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 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 whole body insulin sensitivity, myocardial perfusion, and metabolism in patients with T2D without HF. Research design and 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) or placebo. Whole body glucose uptake (WBGU) and myocardial glucose uptake (MGU) were measured with PET/CT with FDG during euglycemic hyperinsulinemic clamp. Stress (i.v. adenosine infusion) and resting myocardial blood flow (MBF) and myocardial flow reserve (MFR) were calculated by PET/CT with 13N-ammonia. Results 16 patients were randomized (8 dapagliflozin; 8 placebo). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). Dapagliflozin significantly improved MFR (2.56±0.26 vs 3.59±0.35) compared with placebo group (2.34±0.21 vs 2.38±0.24; p for interaction =0.001) and was associated to a reduction of resting MBF corrected for cardiac workload (p=0.045). A trend toward an increase in stress MBF was also detected (p=0.058). Moreover, in dapagliflozin group we observed an increase of WBGU of borderline statistical significance (p=0.06) and no effects on MGU (p=0.41). Conclusions At the best of our knowledge, our study, for the first time, demonstrated that SGLT-2 inhibition increases MFR in T2D patients. The data presented provide a new potential explanation of cardiovascular benefits with SGLT-2i as they make patients more tolerant to the detrimental impact of obstructive coronary atherosclerosis on MFR. Funding Acknowledgement Type of funding sources: None.

Reply to: 'What is the optimal dose of neurohormonal modulators in patients with heart failure? The higher the better?'We thank Xie and coauthors for their interest in our paper on the association between dosing and combination use of medications and outcomes in patients with heart failure and a reduced ejection fraction of the Swedish Heart Failure Registry. 1 We agree that the notion of 'target dose' (TD) might be disputed. However, we would like to clarify that the primary aim of our . .

Background Whether revascularization reduces ischemic events and improves prognosis in patients with chronic coronary artery syndrome (CCS) without left main (LM) disease or reduced left ventricle ejection fraction (LVEF) remains a topic of debate. Nevertheless, the impact of revascularization on outcomes in patients with CCS may be influenced by the revascularization strategy adopted. Purpose We aimed at evaluating the comparative effects of different revascularization strategies in patients with CCS. Methods A total of 18 randomized controlled trials including angiography-guided percutaneous coronary intervention (PCI), physiology-guided PCI and coronary artery bypass graft (CABG), were included. Effect estimates included direct comparisons for all treatments and direct and indirect evidence were in agreement for all included outcomes, fulfilling the consistency assumption. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were used to adjust outcomes according to follow-up durations. Medical therapy was used as reference strategy. Results Compared with medical therapy, at a mean follow-up of 5.1 years, all revascularization strategies were associated with a reduction of the primary endpoint, as defined in each trial, the extent of which was modest with angiography-guided PCI (IRR 0.86, 95% CI 0.75–0.99) and greater with physiology-guided PCI (IRR 0.60, 95% CI 0.47–0.77) and CABG (IRR 0.58, 95% CI 0.48–0.70). Moreover, angiography-guided PCI was associated with increased primary endpoint compared to physiology-guided PCI (IRR 1.43, 95% CI 1.14–1.79) and CABG (IRR 1.49, 95% CI 1.27–1.74). CABG was the only strategy associated with reduced myocardial infarction (IRR 0.68, 95% CI 0.52–0.90), cardiovascular death (IRR 0.76, 95% CI 0.64–0.89), and all-cause death (IRR 0.87, 95% CI 0.77–0.99), but increased stroke (IRR 1.69, 95% CI 1.04–2.76). Results were consistent at secondary analysis exploring the impact on outcomes of baseline characteristics, such as 3-vessel disease, diabetes mellitus, year of publication or stents used. Conclusions In CCS patients without LM disease or reduced LVEF, physiology-guided PCI and CABG were associated with better outcomes than angiography-guided PCI. Compared with medical therapy, CABG was the only revascularization strategy associated with a reduction of myocardial infarction and death rates, at the cost of higher risk of stroke. Funding Acknowledgement Type of funding sources: None.

Background Preclinical predictors of worsening heart failure can be monitored by implanted devices and may support the management of patients with heart failure. However, clinical results of such an approach are controversial. Purpose We aimed to assess if guided heart failure management according to device-based remote monitoring strategies is more effective than standard therapy. Methods A comprehensive literature research for randomized controlled trials (RCTs) comparing a strategy of guided heart failure management versus standard therapy was performed on PubMed, Embase, and CENTRAL databases. Incidence rate ratios (IRRs) and associated 95% confidence intervals (CIs) were calculated using the Poisson regression model with random study effects. The primary outcome was a composite of all-cause death and hospitalizations for heart failure. Secondary endpoints included the individual components of the primary outcome. Results A total of 9216 patients from 14 RCTs were included. The average follow-up duration was of 16 months. Compared with standard therapy, guided heart failure management reduced the risk of the composite of all-cause death and hospitalizations for heart failure (IRR 0.86, 95% CI 0.79–0.94, p<0.001), driven by a reduction in both all-cause death (IRR 0.88, 95% CI 0.77–1.00, p=0.049) and hospitalizations for heart failure (IRR 0.83, 95% CI 0.75–0.92, p<0.001). Findings varied according to the type of parameters monitored, with haemodynamic-guided and multiparameter-guided strategies yielding favorable effects, while impedance-guided strategy was not able to provide significant benefits. Conclusion Device-based remote monitoring systems as a tool to guide the management of patients with heart failure were associated with a valuable reduction in the risks of death, hospitalizations for heart failure, and the composite of both, supporting their routine use in clinical practice. Funding Acknowledgement Type of funding sources: None.