Effect of Dapagliflozin on Myocardial Insulin Sensitivity and Perfusion: Rationale and Design of The DAPAHEART Trial

Sorice, Gian Pio; Cinti, Francesca; Leccisotti, Lucia; D’Amario, Domenico; Lorusso, Margherita; Guzzardi, Maria Angela; Mezza, Teresa; Cocchi, Camilla; Capece, Umberto; Ferraro, Pietro Manuel; Crea, Filippo; Giordano, Alessandro; Iozzo, Patricia; Giaccari, Andrea

doi:10.1007/s13300-021-01083-1

Cited by 8 publications

(17 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Assuming a 10% loss in each group due to protocol violations/loss to follow-up, we estimate that the total number should be 26 patients per group. The details of sample size estimation and statistical analysis are available in the study design [ 18 ] and supplemental material. Data are presented as mean ± SEM or median (95% Confidence Interval, CI) as appropriate.…”

Section: Discussionmentioning

confidence: 99%

“…We had initially hypothesized [ 18 ] that treatment with SGLT-2i in patients with T2D affects cardiomyocyte metabolism via the glucose substrate, assessed by MGU measurement during hyperinsulinemic euglycemic clamp, and MBF. However, our results did not support the initial hypothesis on the effect on myocardial insulin sensitivity, as MGU did not change significantly after 4 weeks of dapagliflozin treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The study design of the DAPAHEART trial has been published recently [ 18 ]. The primary outcome was to detect changes in 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.…”

Section: Methodsmentioning

confidence: 99%

“…Other secondary outcome analyses, i.e., change from baseline in white adipose tissue and microbiota are still ongoing. For details, please see reference [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Leccisotti

Cinti

Sorice

et al. 2022

Cardiovasc Diabetol

Self Cite

View full text Add to dashboard Cite

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 (NCT 03313752). 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; pint = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; pint = 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

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Other secondary outcome analyses, i.e., change from baseline in white adipose tissue and microbiota are still ongoing. For details, please see reference [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Leccisotti

Cinti

Sorice

et al. 2022

Cardiovasc Diabetol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Fatty acid oxidation is greatly influenced by insulin sensitivity, and dapagliflozin has been shown to improve insulin sensitivity and glucose uptake 142 . Therefore, the ameliorated myocardial glucose metabolism and insulin sensitivity induced by SGLT2 inhibitors can improve fatty acid utilization 147 . However, if the myocardium becomes oversaturated with ectopic fatty acids and is unable to utilize them, the oxidation of ketone bodies induced by SGLT2 inhibitors would become the alternative source of fuel 143 .…”

Section: Targeting Eat In Cardiovascular Diseasementioning

confidence: 99%

Epicardial adipose tissue in contemporary cardiology

2022

View full text Add to dashboard Cite

Interest in epicardial adipose tissue (EAT) is growing rapidly, and research in this area appeals to a broad, multidisciplinary audience. EAT is unique in its anatomy and unobstructed proximity to the heart and has a transcriptome and secretome very different from that of other fat depots. EAT has physiological and pathological properties that vary depending on its location. It can be highly protective for the adjacent myocardium through dynamic brown fat-like thermogenic function and harmful via paracrine or vasocrine secretion of pro-inflammatory and profibrotic cytokines. EAT is a modifiable risk factor that can be assessed with traditional and novel imaging techniques. Coronary and left atrial EAT are involved in the pathogenesis of coronary artery disease and atrial fibrillation, respectively, and it also contributes to the development and progression of heart failure. In addition, EAT might have a role in coronavirus disease 2019 (COVID-19)-related cardiac syndrome. EAT is a reliable potential therapeutic target for drugs with cardiovascular benefits such as glucagon-like peptide 1 receptor agonists and sodium–glucose co-transporter 2 inhibitors. This Review provides a comprehensive and up-to-date overview of the role of EAT in cardiovascular disease and highlights the translational nature of EAT research and its applications in contemporary cardiology.

show abstract

Dapagliflozin-Induced Myocardial Flow Reserve Improvement is not Associated with HDL Ability to Stimulate Endothelial Nitric Oxide Production

Capece,

Pavanello,

Cinti

et al. 2023

Diabetes Ther

Self Cite

View full text Add to dashboard Cite

Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown controversial results in modulating plasma lipids in clinical trials. Most studies found slight increases in high-density lipoprotein (HDL) cholesterol but few have provided evidence on HDL functionality with disappointing results. However, there is broad agreement that these drugs provide cardiovascular protection through several mechanisms. Our group demonstrated that dapagliflozin improves myocardial flow reserve (MFR) in patients with type 2 diabetes (T2D) with coronary artery disease (CAD). The underlying mechanisms are still unknown, although in vitro studies have suggested the involvement of nitric oxide (NO). Aim To investigate changes in HDL-mediated modulation of NO production with dapagliflozin and whether there is an association with MFR. Methods Sixteen patients with CAD-T2D were enrolled and randomized 1:1 to dapagliflozin or placebo for 4 weeks. Blood samples were collected before and after treatment for each group. The ability of HDL to stimulate NO production in endothelial cells was tested in vitro by incubating human umbilical vein endothelial cells (HUVEC) with apoB-depleted (apoB-D) serum of these patients. The production of NO was assessed by fluorescent assay, and results were expressed as fold versus untreated cells. Results Change in HDL-mediated NO production remained similar in dapagliflozin and placebo group, even after adjustment for confounders. There were no significant correlations between HDL-mediated NO production and MFR either at baseline or after treatment. No changes were found in HDL cholesterol in either group, while low-density lipoprotein cholesterol (LDL cholesterol) significantly decreased compared to baseline only in treatment group ( p = 0.043). Conclusions In patients with T2D-CAD, beneficial effects of dapagliflozin on coronary microcirculation seem to be unrelated to HDL functions. However, HDL capacity to stimulate NO production is not impaired at baseline; thus, the effect of drug treatments would be negligible. To conclude, we can assume that HDL-independent molecular pathways are involved in the improvement of MFR in this population. Trial Registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.

show abstract

Effect of Dapagliflozin on Myocardial Insulin Sensitivity and Perfusion: Rationale and Design of The DAPAHEART Trial

Abstract: Introduction: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been shown to have beneficial effects on various cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) in primary prevention and in those with a high CV risk profile. However, the mechanism(s) re-

Cited by 8 publications

References 54 publications

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

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

Epicardial adipose tissue in contemporary cardiology

Dapagliflozin-Induced Myocardial Flow Reserve Improvement is not Associated with HDL Ability to Stimulate Endothelial Nitric Oxide Production

Contact Info

Product

Resources

About