Serial NT-proBNP found to identify risk for adverse CV outcomes

But this study, the authors say, indicates the potentially heightened clinical relevance of strategies for biomarker-based CV risk stratification in patients with type 2 diabetes. As examples of such strategies, they cite the emerging data demonstrating the efficacy of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 agonists in modifying the risk for heart failure in type 2 diabetes patients.

For the laboratory, the clinical implications of the study should also be of interest. “If you read most papers, there is one way to evaluate data which is really proper and statistically correct. And we have it in our paper. Our study is statistically sound. We didn’t introduce any bias. When you just look at the distribution of test results, you either get or you don’t get a statistical association of the biomarker level to outcomes.”

There is a problem with this approach, however. “All of the graphs are fine and helpful,” Dr. Jarolim says. “But then you have to transfer this knowledge to clinical practice. You have to decide what the clinically useful cutoff should be.”
“Once you want to transfer the findings into clinical use, you obviously cannot just tell clinicians that patients in the highest quartile are at the highest risk. They don’t know when one quartile ends and another starts. They need a really defined cutoff, which typically doesn’t coincide with any quartile or quintile. You have to give them numbers.”

Therefore, in many studies, “we try to not only use statistically correct stratification, but also to come up with a number that will be clinically useful. In this particular study, we explored various cut points and found that NT-proBNP concentration of 400 pg/mL as the point between so-called high and low NT-proBNP worked very well.” It’s not a magic number, he says. “It could be adjusted or optimized once we study an average type 2 diabetes patient population, not just those at high risk.” But here, the 400 pg/mL cutoff showed a clear discrimination of risk and may be most practical for clinical practice.

Dr. Jarolim describes a paradox that arises with the drugs that protect the natriuretic peptides. “Natriuretic peptides are established biomarkers of both BNP, which is the biologically active part of the precursor molecule proBNP, and NT-proBNP, which is the inactive N-terminal portion of the molecule that hangs in the circulation and is more stable and somewhat easier to measure.”

Both BNP and NT-proBNP are elevated in patients with heart failure, Dr. Jarolim notes. “BNP is generally good for you. So why would the patient be doing worse with a higher BNP? It was discovered some years ago that only a small fraction of BNP molecules in patients are the full-size molecule that is biologically active, and most BNP measured by current clinical assays are the less active or inactive fragments of BNP.” The other part of the precursor molecule that is measured, proBNP, just goes down, as expected, because it’s not cleaved; it’s not protected, he explains. BNP, however, does not go down.

Alogliptin, the dipeptidyl peptidase 4 (DPP-4) inhibitor studied in the EXAMINE trial, is one of the molecules that should protect full-size BNP cleaved by DPP-4. But in this study, the researchers found that treatment with a DPP-4 inhibitor did not meaningfully alter either NT-proBNP or BNP concentrations. “We didn’t see any differences between alogliptin patients and patients getting a placebo.”

A new medication heavily advertised in the past two years that combines neprilysin inhibitor sacubitril and angiotensin receptor blocker valsartan to treat heart failure patients is not mentioned by name in the study. This medication, marketed as Entresto, works as a treatment by inhibiting protease, which cleaves BNP, he says. “When you start treating patients with a neprilysin inhibitor, they get clinically better and you would expect they should have lower BNP levels. But, paradoxically, they don’t show lower levels. They have higher levels of BNP.”

“It seems obvious that the more of the good, full-size BNP your patients have, the better,” Dr. Jarolim says. “But that can be confusing to clinicians since favorable response to heart failure treatment is typically associated with lower BNP levels. In contrast, NT-proBNP responds to this therapy as one would expect, that is, we see its levels decline.”
When Entresto came on the market, “it created a bit of a panic among laboratories that didn’t have the NT-proBNP assay available or that had only BNP.” Some diagnostic companies offer only the BNP assay, he says, while other companies offer the NT-proBNP assay.

Further research on how biomarkers may help to predict and stratify possible side effects of selected treatments is underway. “We are definitely addressing the cardiovascular safety of certain medications. As an example, we are evaluating biomarkers that may predict the risk of bleeding in patients with atrial fibrillation treated by anticoagulants.”
“Clinicians should welcome this study’s support for use of serial NT-proBNP results to assess—and potentially to aggressively treat—diabetes and ischemic heart disease patients at highest risk of heart failure,” Dr. Jarolim says. “You can be more aggressive in various approaches with antidiabetic medications, blood pressure medications, and so on, so it’s very important to identify those patients at high risk.”

Dr. Jarolim doesn’t wish to oversell the study, however. “But it would be a logical outcome of these findings that there may be a recommendation to conduct monitoring of CV patients every several months,” he says.

Anne Paxton is a writer and attorney in Seattle.