Metabolic factors associated with heart failure and cardiovascular events in patients with diabetes and effects of sodium-glucose cotransporter 2 inhibitors

• Applicant: Paul Haller, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511983400

Patients with diabetes are at high risk for heart failure (HF), major adverse cardiovascular events (MACE) and renal events, respectively. Sodium glucose cotransporter 2 inhibitors (SGLT2i) exert beneficial effects on these events and, thus, are increasingly used in daily clinical routine. However, it remains unknown whether biomarkers reflecting specific metabolic pathways are involved in the mediation of the beneficial effects observed, as also whether these biomarkers themselves may exert predictive ability for the above-metioned events. Overall, different metabolic pathways and biomarkers are associated with the development of e.g., HF and coronary artery disease. Among others, these include insulin, c-peptide, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 1 (IGFBP-1) and fibroblast growth factor 21 (FGF-21). Thus, this project aims to 1) investigate the predictive ability of the above-mentioned biomarkers on HF events, renal events, and MACE and 2) improve the understanding of SGLT2i affecting metabolic biomarkers and their associated pathways. For this research project, data of the large randomized, placebo-controlled DECLARE TIMI-52 trial testing the SGLT2i dapagliflozin in approximately 16,000 patients with diabetes is available. The biomarkers insulin and c-peptide will be available in the overall study cohort at baseline and will be assessed for their association with heart failure, MACE and renal events. Additionally, using a nested case-control study design, including all approximately 1,800 patients with events during a median follow-up of 4 years and 1,800 randomly matched controls from the remaining study population, the biomarkers IGF-1, IGFBP-1 and FGF-21 will be assessed for their ability to predict HF events, renal events and MACE. Finally, potential mechanistic actions of the SGLT2i dapagliflozin on the biomarkers insulin, IGF-1, IGFBP-1 and FGF-21 will be investigated in a longitudinal study. For this purpose, all biomarkers will be assessed at baseline and at six months follow-up in 250 randomly selected patients of each study arm (dapagliflozin versus placebo, in total 500 patients).

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Marc Sabatine