Cardiac Troponin as a Marker of Heart Failure Risk in Diabetes

There is an apparently inexorable rise in the worldwide prevalence of diabetes, with the International Diabetes Federation estimating 537 million adults living with the disease in 2021 and predicting an increase to 784 million by 2045 (1). Historically, the International Diabetes Federation’s predictions have not been overstated, with their 2003 report estimating a global prevalence of 333 million patients by 2025. These extra patients will place an increasing burden on all healthcare systems for both the management of the condition and treatment of its complications. The long-term complications of diabetes include small vessel (microvascular) retinopathy, nephropathy, and neuropathy as well as large vessel (macrovascular) disease, the latter contributing to cardiac, cerebral, and peripheral vascular disease. Cardiac complications present not only as an increased risk of ischemic heart disease but also, largely independently of this, as an average 2-fold increased risk of heart failure compared to persons without diabetes (2). Heart failure itself brings with it a largely underappreciated poor prognosis, with 5-year survivals comparable to, or worse than, many of the commonest cancers (3). The concentrations of circulating cardiac troponins beyond their traditional use in acute coronary syndrome have been found to be increased in many other cardiac conditions including the whole spectrum of heart failure, ranging from acute decompensated heart failure to stable heart failure with preserved ejection fraction (4). It is assumed that these increases are indicative of ongoing subclinical myocardial injury, although the mechanism(s) for their release are still unclear. Whatever the cause, importantly their concentrations seem to add independently to the ability of natriuretic peptides to predict incipient heart failure, including in patients with diabetes (5). Some heart failure guidelines now advise use of the test in categorizing heart failure staging (6). The Atherosclerosis Risk In Communities (ARIC) study has followed community subjects prospectively in 4 US communities since the 1980s and has, among many other achievements, proven to provide a wealth of knowledge related to diabetes, including the role the disease has in the development of heart failure. It has already established an association between hemoglobin A1c and severe heart failure, irrespective of the presence of coronary heart disease (7), and that poor glycemic control is associated with progression from preclinical to overt heart failure, especially in elderly patients. Longer duration of diabetes is another, perhaps predictable, risk for developing diabetes complications, and that too has been found to be a risk for incident heart failure in the ARIC study (8). Separately, the ARIC group also found that 11% of patients with diabetes had high-sensitivity cardiac troponin T (cTnT) values at or above the assay’s stated 99th percentile of normal (14 ng/L) 6 years into their follow-up, which was 2 to 3 times more prevalent than in nondiabetic subjects following adjustment for other cardiovascular risk factors (9). In turn, raised cTnT concentrations subsequently predicted an increased risk of both heart failure and death irrespective of diabetes status, but patients with diabetes and raised cTnT together fared worst overall, being approximately 6 times as likely to develop heart failure as nondiabetic subjects with low cTnT (9). Counterintuitively, excluding individuals with cTnT concentrations >30 ng/L did not appreciably change these findings. In this issue of Clinical Chemistry, a further analysis of the ARIC data set has investigated whether a longer duration of diabetes is associated with an increased likelihood of having subclinical myocardial damage, again as represented by a cTnT concentration ≥14 ng/L (10). The authors of this study found a rise in the prevalence of raised cTnT concentration ranging from 5.4% among subjects without diabetes up to 31% of patients who had diabetes for at least 15 years, with a steady rise between the 2 extremes among patients with intermediate diabetes durations. After adjustment for other cardiovascular risk factors, patients with diabetes for ≥15 years had an approximate 4.5 times higher risk of a raised cTnT concentration than those within the first 5 years following diagnosis and over 9 times the risk of someone without diabetes. Extending this last observation, of particular interest was the authors’ finding of new-onset diabetes already being associated with a 1.9-fold relative risk of raised cTnT concentration compared to not having diabetes. This adds to the long-standing hypothesis that type 2 diabetes is a ticking time bomb for cardiovascular disease whose risks develop several years before a diagnosis is made. Studies, such as the one published here, often raise further questions. One is whether the findings are likely to be generalizable between all sensitive troponin assays beyond just troponin T. Certainly, there are reasons to envisage why this may not be the case. For example, in one general population study, the r2 between the Roche cTnT and a sensitive cardiac troponin I (cTnI) assay from Abbott was found to be as low as 9.5%, with cTnT being more strongly associated with diabetes than cTnI (11). However, again the ARIC study has provided further insight by identifying in diabetic subjects that the highest (>90%) percentile values of cTnT or cTnI assays (coincidentally also Roche and Abbott assays) could each individually predict a subsequent approximate 3-fold risk of heart failure compared to those below the 50th percentile (12). In addition, irrespective of diabetes status, both markers seemed to be doing so in a complementary manner such that if both were in the highest tertile, then the relative risk of future heart failure hospitalization rose beyond that of either cTnT or cTnI alone (13). Another question is what can be done to either prevent or treat the development of heart failure among patients with long-standing diabetes. Ensuring that as few individuals as possible develop type 2 diabetes in the first place would presumably be a preferred course, but as is shown by the International Diabetes Federation’s current and future predicted prevalence of the disease, this approach cannot be relied upon on its own. In patients already diagnosed with diabetes, it is known that cTnT is more closely associated with risk factors for microvascular complications (glycemic control and hypertension) than with cardiovascular risk factors such as LDL cholesterol (9), so it might be imagined that antihypertensives and hypoglycemic agents would have the greatest potential to slow its rise and perhaps then its associated heart failure risk. Regarding oral hypoglycemic agents, the sodium glucose cotransporter 2 inhibitor class of drugs is very promising in this regard. Its mode of action is by preventing renal reabsorption of glucose, and as well as improving glycemic control in diabetes, it reduces the risk of heart failure hospitalization in patients with or without a prior cardiac history (14). Encouragingly, one such agent, canagliflozin, has been shown in type 2 diabetes to largely prevent the rise in both N-terminal pro-B-type natriuretic peptide and cTnI experienced by a placebo group comparator over the course of 2 years (15). Taken together, there is rapidly accumulating evidence clarifying the role of cardiac troponins in the prediction and treatment of heart failure among patients with diabetes. It could be envisaged that the measurement of highly sensitive cardiac troponins serves several future purposes in diabetes patients: to help assess heart failure risk in all patients; to becomes a companion diagnostic to identify newly diagnosed type 2 patients who might benefit most from a particularly early use of an sodium glucose cotransporter 2 inhibitor agent; and to be used as a measure of how successful treatment interventions have been in preventing its rise throughout a patient’s life with diabetes. All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: E.S. Kilpatrick, Clinical Chemistry, AACC. None declared. None declared. None declared. None declared. None declared. None declared.