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EASD: Biomarkers May Predict CAD, Death in Diabetes Patients

Posted: Monday, September 26, 2011

Two biomarkers may be associated with cardiovascular events and death in type 2 diabetes patients, researchers reported at EASD.

The antioxidant peroxiredoxin-4 (Prx4) and the inflammatory protein resistin were significantly associated with both outcomes in two separate trials.

Esther Gerrits, MD, of the University Medical Center Groningen in the Netherlands, said hyperglycemia induces oxidative stress and endothelial damage, which subsequently leads to both microvascular and macrovascular complications in patients with diabetes. The antioxidant stress system typically protects against oxidative stress, she said, and circulating levels of Prx4 have been proposed as a novel biomarker of oxidative stress.

It is the only secretable form of the six isoforms of the antioxidant, she added, and has previously been linked with sepsis, type 1 diabetes, and myocardial infarction, as well as other inflammatory markers such as C-reactive protein and interleukin-6.

To investigate, Gerrits and colleagues looked at data from the prospective, observational ZODIAC-28 study of 1,067 Dutch primary care patients with type 2 diabetes. They assessed two cohorts, one starting in 1998 and the other in 2001. Prx4 was assessed in baseline serum samples, and the median value was 0.86 U/L. Over a median follow up of 9.8 years, 32.3% of patients died. Of those, 43% were attributable to cardiovascular causes.

She and colleagues found that increased levels of Prx4 were associated with high rates of both cardiovascular and all-cause death, and remained significant after controlling for numerous confounders, including age, gender, body mass index (BMI), serum creatinine, smoking, diabetes duration, systolic blood pressure, cholesterol-HDL ratio, history of complications, and albuminuria.

These patients had an 80% increased risk of all-cause death (95% CI 1.53 to 2.12), which remained a significant 51% increased risk in controlled analyses (95% CI 1.24 to 1.82). The results were similar for cardiovascular mortality, with an 83% higher risk for those with elevated Prx4 (95% CI 1.46 to 2.30), which remained a significant 52% greater risk after controlling for confounders (95% CI 1.13 to 2.04).

Gerrits noted that although antioxidants are thought to be protective of oxidative stress, it is clearly a biomarker of mortality in this study. "We don't know the underlying mechanisms yet, but we can speculate that Prx4 has been upregulated in cases of oxidative stress," she said.

But Lise Tarnow, MD, of the Steno Diabetes Center in Gentofte, Denmark, who moderated the session, noted that the researchers did not add other makers of inflammation to their adjusted model.

In a second study, Claudia Menzaghi, PhD, of the Casa Sollievo della Sofferenza in San Giovanni Rotondo in Italy, and colleagues found that elevated levels of resistin also are tied to cardiovascular events and death in type 2 diabetes patients.

Serum resistin, a pro-inflammatory cysteine-rich protein secreted by macrophages, has been associated with an increased risk of cardiovascular events in the general population, but few studies have looked at associations specifically for type 2 diabetes patients.

So they looked at data from four studies -- two case-control studies and two prospective trials. The case-control data came from 798 patients in the Gargano Heart Study and 1,050 patients in the Joslin Heart Study.

Prospective data came from the 350 patients in the Gargano Heart Study-Prospective and from the 1,028 patients in the Gargano Mortality Study.

Menzaghi and colleagues found that in the case-control studies, serum resistin was significantly higher in patients with coronary artery disease than in those without, and remained so even after controlling for BMI, diabetes duration, and baseline therapies.

In the prospective studies, those with higher levels had a significantly greater risk of cardiovascular events and all-cause death than those with lower levels, which remained after controlled analyses:

    Gargano Heart Study-Prospective: HR 1.35, 95% CI 1.14 to 1.59, P=0.001
    Gargano Mortality Study: HR 1.13, 95% CI 1.05 to 1.21, P=0.001

The researchers also found that patients in the prospective studies who had resistin levels greater than the median were significantly more likely to have a major cardiovascular event and were more likely to die (P=0.000023 and P=0.0006, respectively).

Menzaghi said resistin is an independent predictor of major cardiovascular events and all-cause death, and may be useful for "improving the predictability of cardiovascular disease in patients with type 2 diabetes."

Tarnow noted that the researchers in this study also did not control for other well-known markers of inflammation, and that correcting for these factors "is very important in the future, as we are facing more challenges with the increasing number of markers that we are measuring."

Practice Pearls

    Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

    Explain that both elevated peroxiredoxin-4 and resistin were associated with cardiovascular events and death in patients with type 2 diabetes in two separate studies.

    Note that the association with both new biomarkers remained significant after controlling for a number of variables, but that other markers of oxidative stress or inflammation were not measured.

Source:, Alkhalaf A, et al "Serum peroxiredoxin-4 and mortality in patients with type 2 diabetes (ZODIAC-28)" EASD 2011; Abstract OP21-122.

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