The Impact of SGLT2 Inhibitor Dapagliflozin on Adropin Serum Levels in Men and Women with Type 2 Diabetes Mellitus and Chronic Heart Failure

Abstract

Background: adropin plays a protective role in cardiac remodeling through supporting energy metabolism and water homeostasis and suppressing inflammation. Low circulating levels of adropin were positively associated with the risk of cardiovascular diseases and type 2 diabetes mellitus (T2DM). We hypothesized that sodium–glucose linked transporter 2 (SGLT2) inhibitor dapagliflosin might represent cardiac protective effects in T2DM patients with known chronic HF through the modulation of adropin levels. Methods: we prospectively enrolled 417 patients with T2DM and HF from an entire cohort of 612 T2DM patients. All eligible patients were treated with the recommended guided HF therapy according to their HF phenotypes, including SGLT2 inhibitor dapagliflozin 10 mg, daily, orally. Anthropometry, clinical data, echocardiography/Doppler examinations, and measurements of biomarkers were performed at the baseline and over a 6-month interval of SGLT2 inhibitor administration. Results: in the entire group, dapagliflozin led to an increase in adropin levels by up to 26.6% over 6 months. In the female subgroup, the relative growth (Δ%) of adropin concentrations was sufficiently higher (Δ% = 35.6%) than that in the male subgroup (Δ% = 22.7%). A multivariate linear regression analysis of the entire group showed that the relative changes (Δ) in the left ventricular (LV) ejection fraction (LVEF), left atrial volume index (LAVI), and E/e` were significantly associated with increased adropin levels. In the female subgroup, but not in the male subgroup, ΔLVEF (p = 0.046), ΔLAVI (p = 0.001), and ΔE/e` (p = 0.001) were independent predictive values for adropin changes. Conclusion: the levels of adropin seem to be a predictor for the favorable modification of hemodynamic performances during SGLT2 inhibition, independent ofN-terminal brain natriuretic pro-peptide levels.

Adropin Predicts Chronic Kidney Disease in Type 2 Diabetes Mellitus Patients with Chronic Heart Failure

“…The results of our study showed that the levels of adropin in chronic HF patients with T2DM were lower than in healthy volunteers and T2DN individuals without HF, whereas in other studies [ 31 , 66 ] elevated levels of adropin were detected in HF patients. We, however, suggested that the use of adropin could be practically useful in patients with T2DM and HF regardless of CKD to stratify the patients at risk of CKD and provide continuous monitoring for risk modification during treatment, including a prediction of target organ damages and a response to the therapy.…”

“…Yet, low levels of adropin were found in patients with acute myocardial infarction [ 64 ] and stable coronary artery disease (CAD) [ 65 ]. In fact, decreased circulating concentrations of adropin in peripheral blood corresponded to a higher risk of T2DM, CAD, and CKD, but not for HF [ 66 ].…”

The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy

“…However, the level of serum LA remained unchanged in 2 clinical studies ( 11 , 26 ). In addition, 12 studies could not decide the effect of SGLT2i on cardiac glucose metabolism due to incomplete indicators ( 19 , 21 , 24 , 26 , 27 , 33 , 34 , 38 , 40 , 45 , 47 ).…”

Plausible prediction of renoprotective effects of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney diseases

“…Indeed, SGLT2 inhibitors demonstrated their ability to reduce the levels of hepcidin, inflammatory cytokines, such as IL-6, TNF-alpha, CRP and markers of kidney injury, as well as increase the levels of hemoglobin, erythropoietin, serum uric acid, adropin, irisin, and apelin. 19,22,28,34,[44][45][46][47][48] The majority of these studies did not report any correlations between changes in the biomarkers of glomerular/tubular injury, altered glucose and lipid metabolism, adipocyte/skeletal muscle cell dysfunction and changes in UACR, whereas benefits in their changes were closely associated with slower decline in eGFR, for instance in the CREDENCE and DAPA-CKD trials. 19,28 Moreover, SGLT2 inhibitors seem to show improving kidney function independently of their glycemic effects, 49 while they are able to reduce tubular cell glucotoxicity via inhibition of sodium transporters, modulating mitochondrial dysfunction and suppressing local and systemic inflammatory reactions.…”

“…SGLT2 inhibitors have been suggested to prevent kidney fibrosis, podocyte injury and apoptosis of glomerular cells by increasing protective adipokine expression, such as adropin, irisin and apelin, which act directly through the activation of Akt/STAT3 and tyrosine protein kinase JAK2 (JAK2)/signal transducer pathways. 34,45,48,51,52 Finally, SGLT2 inhibitors adapt metabolic homeostasis by mediating the activity of NADPH oxidase and transcription factors (nuclear factor-κB and nuclear factor erythroid 2-related factor 2) preventing advanced glycation and autophagy. 51,52 These effects are considered to be crucial in the treatment of patients with either T2DM- or non-T2DM-related CKD who have HF.…”