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

Anne Paxton

October 2020—When Elizabeth Selvin, PhD, MPH, of Johns Hopkins Bloomberg School of Public Health, began her studies of high-sensitivity cardiac troponin assays, they had not yet been approved in the U.S., as they are now, for use in diagnosing myocardial infarction. But some of her studies and those of Amy K. Saenger, PhD, DABCC, medical director of clinical laboratories and director of clinical chemistry at Hennepin County Medical Center in Minneapolis, take high-sensitivity cardiac troponin in a new direction by exploring its potential use as an aid in monitoring cardiovascular risk in the general population.

The new high-sensitivity assays detect circulating concentrations of high-sensitivity cardiac troponins I and T in 50 to 100 percent of the general ambulatory population and may indicate subclinical myocardial injury if concentrations are increased above the sex-specific reference interval (99th percentile).

How far can troponin’s uses as a biomarker now be expanded beyond its essential role in diagnosing MI in the acute care setting? Two new Diabetes Care studies conducted by Drs. Selvin and Saenger and others report on the potential usefulness of high-sensitivity cardiac troponin as a biomarker for improving mortality risk stratification in adults with diabetes and for predicting cardiovascular disease and major adverse cardiovascular events in childhood-onset type one diabetes.

In the first study, Dr. Selvin, professor of epidemiology and principal investigator of several research grants, and her colleagues investigate how well high-sensitivity cardiac troponin assays perform at reflecting comorbidity burden and improving mortality risk stratification in older adults with diabetes (Tang O, et al. Diabetes Care. 2020;43[6]:1200–1208). Such a potential use would be valuable because, as the population ages, cardiovascular risk reduction in older adults continues to be of central importance but the heterogeneity in the health of older adults presents challenges in evaluating their risk, the study notes.

Dr. Selvin and coauthors hypothesized that hs-cTnI or hs-cTnT may either replace or supplement comorbidity burden in the prediction of mortality risk in older adults with diabetes. The results of their study confirm that both might well serve such a role.

“I’m particularly interested in understanding use of troponin for risk stratification in certain populations, and in particular diabetes, because people with diabetes are in a very high-risk group for cardiovascular complications,” Dr. Selvin says. “New classes of diabetes medications, including SGLT2 inhibitors, have cardiovascular benefits. The question is who should be first in line to receive these medications, which should be targeted to people in highest cardiovascular risk groups.”

“How do we optimize who should get these more expensive and cardioprotective medications?”

One of the interests of Dr. Selvin and her colleagues was determining whether troponin could be an aid in understanding who is at the highest risk of disease. “We have demonstrated that in people with diabetes, individuals who have elevated high-sensitivity cardiac troponin concentrations are at the highest risk of death and cardiovascular outcomes, particularly heart failure,” she says.

Drawing on the data from the longitudinal Atherosclerosis Risk in Communities (ARIC) study, Dr. Selvin and colleagues included 1,835 older adults (ages 67 to 89) with diabetes and assessed these subjects’ comorbidities at visit five (2011–2013). High comorbidity burden was defined as three or more comorbidities (cancer history, arthritis, hypertension, emphysema, incontinence, etc.). The research team measured concentrations of hs-cTnI in plasma obtained from a biobank using the Abbott Architect Stat hs-TnI assay and hs-cTnT concentrations using the Roche Elecsys Troponin T Gen 5 Stat assay in all the participants.

Both hs-cTnI and hs-cTnT reflected similar comorbidity profiles. There were 418 deaths that occurred over a median follow-up period of 6.2 years. In the study, higher concentrations of hs-cTnI and hs-cTnT were strongly associated with higher all-cause mortality risk. Specifically, the four-year cumulative mortality among those with troponin values less than the 40th percentile in the ARIC population at visit five was 5.4 percent (hs-cTnI) and 5.4 percent (hs-cTnT). This is compared with 27.8 percent (hs-cTnI) and 29.4 percent (hs-cTnT) among those with hs-cTnI or hs-cTnT greater than or equal to the 85th percentile.

A high comorbidity burden was associated with elevated mortality risk compared with those with a low burden, but including either cardiac troponin in risk equations improved prediction even above and beyond comorbidity burden. Inclusion of the two high-sensitivity cardiac troponin tests predominantly down-classified those who did not die during follow-up.

When the researchers assessed the use of troponin to risk stratify beyond health status levels defined by a high comorbidity burden or dementia or frailty, those with high hs-cTnI or hs-cTnT and the presence of a high comorbidity burden or frailty or dementia were at the highest risk of mortality. “Even among those with a low comorbidity burden, no dementia, and no frailty,” they write, “high hs-cTnI or hs-cTnT was independently associated with a higher mortality risk.”

The results led the coauthors to conclude that there may be a role for measuring hs-cTnI or hs-cTnT to supplement the overall clinical impression of the patient, thus refining comorbidity burden to improve individualization of cardiovascular risk reduction strategies in older age.

In their commentary published in the same issue, Ian J. Neeland, MD, and James A. de Lemos, MD, of the University of Texas Southwestern Medical Center, say “the cohort is reflective of the contemporary older adult population with diabetes and study findings are likely generalizable to the aging U.S. population.”

The ARIC study, Dr. Selvin notes, has been ongoing for decades and is one of the biggest cohort studies of cardiovascular disease in the United States. “We’ve been following these patients for over 30 years. Originally we recruited almost 16,000 people in the late 1980s when they were middle-aged. We’re seeing all the participants annually; they are all over 75 now.” The average age was about 75 at the time she and colleagues did their study.

“Traditional risk factors do a very good job with cardiovascular risk prediction, so it’s hard to get the prediction statistics to budge,” Dr. Selvin says. With this study, the researchers wished to know whether these troponin assays are independently able to improve prediction for cardiovascular events, particularly heart failure and mortality.

“What our research has showed,” she says, “is that a single elevated troponin can help us identify people who are at the highest risk of poor outcomes. That was an exciting, important finding.”

The researchers categorized subjects in the study according to the number of different comorbidities in their profile. In theory, “Physicians should holistically think of their patients and think about the morbidities and the effects they have,” Dr. Selvin says. “In the American Diabetes Association guidelines, it is recommended that treatment decisions in older adults should depend on number of comorbidities.” But it’s not clear how clinicians should operationalize the guidelines, she adds.

“We looked at how these comorbidities are related to outcomes. For the most part, what we showed is that if you have high comorbidity, you’re likely to have an elevated high-sensitivity troponin, but that the troponin itself is just much more discriminatory. Using an objective biomarker such as troponin that is easily measured may be an approach to risk stratification that overcomes some of the complexity of trying to think about all the wide variety of comorbidities in the context of patients with diabetes.”

A criticism of the ADA guidelines for older adults, she says, is the wide differences among comorbidities, which can range from cancer, dementia, or hypertension to frailty or incontinence. “Metastatic cancer is very different from osteoarthritis or urinary incontinence, and treatment decisions should not treat them equally. Troponin is an objective biomarker that reflects undetected, chronic damage to the heart. It is an incredibly potent marker. We’re identifying people who have heart damage and are much more likely to experience heart failure or a cardiovascular event and die. And we think troponin could be a useful way to monitor risk and identify individuals in clinical practice who should be targeted for more intensive cardiovascular intervention.”

The robust association of high-sensitivity cardiac troponin with cardiovascular and even microvascular outcomes is now well established, Dr. Selvin says. “The protein is a highly specific biomarker of damage to the heart, but many conditions can cause elevations in troponin. That’s what makes it so useful as a global measure of end organ damage. We’re seeing the underlying chronic cardiac damage when we measure a troponin in the population.”

One important implication of the study is that high-sensitivity cardiac troponins could improve discrimination more than other biomarkers such as C-reactive protein. Could high-sensitivity troponin take CRP’s place? “It wasn’t a question we specifically set out to answer in this study,” Dr. Selvin says. “But CRP is a nonspecific marker of inflammation, and elevations in CRP are not a specific biomarker of underlying cardiac disease. Elevations in CRP can be caused by many different things, and the test is less reliable than many other standard laboratory measures. It’s not as stable a marker as troponin.”