Increased serum tenascin-C concentrations are associated with risk for death and major adverse cardiovascular events (MACE) in individuals with type 2 diabetes, according to the results of a prospective study published in Diabetologia.
Although there are several known biomarkers for cardiovascular (CV) risk that have been proposed to improve risk stratification in diabetes, they have not been incorporated into international guidelines. Studies have shown that the glycoprotein tenascin-C (TN-C) is transiently upregulated at sites of inflammation (eg, after acute myocardial infarction), and as such, it is generally considered a marker of inflammation in CV diseases. Studies have shown a significant association between elevated TN-C levels and CV-associated morbidity, but this association in has not been demonstrated in patients with isolated diabetes.
To examine the association of TN-C with all-cause mortality and CV-associated morbidity in individuals with type 2 diabetes, 1321 individuals in the SURDIAGENE study (58% men) were prospectively followed until death or until December 31, 2015, whichever came first. The average age of the included individuals was 64±11 years. Patients with a baseline estimated glomerular filtration rate <30 mL/min/1.73 m2, a history of prior renal replacement therapy, or a follow-up duration of <3 months were excluded.
Blood samples and second morning urine samples were obtained from individuals after an overnight fast to measure various biological characteristics, such as hemoglobin A1c, low-density lipoprotein cholesterol, serum creatinine, and TN-C levels.
Higher TN-C concentrations were significantly associated with older age, longer duration of diabetes, history of CV disease, and diabetic retinopathy severity.
Median follow-up duration was 89 months (range, 57-130 months), corresponding to 9965 person-years. The overall mortality rate was 4.4% of total person-years of follow-up duration (95% CI, 4.0-4.8) and the MACE rate was 5.2% of total person-years (95% CI, 4.8-5.7). The most common cause of death was CV diseases (54%).
Baseline serum TN-C concentrations were higher in the group of individuals who died compared with survivors (89.3±49.8 vs 69.0±38.1 ng/mL; P <.0001) and higher in individuals with vs without incidental MACE (87.2±48.4 vs 68.9±38.6 ng/mL; P <.0001).
After adjustment for predetermined risk factors, including smoking status, treatment with statins, and hypertension, higher TN-C concentrations were significantly associated with risks for all-cause death (adjusted hazard ratio per 1 SD, 1.27; 95% CI, 1.17-1.38; P <.0001) and MACE (adjusted hazard ratio per 1 SD, 1.23; 95% CI, 1.13-1.34; P <.0001).
Adding TN-C concentrations to the established prognostic factors in type 2 diabetes significantly improved the accuracy of the risk modelling for all-cause death (change in C-statistics, 0.0111 [95% CI, 0.0107-0.0114]; relative integrated discrimination improvement, 8.2%; P =.0006) and for MACE (change in C statistics: 0.0095 [95% CI, 0.0092-0.0099]; relative integrated discrimination improvement, 6.7%; P =.0014).
This study showed that higher serum TN-C concentrations were significantly associated with an increased risk for mortality and MACE in type 2 diabetes, even after adjustment for inflammatory markers such as angiopoietin-like 2 and tumor necrosis factor receptor 1 (TNFR1). “TN-C showed a significant predictive value not only for all-cause death, but also for MACE, suggesting that TN-C overexpression in individuals with type 2 diabetes may be linked to CV disease development and progression,” noted the researchers.
Limitations to this study included its monocentric cohort, thus requiring future studies with greater breadth in design and recruitment.
Taken together, the study findings showed that TN-C could be a promising biomarker for improved risk stratification in individuals with type 2 diabetes, but future research is necessary to determine if TN-C is a potential therapeutic target.
Gellen B, Thorin-Trescases N, Thorin E, et al. Serum tenascin-C is independently associated with increased major adverse cardiovascular events and death in individuals with type 2 diabetes: a French prospective cohort [published online February 10, 2020]. Diabetologia. doi:10.1007/s00125-020-05108-5