Patients with diabetes have a high probability of adverse outcomes due to atherosclerotic cardiovascular disease (ASCVD), heart failure including renal disease. The FDA therefore now requires that all new diabetes drugs must also show cardiovascular safety.

Published in 2019, the DECLARE-TIMI 58 established the CV safety of dapagliflozin, an antidiabetic drug which is a selective inhibitor of sodium–glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes. DECLARE-TIMI 58 was a randomized, placebo-controlled CVOT trial for dapagliflozin regardless of the presence of ASCVD or heart failure. While dapagliflozin treatment improved glycemic control, it was non-inferior to placebo for MACE (cardiovascular death, myocardial infarction or ischemic stroke). But it reduced cardiovascular deaths or hospitalizations for heart failure and also reduced the rate of progression of renal disease.¹

A secondary analysis of the DECLARE-TIMI 58 trial was conducted by a team of researchers from Austria, Israel, Canada, Russia, Poland, Ukraine, UK and the United States.² Their objective was to investigate if levels of cardiac biomarkers like N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) could identify type 2 diabetes patients at a higher risk for atherosclerotic events and if dapagliflozin was beneficial in such patients. More than half (62.8%) of the 14,565 patients included in the trial were male; the mean age of the participants was 63.9 years.

Results showed a significant association of both NT-proBNP and hsTnT with the risk of MACE, which was the primary outcome of the trial, with adjusted hazard ratio (aHR) of 1.62 and 1.59. No difference in the magnitude of association between patients who had ASCVD (aHR of 1.60 for NT-proBNP and 1.62 for hsTnT aHR 1.62) and were at risk for ASCVD (aHR of 1.62 for NT-proBNP and 1.51 for hsTnT aHR) was observed. This association was found to persist on multivariate analysis with aHR of 1.46 for NT-proBNP and 1.39 for hsTnT.

Following dapagliflozin treatment, rate of occurrence of MACE showed a marginal decline among patients in whom the biomarker levels were in quartile 4 (NT-proBNP HR 0.83 with absolute risk reduction [ARR] of 2.4% and hsTnT HR with ARR of 2.7%) when compared to the placebo-treated patients. However, among patients with biomarker levels in quartiles 1 to 3, no significant treatment effect was noted (NT-proBNP HR 1.02 with ARR of 0%; hsTnT HR 0.97 with ARR of 0.2%).

This substudy of the DECLARE-TIMI 58 trial shows that high levels of NT-proBNP and hsTnT were associated with high risk of MACE in patients with type 2 diabetes at high risk of atherosclerotic vascular events such as MI, angina, TIA, stroke. Treatment with dapagliflozin resulted in fewer MACEs in patients with biomarker levels in the top quartile. Hence, these biomarkers can aid identification of high risk type 2 diabetes patients who could benefit from dapagliflozin treatment.

References

1. Wiviott SD, et al; DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019 Jan 24;380(4):347-357. doi: 10.1056/NEJMoa1812389.
2. Zelniker TA, et al. Association of cardiac biomarkers with major adverse cardiovascular events in high-risk patients with diabetes: a secondary analysis of the DECLARE-TIMI 58 Trial. JAMA Cardiol. 2023 Mar 1;e230019. doi: 10.1001/jamacardio.2023.0019.