammation in diabetes date back to more than a century ago, when high doses of sodium salicylate (5.0–7.5 g/d) were first demonstrated to diminish glycosuria in diabetic patients having `the milder form of the disease,' presumably type 2 diabetes."1
Today, investigators recognize that inflammation stemming from a variety of pathogens or viruses acts as a defense mechanism and influences insulin sensitivity. With current technology's inability to pinpoint specific inflammation sites, inflammation is regarded largely as systemic, although scientists suspect that the arterial wall may be involved.
The most practical risk predictor for coronary events is C-reactive protein (CRP) when measured using a highly sensitive assay. Not only is CRP often elevated in patients with atherosclerosis, type 2 diabetes, or both, but it also is linked to cardiometabolic syndrome and insulin resistance, foretelling the onset of type 2.
Researchers still don't know whether treatment aimed at CRP will lower the incidence of cardiovascular events. Nonetheless, elevated CRP clusters are found in obese patients and those with cardiometabolic syndrome, making it a useful predictor of cardiovascular events as well as future diabetes.
The good news is that several therapies used to manage diabetes have demonstrated effects on CRP levels. Beyond diet and exercise lifestyle modifications as well as aspirin, recent data suggest that all statins decrease plasma CRP >20% from baseline. The mean reduction has been 35%, with the highest-level statins achieving the most impressive results, says Fonseca.
Other nontraditional risk factors include plasminogen activator inhibitor-1 and homocysteine—markers that increase acutely after myocardial infarction, leading some researchers to view them as inflammatory.
"Treatment to modulate low-grade inflammation is the focus of very active research," Fonseca writes in his abstract from the session. "Some therapeutic agents commonly used in cardiovascular disease (statins) and diabetes (insulin, TZDs, and metformin) seem to decrease CRP."
More large-scale, prospective randomized clinical trials are needed to confirm these suspicions. "The possibility of finding new agents that block the inflammatory cascade is important when one considers the substantial burden that both diabetes and cardiovascular disease have on modern society," says Fonseca.
IMAGING AND EARLY INTERVENTION
A preventive strategy for avoiding myocardial infarctions and strokes by controlling lipids with statins may not work in all patients, according to a presentation by cardiologist Arthur S. Agatston, MD, FACC, an associate professor at University of Miami Miller School of Medicine and author of the best-selling book The South Beach Diet. Several years ago, he founded the Agatston Research Foundation, a Miami-based nonprofit center focused on heart health and wellness.
For patients with a strong genetic predisposition, diet and exercise changes may not be adequate interventions, says Agatston. "You can be building up a lot of plaque with a healthy lifestyle." Known and unknown risk factors exist years before a cardiovascular event occurs. Over time, calcium increasingly builds in arteries, forming cholesterol-building plaques that begin proximally and extend distally, he says.
Patients can be asymptomatic and pass a stress test, while harboring lesions that may grow and rupture unexpectedly. "There are a lot of myths about coronary calcium and obstructive disease," adds Agatston. Patients don't usually present with only one vessel disease, but rather with multiple vessel disease, which is much more likely to kill them than a blockage as significant as 80%.
Screening for cardiovascular disease and interpreting heart scans has been fraught with major clinical pitfalls. New imaging techniques, however, are enabling physicians to better view the size and density of cholesterol-filled plaques.
Intravascular ultrasound also has advantages over angiography because it allows for more accurate visualization not only of the lumen to the coronary arteries, but also the plaques hidden within the walls. PET scanning is another modality that can help detect coronary heart disease before clinical symptoms appear.
Proper treatment depends on the degree of disease severity and its impact on the heart's function. Armed with this knowledge, physicians can treat patients more aggressively in the preclinical disease stage before progression occurs, says Agatston. This may even cause soft lesions to regress. "Practicing with all of this information is frankly a lot of fun, and I'm very optimistic about the future."
A MOVE TO STANDARDIZE
Also on the prevention front, the glycated hemoglobin (A1C) test—a vital diagnostic tool in diabetes management—is evolving toward a more globally harmonized standard. More than 30 different reference methods are available commercially to gauge A1C, leading to wide variations in numbers reported by laboratories, says David B. Sacks, MD, FRCP, a pathologist at Brigham and Women's Hospital in Boston and an associate professor at Harvard Medical School in Cambridge, Mass.2
Although glycated hemoglobin can be measured in three different tests, A1C is commonly used to follow long-term glycemic control. Two major research endeavors—the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS)—showed that A1C is a marker for the risk of contracting complications in type 1 and type 2 diabetes, respectively.
Even "a 1 percent change in A1C translates into dramatic increase in risk of cardiovascular complications," explains Sacks. Currently, the ADA recommends that A1C be measured at least twice a year in patients who are reaching treatment objectives. In patients who are changing therapy or not achieving these goals, it suggests screening every three months.
The National Glycohemoglobin Standardization Program (NGSP) in the U.S. has decreased interlaboratory differences by basing its values on the DCCT reference method. Meanwhile, the International Federation for Clinical Chemistry (IFCC) has formulated a method for A1C employing mass spectrometry. Because IFCC's A1C figures are much lower than NGSP's findings, there is formidable debate regarding the reporting of these values.
To resolve this matter, researchers are exploring a third option—an assay that would reflect the mean blood glucose (MBG). An international multicenter study commenced in April 2006, enrolling patients with type 1 or type 2 diabetes and healthy individuals, says Sacks. However, Sacks contends primary caregivers will likely experience difficulty trying to obtain the mean blood glucose, he contends.
"Clinically meaningful DCCT/UKPDS traceable numbers will continue to
be used for the care of patients with diabetes until there is consensus to
change," he says. "A1C is an integral component in the management
of patients with diabetes. Standardization has markedly improved A1C
measurement in patient samples." 
References
2. Sacks DB for the ADA/EASD/IDF working group of the HbA1c assay.
Clin Chem 51:681–683, 2005.
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