Becky McCall

September 14, 2016

MUNICH — A panel of 10 biomarkers that predicted cardiovascular outcomes in patients with dysglycemia in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial similarly predicted cardiovascular outcomes in Heart Outcomes Prevention Evaluation (HOPE) study participants with diabetes when added to routine clinical risk factors.

The candidate biomarkers might be of research value and help identify diabetic patients with high cardiovascular risk for further trials, said the lead investigator, Hertzel Gerstein, MD, from McMaster University, Hamilton, Ontario. He reported the findings at the European Association for the Study of Diabetes (EASD) 2016 Annual Meeting.

"We found that in addition to clinical risk factors, the biomarkers increased the ability to differentiate people with increased risk of cardiovascular events," he said, adding, "The biomarkers do not replace the clinical risk factors but…they enhance and improve prediction of cardiovascular events, over and above using clinical risk factors alone."

10 Biomarkers and Their Hazard Ratios for Risk of Cardiovascular Events

Biomarker Hazard ratio
N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1.12
Trefoil factor 3 1.12
Growth/differentiation factor 15 1.30
Apolipoprotein B 1.38
Angiopoietin-2 1.17
Osteoprotegerin 1.10
α-2-macroglobulin 1.24
Hepatocyte growth factor receptor 0.74
Glutathione S transferase α 0.80
Chromogranin A 1.27

One of the chairs of the session told Medscape Medical News, however, that, although they may be useful in a research capacity, risk scores from these biomarkers are far from prime time in terms of being used clinically.

Naveed Sattar, MD, professor of metabolic medicine, University of Glasgow, Scotland, said, "We do have risk scores for diabetes that work well but they are not used clinically."

Nevertheless, there has been published evidence that they can alter care, for example by identifying diabetes patients in whom to intensify therapy, so the research is definitely worth pursuing, he noted.

ORIGIN Trial Biomarkers Identified and Verified in HOPE

Explaining the rationale for trying to identify the biomarkers in the (ORIGIN) — which examined the cardiovascular safety of using insulin glargine (Lantus, Sanofi) early on in the course of treatment in patients with dysglycemia/type 2 diabetes — Dr Gerstein explained, "We wanted to know whether other blood tests, in addition to routine clinical risk factors, added further to the ability to predict cardiovascular events."

The results of the ORIGIN biomarker analysis were published in 2015 (Circulation. 2015;132:2297-2304).

In the new work presented at the EASD meeting, the researchers wondered how these 10 biomarkers would perform in a totally different trial population — the HOPE study.

This was a landmark study employing the blood-pressure lowering ACE inhibitor ramipril in a patient population at risk for vascular events and ran from 1995 to 2000.

From a total of 350 HOPE participants with baseline diabetes, 77 participants who had had a composite outcome of cardiovascular events were included in this latest analysis.

The samples were analyzed for the 10 biomarkers identified in ORIGIN, and a potential link between these biomarkers and the composite outcome was assessed, after researchers accounted for seven of the eight clinical risk factors (LDL/HDL was not available for HOPE participants).

They took the 10 biomarkers with their hazard ratios plus clinical risk factors, as used in ORIGIN, and asked whether the exact same model was predictive of events in HOPE.

The results showed that all biomarkers, apart from chromogranin A, yielded hazard ratios highly consistent with those in ORIGIN. The biomarkers improved the C statistic, a measure of predictive accuracy of the composite outcome, from 0.66 to 0.74 (P < .001).

"We found that nine of the 10 showed the same effect [as previously identified in ORIGIN] qualitatively. One went in the opposite direction. But they all seemed to predict cardiovascular events," reported Dr Gerstein.

"Some we know more about — for example, angiopoietin 2 — and some of the biomarkers identified come up in other studies, so they must be important," he remarked.

"With apolipoprotein B, for example, even after lipid levels [are controlled for], it still predicts cardiovascular events, and angiopoietin 2 is involved in capillary angiogenesis and might be important for complications of diabetes."

More Evidence for Angiopoietinlike Protein 2 as a Marker of CVD

Indeed, in another presentation during the same session, Mathilde Fraty, MD, from CHU Poitiers, France, reported results of a study that examined whether circulating angiopoetinlike protein 2 was helpful in the long-term risk assessment of type 2 diabetes with regard to all-cause mortality and cardiovascular morbidity and mortality, in addition to established risk factors.

End points comprised a primary one of all-cause death and a secondary end point of major adverse cardiac events (MACE, a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), similar to the end points in the ORIGIN and HOPE analyses.

The results showed that in patients with type 2 diabetes, serum concentrations of angiopoetinlike protein 2 were independently associated with death (HR, 1.36) and MACE (HR, 1.48).

"For this reason, angiopoetinlike protein 2 is a promising candidate biomarker for improving risk stratification in type 2 diabetes patients and may prove to be a valuable therapeutic target," Dr Fraty and colleagues said.

Implications for Clinical Practice and Further Research

Dr Gerstein explained that while his new analysis constitutes a risk model, in theory, blood tests for these markers could help better determine patients' risk of myocardial infarction, stroke, or CV death.

"We now have the ability to simultaneously measure many different biomarkers in the blood that we couldn't measure only a few years ago, and this marks the beginning of a new phase of research to further our understanding of cardiovascular events," he said.

Any refinement in risk prediction "might be a reason for being more aggressive with treatment. It's all about the ability to apply what we know to the patient before us."

Dr Sattar said, "What we need going forward is biomarkers that tell us about risk but that also tell us that we need to treat patients differently" — for example, more aggressively.

By way of example, he cited the PONTIAC trial, a study published that demonstrated that, in patients with type 2 diabetes and elevated NT-proBNP, better outcomes were obtained by intensifying therapy with an ACE inhibitor and adding a beta-blocker (J Am Coll Cardiol. 2013;62:1365-1372).

"Accelerated uptitration of renin-angiotensin antagonists and beta-blockers to maximum tolerated dosages is an effective and safe intervention for the primary prevention of cardiac events for diabetic patients preselected using NT-proBNP," those authors concluded.

Dr Sattar said that currently, the best data are on cardiac biomarkers.

The ones most likely to be employed clinically right now are NT-proBNP and possibly troponin. "The evidence base for these biomarkers is better than [it is for some of these other] emerging biomarkers."

Nevertheless, it's still a matter of cost, he noted. "We don't use NT-proBNP and troponin [as much as we would like] because of the expense associated with their use…compared with a sugar test, which costs pennies."

Dr Gerstein declared a grant from Sanofi. Dr Sattar and Dr Fraty have declared no relevant financial relationships.

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European Association for the Study of Diabetes (EASD) 2016 Meeting; September 13, 2016; Munich, Germany. Abstracts 58, 60.

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