Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report

Abstract

Objective: Cardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and < 80%), with or without previous percutaneous coronary intervention (> 6 months) but no HF.

Methods: This was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by ¹³N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT03313752).

Results: 16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 μmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 μmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; p_int = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; p_int = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054).

Conclusions: SGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction. Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.

Keywords: Diabetes; Metabolism; Myocardial blood flow; PET; Perfusion; SGLT-2.

Fig. 1

Myocardial glucose uptake (MGU). A Data are mean ± SEM; B FDG PET/CT images during euglycemic hyperinsulinemic clamp of two representative cases: fused and 3D maximum intensity projection anterior views pre- and post-placebo and pre- and post-dapagliflozin, respectively

Fig. 2

Myocardial perfusion: Myocardial flow reserve (A); resting myocardial blood flow (MBF) corrected for rate pressure product (B); stress myocardial blood flow (C); Data are mean ± SEM; **p < 0.01. Myocardial perfusion PET images of two representative cases: regional and global myocardial blood flow (MBF) and myocardial flow reserve (MFR) quantification at rest and during adenosine stress pre- and post-placebo (D) and pre- and post-dapagliflozin (E), respectively