Fibroblast Growth Factor-23 und Klotho bei Herzinsuffizienz und Diabetes Mellitus Typ 2
Zusammenfassung der Projektergebnisse
Substantial changes in the regulatory approval process of glucose lowering drugs in patients with type 2 diabetes mellitus (T2DM) led to large and well-powered clinical trials and resulted in significant advances in the understanding of the disease and its complications. The objective of this research fellowship as a dedicated training as a clinical trialist was to improve risk stratification (using biomarkers) and guidance of T2DM patients at high risk for heart failure. The first project was planned to be an additional analysis of the EXAMINE trial to study the utility of FGF-23 and klotho in guiding therapy with gliptins. However, after a series of neutral cardiovascular outcomes trials, the EMPA-REG OUTCOME trial, a randomized, double-blind, placebo-controlled trial that studied the sodium glucose co-transporter 2 inhibitor (SGLT2i) empagliflozin reported that its primary endpoint major adverse cardiovascular events (MACE), a composite of myocardial infarction, stroke, and cardiovascular death, was significantly reduced over a median follow-up of 3.1 years. Surprisingly, this effect was driven primarily by a 38% reduction of cardiovascular death. A 35% reduction in hospitalization for heart failure in patients randomized to empagliflozin was also observed, suggesting that the reductions in both cardiovascular and total mortality were mediated by favorable hemodynamic effects. The applicant was granted to join the clinical trial team of the DECLARE-TIMI 58 trial to study the effects of dapagliflozin, another member of this drug class, in 17,160 patients with T2DM and multiple risk factors for or established atherosclerotic cardiovascular disease. In DECLARE-TIMI 58, dapagliflozin significantly reduced the risk of the composite of cardiovascular death and hospitalization for heart failure and was non-inferior with regard to MACE. In a meta-analysis of all SGLT2i cardiovascular outcome trials, SGLT2i were found to have moderate benefits on atherosclerotic MACE that appear confined to those with established atherosclerotic cardiovascular disease. In contrast, SGLT2i have robust effects on reducing the risk of heart failure and renal outcomes which do not appear dependent on baseline atherosclerotic risk and prior heart failure. SGLT2i and glucagon-like peptide 1 receptor agonists (GLP1-RA) reduce MACE to a similar degree in patients with established atherosclerotic cardiovascular disease, but SGLT2i have a more marked effect on preventing hospitalization for heart failure and progression of kidney disease. Furthermore, we report the first observation of a significant reduction of atrial fibrillation/flutter (AF/AFL) events in the class. Dapagliflozin lowered the risk of time to the first AF/AFL event during follow-up as well as the total number of events. These reductions were found to be consistent across major subgroups that are well established to have associations with burden of AF/AFL. Moreover, dapagliflozin consistently reduced the relative risk of cardiovascular death and hospitalization for heart failure regardless of baseline NT-proBNP or hsTnT quartiles but given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin. Cardiac and kidney disease in T2DM are well intertwined and have a bidirectional relationship. We therefore examined whether traditional cardiac and inflammatory biomarkers may also aid in the identification of patients with T2DM at high risk for renal dysfunction as reflected in the eGFR and UACR. In a nested biomarker study from SAVOR-TIMI 53, hsTnT, NT-proBNP, and hsCRP were found to be independently associated with worsening of eGFR and UACR category. These results, therefore, expand the utility in measuring traditional cardiac biomarkers in patients with T2DM, as they improve both macrovascular and microvascular risk stratification.
Projektbezogene Publikationen (Auswahl)
- Cardiac and Inflammatory Biomarkers Are Associated with Worsening Renal Outcomes in Patients with Type 2 Diabetes Mellitus: Observations from SAVOR-TIMI 53. Clin Chem. 2019; 65:781-790
Zelniker TA, Morrow DA, Mosenzon O, Gurmu Y, Im K, Cahn A, Raz I, Steg PG, Leiter LA, Braunwald E, Bhatt DL and Scirica BM
(Siehe online unter https://doi.org/10.1373/clinchem.2018.298489) - Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus. Circulation. 2019;139:2022-2031
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH and Sabatine MS
(Siehe online unter https://doi.org/10.1161/CIRCULATIONAHA.118.038868) - Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380:347- 357
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS and Investigators D-T
(Siehe online unter https://doi.org/10.1056/NEJMoa1812389) - SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393:31-39
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH and Sabatine MS
(Siehe online unter https://doi.org/10.1016/S0140-6736(18)32590-X) - Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus: Insights from the DECLARE-TIMI 58 Trial. Circulation. 2020
Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Budaj A, Kiss RG, Padilla F, Gause-Nilsson I, Langkilde AM, Raz I, Sabatine MS and Wiviott SD
(Siehe online unter https://doi.org/10.1161/CIRCULATIONAHA.119.044183) - Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75:422-434
Zelniker TA and Braunwald E
(Siehe online unter https://doi.org/10.1016/j.jacc.2019.11.031)
