Higher CVD risk, or lower risk? hs-cTn in diabetes

“Your CRP today may be quite different from your CRP a few weeks from now whereas troponin does not have as much variability. So, absolutely, I think troponin could be more useful than CRP in many circumstances if we’re talking about cardiovascular risk stratification.”

The authors note that their findings about high-sensitivity troponin might be more significant for down-stratifying cardiovascular risk than for up-stratifying patients according to risk. Says Dr. Selvin: “Showing improvements in prediction means we are reclassifying people according to their risk, either up or down. The improvement in down-classification means that oftentimes these comorbidities are classifying people as high risk, when really, they’re not. And so, when you measure troponin, it correctly classifies these individuals downward into their correct risk group.”

Thus, the cost ramifications of the study are significant. “Again, we didn’t study cost-effectiveness specifically. But if we’re doing a more accurate job of classifying people according to their risk, that means more efficiency and hopefully better treatment decisions, overall care, and patient outcomes,” Dr. Selvin says.

High-sensitivity troponin can clearly improve cardiovascular stratification, she says. “So we think there is great potential for these high-sensitivity troponin assays to be used in clinical practice routinely to help monitor risk.”

“A 70 year old is not a 70 year old is not a 70 year old. Some older adults are still working and even running marathons,” Dr. Selvin says, “while others are frail and unable to perform routine daily tasks without assistance. Using objective biomarkers can help us understand that heterogeneity in older patients, and accurately assess mortality risk in what is clearly not a homogeneous group.”

The second Diabetes Care study, by Dr. Saenger and colleagues, also supplies useful information to guide selection of biomarkers to predict development of CVD and major adverse cardiovascular events (MACE) in diabetes. With their focus on childhood-onset type one diabetes, the authors studied the ability of high-sensitivity cardiac troponin and N-terminal prohormone B-type natriuretic peptide to predict CVD and MACE. They examined a cohort of childhood-onset type one diabetes patients, the subject of a historic study, and tested biobanked specimens available at their first presentation following their diabetes diagnosis, which occurred more than 20 years earlier (Costacou T, et al. Diabetes Care. 2020;43[9]:2199–2207).

The two biomarkers, hs-cTnT and NT-proBNP, have been suggested for use in general and at-risk populations with acute illness from CVD or heart failure, but their potential value as biomarkers in stable settings for prediction of long-term cardiovascular events has been less well studied. The predictive value of the two biomarkers has been fairly well characterized for individuals with type two diabetes (and found to contribute to improved CVD prediction) but not in type one, says Dr. Saenger.

“It may in part be due to the fact that there has been a focus more on type two diabetes simply because there is a greater prevalence of type two compared to type one diabetes, and easier in one sense to enroll patients in trials and studies,” explains Dr. Saenger, who serves as the AACC liaison to the CAP Clinical Chemistry Committee. “However, now treatments have improved for type one diabetes, people are diagnosed earlier, they’re living longer, but they’re developing more cardiovascular-related complications. With type two, they’re generally not diagnosed until middle age and can also already manifest a lot of other comorbidities.”

People with type one diabetes are developing similar cardiovascular complications compared with those without diabetes, she says, “but seemingly at an earlier phase because of the toll that diabetes has taken on their bodies.” Dysglycemia and traditional risk factors are known to contribute to the disproportionate cardiovascular risk in type one diabetes compared with the general population—a more than 30-fold risk among young adults. But she and her coauthors believe identification of factors beyond those is long overdue. The team chose hs-cTnT and NT-proBNP as biomarkers of myocardial injury and heart failure, respectively.

To conduct the study, the researchers drew upon data from the Epidemiology of Diabetes Complications study, a prospective investigation of a childhood-onset (<17 years) type one diabetes cohort diagnosed, or seen within one year of diagnosis, at Children’s Hospital of Pittsburgh between 1950 and 1980. The EDC study ran from 1986 to 1988 and continued to follow subjects biennially with surveys for 25 years.

Dr. Saenger’s study determined that quartiles of NT-proBNP were linked with CVD incidence in both sexes and incidence of CVD increased incrementally with each increasing quartile of hs-cTnT in males. Both hs-cTnT and NT-proBNP independently and significantly predicted the incidence of cardiovascular events and MACE more than 20 years later, although sex differences were observed. They are strong, independent predictors of CVD and MACE among individuals with childhood-onset type one diabetes, the authors say. Unfortunately, however, the addition of both biomarkers to a model that included traditional CVD risk factors (BMI, smoking, non-HDL-C, albumin excretion) did not significantly improve the prediction of CVD, Dr. Saenger says.

Similarly, when the two biomarkers were simultaneously added to the model for predicting MACE (which included HbA1c, hypertension status, non-HDL-C, WBC count, and albumin excretion), NT-proBNP was a better predictor of MACE compared with hs-cTnT, but addition of both biomarkers did not improve the prediction of MACE.

The authors write, “Although we were unable to show that their assessment improves outcome prediction beyond that offered by traditional cardiovascular risk factors, it would be unlikely that a single biomarker or even a combination of two biomarkers would significantly improve disease prediction, given the multitude of factors contributing to the pathogenesis of cardiovascular complications in diabetes.”

The observed differences in the distribution of the two biomarkers and the strength of their association with the outcomes studied by sex highlights the value of disaggregating study findings by sex, the authors say. The concentrations of cardiac troponin in females, when using high-sensitivity troponin assays, is lower compared with males. But, they write, “the ability of hs-cTnT to independently predict cardiovascular outcomes has generally not been evaluated separately in men and women, with few exceptions.”

“Our results suggest that compared with men,” they continue, “women are dramatically more likely to experience a subsequent cardiovascular event with hs-cTnT concentrations below the assay limit of detection (LoD) (i.e., <5 ng/L), with no further increase in risk at higher hs-cTnT concentrations.” Confirmation of their results in other cohorts and/or diverse populations with or without diabetes is important, they say, to determine clinical relevance, “because it would suggest that separate prognostic cutoff points should be established for men and women.”

“This is similar to what is noted for a normal, healthy population,” Dr. Saenger says, “and is why sex-specific cutoffs are advocated for when using high-sensitivity troponin assays, with females having a lower 99th percentile compared to males. We were hoping to see more of a signal in our cohort, which was approximately half female, but we were right at the limit of detection and the hs-cTnT assay isn’t the best in terms of sensitivity. But it’s what we had available.” According to the International Federation of Clinical Chemistry and Laboratory Medicine specifications for designations for high-sensitivity troponin assays, the assay needs to detect more than 50 percent of normal individuals in males and females. “The Roche electrochemiluminescence immunoassay, due to its analytical design, does meet that criteria for males but not for females,” Dr. Saenger says of the assay used in the study. She maintains an updated list of analytical characteristics for hs-cTn assays on the International Federation of Clinical Chemistry and Laboratory Medicine website (http://bit.ly/2qKSK25).

The study also determined that NT-proBNP didn’t add a great deal of predictive ability. “It was a stronger predictor of major adverse cardiac events in females compared to males, but we didn’t find this association to be as strong as we thought we would.”

However, Dr. Saenger says, “With an analytically superior high-sensitivity assay, if you’re able to essentially follow a patient’s risk over time, it would be important to know at what timepoint it can accurately predict development of cardiovascular disease. We don’t know that just yet. It would be of value in the outpatient setting to prospectively measure some of these biomarkers in real time and implement routine testing in the future if they show promise.”

She continues to work with her study coauthors by looking at other high-sensitivity cardiac troponin assays as the analytical and diagnostic capabilities of those assays evolve. “Another hs-cTn assay may demonstrate significant results in our type one diabetes cohort, simply because it is analytically superior and can quantitate more values in females,” as one example, she says.

A study that applies the same methodology used in her type one diabetes study to a different cohort might be worthwhile, Dr. Saenger says. “The patients in our study were followed pretty closely and are on the physicians’ radar. It would be really interesting if there were a similar cohort that had specimens collected over decades to look at each individual’s biomarker patterns, in particular with females since a large proportion of type one diabetics are women, and evaluate the correlation of biomarkers with cardiovascular disease or some type of subclinical myocardial dysfunction that we didn’t know about.” 

Anne Paxton is a writer and attorney in Seattle.