Effects of 6 weeks of treatment with dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo‐controlled, exploratory study

Abstract

Aim: To explore the early effects of dapagliflozin on myocardial function and metabolism in patients with type 2 diabetes without heart failure.Materials and Methods: Patients with type 2 diabetes on metformin treatment were randomized to double-blind, 6-week placebo or dapagliflozin 10 mg daily treatment.Investigations included cardiac function and structure with myocardial resonance imaging; cardiac oxygen consumption, perfusion and efficiency with [ 11 C]-acetate positron emission tomography (PET); and cardiac and hepatic fatty acid uptake with [ 18 F]-6-thia-heptadecanoic acid PET, analysed by ANCOVA as least square means with 95% confidence intervals.Results: Evaluable patients (placebo: n = 24, dapagliflozin: n = 25; 53% males) had a mean age of 64.4 years, a body mass index of 30.2 kg/m 2 and an HbA1c of 6.7%.Body weight and HbA1c were significantly decreased by dapagliflozin versus placebo. Dapagliflozin had no effect on myocardial efficiency, but external left ventricular (LV) work (−0.095 [−0.145, −0.043] J/g/min) and LV oxygen consumption were significantly reduced (−0.30 [−0.49, −0.12] J/g/min) by dapagliflozin, although the changes were not statistically significant versus changes in the placebo group.Change in left atrial maximal volume with dapagliflozin versus placebo was −3.19 (−6.32, −0.07) mL/m 2 (p = .056). Peak global radial strain decreased with dapagliflozin versus placebo (−3.92% [−7.57%, −0.28%]; p = .035), while peak global longitudinal and circumferential strains were unchanged. Hepatic fatty acid uptake

The SGLT2 inhibitor dapagliflozin promotes systemic FFA mobilization, enhances hepatic β-oxidation, and induces ketosis

“…Elevated β-oxidation increased hepatic acetyl-CoA levels and drove ketogenesis, evidenced through elevations in liver tissue HMG-CoA and plasma β-HBA. Recent publications following dapagliflozin treatment to patients with type 2 diabetes support the translational value of this study as increased whole body fatty acid oxidation, and specifically increased hepatic FFA uptake was observed in these clinical trials (25,26).…”

Predicted Cardiac Functional Responses to Renal Actions of SGLT2i in the DAPACARD Trial Population: A Mathematical Modeling Analysis

“…30,31 Clinically, the cardiac magnetic resonance imaging protocol was used to assess variables related to the function and structure of the left ventricle in the DAPACARD study. 32 In this analysis, the cardiorenal model approximates the ventricle as a sphere, and thus global longitudinal strain can be expressed as a function of the chamber radius r at end-diastole (ED) and end-systole (ES):…”

“…Detailed descriptions of the DAPACARD clinical trial, including inclusion/exclusion criteria, have been described previously. 32 Overview of DAPACARD Simulation Procedure Figure 2 summarizes the process used to simulate the DAPACARD study. Following the approach we have previously described, 24 we first generated a virtual population of participants with T2DM by sampling a subset of model parameters over a range of values with uniform distribution, summarized in Table 1 and described later.…”

“…Following the approach we have previously described, 24 we first generated a virtual population of participants with T2DM by sampling a subset of model parameters over a range of values with uniform distribution, summarized in Table 1 and described later. The parameter ranges were calibrated to ensure that the distribution of simulated baseline characteristics matched the DAPACARD clinical trial population, 23,32 including baseline estimated glomerular filtration rate (eGFR), blood glucose, systolic blood pressure (SBP), and diastolic blood pressure (DBP), covered the range of observed baseline values in DAPACARD. 32 This process generated 220 plausible participants with T2DM.…”

The utilization of positron emission tomography in the evaluation of renal health and disease

“…While PET applications in studies of brain [18], heart [19], liver [20], skeletal muscle [21] and adipose tissue [22,23] are well established, there have been challenges in its implementation for the study of the kidneys. We believe, however, that renal PET has begun to demonstrate its unique potential in providing useful information in a relatively noninvasive manner.…”