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Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).

Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor that reduces blood glucose in patients with type 2 diabetes mellitus (T2DM) by promoting glycosuria via inhibiting urinary glucose reabsorption. In addition to improving blood glucose control, treatment with dapagliflozin results in glucose-induced osmotic diuresis, weight loss, and blood pressure lowering. Previous trials of SGLT-2 inhibitors showed reductions in cardiovascular (CV) events, including CV death and hospitalization for heart failure, and ischemic events in patients with atherosclerotic cardiovascular disease (ASCVD). DECLARE–TIMI 58 (NCT01730534) is a phase 3b randomized, double-blind, placebo-controlled trial designed to evaluate the CV safety and efficacy of dapagliflozin that has completed randomization of 17,160 patients with T2DM and a history of either established ASCVD (n=6,971) or multiple risk factors for ASCVD (n=10,189). Patients were randomized in a 1:1 fashion to dapagliflozin 10 mg or matching placebo. The primary safety outcome is the time to the first event of the composite of CV death, myocardial infarction, or ischemic stroke (major adverse cardiovascular events; MACEs). The co-primary efficacy outcomes are the composite of CV death, myocardial infarction, or ischemic stroke and the composite of CV death or hospitalization for heart failure. This event-driven trial will continue until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin measured by rejecting the hypothesis that the upper bound of the CI >1.3 for the primary outcome of MACE, as well as 85% power to detect a 15% relative risk reduction in MACE and an estimated 87% power to detect a 20% reduction in the composite of CV death or hospitalization for heart failure at a 1-sided α level of .0231. The DECLARE–TIMI 58 trial is testing the hypotheses that dapagliflozin is safe (does not increase) and may reduce the occurrence of major CV events. DECLARE–TIMI 58 is the largest study to address this question with an SGLT-2 inhibitor in patients with T2DM and with established CV disease and without CV disease but with multiple risk factors.

The growing number of cancer cases highlights the urgent need to develop new therapies based on effective molecules. Although anticancer activity remains a key element of oncological pharmacology, the importance of agents that support physiological functions and improve the quality of life of cancer patients is also recognised. Compounds that combine these two functions could represent a significant trend in oncology. Moreover, repurposing approved drugs for conditions beyond their original indications could be a promising strategy. An interesting example of this is synthetic flozins (SGLT2 inhibitors), which were originally designed and developed to treat type 2 diabetes mellitus. These compounds contain various aromatic and heteroaryl structures, and changes in these substituents affect the binding strength and therapeutic potency of SGLT2 inhibitors. Beyond their antidiabetic effects, SGLT2 inhibitors exert well-documented cardioprotective and nephroprotective actions, restoring metabolic homeostasis. Given these pleiotropic properties, they could benefit oncology by improving systemic functions and by directly influencing the invasion of cancer cells. This article provides an overview of the use of synthetic flozins in various contexts, with a particular focus on their potential impact on cancer biology and treatment, consolidating their position as multifunctional agents of growing systemic relevance.

In this trial, patients with CKD (with or without type 2 diabetes) were randomly assigned to receive dapagliflozin or placebo. The primary composite outcome — a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes — was less frequent with dapagliflozin.

EMPA-REG OUTCOME is recognised by international guidelines as a landmark study that showed a significant cardioprotective benefit with empagliflozin in patients with type 2 diabetes (T2D) and cardiovascular disease. To assess the impact of empagliflozin in routine clinical practice, the ongoing EMPRISE study is collecting real-world evidence to compare effectiveness, safety and health economic outcomes between empagliflozin and DPP-4 inhibitors. A planned interim analysis of EMPRISE was recently published, confirming a substantial reduction in hospitalisation for heart failure with empagliflozin across a diverse patient population. In this commentary article, we discuss the new data in the context of current evidence and clinical guidelines, as clinicians experienced in managing cardiovascular risk in patients with T2D. We also look forward to what future insights EMPRISE may offer, as evidence is accumulated over the next years to complement the important findings of EMPA-REG OUTCOME.

Sotagliflozin is a dual sodium–glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). Sotagliflozin inhibits renal sodium–glucose co-transporter 2 (determining significant excretion of glucose in the urine, in the same way as other, already available SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose absorption and therefore reducing post prandial glucose. Well-designed clinical trials, have shown that sotagliflozin (as monotherapy or add-on therapy to other anti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with beneficial effects on bodyweight and blood pressure. Similar results have been obtained in adults with T1D treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections, even after insulin optimization. A still ongoing phase 3 study is currently evaluating the effect of sotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In this review we illustrate the advantages and disadvantages of dual SGLT 2/1 inhibition, in order to better characterize and investigate its mechanisms of action and potentialities.

In a randomized trial of patients with type 2 diabetes, treatment with dapagliflozin, an SGLT2 inhibitor that promotes glucosuria, did not result in a higher or lower rate of cardiovascular death, myocardial infarction, or stroke than placebo but did result in a lower rate of hospitalization for heart failure.

The management of type 2 diabetes mellitus (T2DM) is becoming increasingly complex. Sodium–glucose cotransporter type 2 inhibitors (SGLT2is) are the newest antidiabetic agents for T2DM. By targeting the kidney, they have a unique mechanism of action, which results in enhanced glucosuria, osmotic diuresis and natriuresis, thereby improving glucose control with a limited risk of hypoglycaemia and exerting additional positive effects such as weight loss and the lowering of blood pressure. Several outcome studies with canagliflozin, dapagliflozin or empagliflozin reported a statistically significant reduction in major cardiovascular events, hospitalization for heart failure and progression to advanced renal disease in patients with T2DM who have established atherosclerotic cardiovascular disease, several cardiovascular risk factors, albuminuric mild to moderate chronic kidney disease or heart failure. Current guidelines proposed a new paradigm in the management of T2DM, with a preferential place for SGLT2is, after metformin, in patients with atherosclerotic cardiovascular disease, heart failure and progressive kidney disease. Ongoing trials might extend the therapeutic potential of SGLT2is in patients with, but also without, T2DM. This Review provides an update of the current knowledge on SGLT2is, moving from their use as glucose-lowering medications to their new positioning as cardiovascular and renal protective agents.Sodium–glucose cotransporter type 2 inhibitors (SGLT2is) are used for the treatment of type 2 diabetes mellitus. This Review provides an in-depth overview of the role of SGLT2is as glucose-lowering agents and as cardiovascular and renal protective agents.

Background To compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin. Methods We conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium–glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients’ age, sex, laboratory data, co-morbidities, and concomitant medications. Results We identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73–1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14–2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49–1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80–1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49–0.95). Conclusion The risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.

Dapagliflozin (Forxiga ® ) is a highly potent, reversible and selective sodium-glucose cotransporter-2 inhibitor indicated worldwide for the treatment of type 2 diabetes (T2D). In the EU, oral dapagliflozin once daily is approved for use as monotherapy (in patients who are intolerant of metformin) and as add-on combination therapy (with other glucose-lowering agents, including insulin) for T2D when diet and exercise alone do not provide adequate glycaemic control. In numerous well-designed clinical studies and their extensions, dapagliflozin as monotherapy and combination therapy with other antihyperglycaemic agents provided effective glycaemic control and reduced bodyweight and blood pressure (BP) across a broad spectrum of patients. Dapagliflozin reduced the rate of cardiovascular (CV) death or hospitalization for heart failure (HHF), did not adversely affect major adverse CV events (MACE) and possibly reduced progression of renal disease relative to placebo in patients with established atherosclerotic CV disease (CVD) or multiple risk factors for CVD. Dapagliflozin was generally well tolerated, with a low risk of hypoglycaemia; diabetic ketoacidosis (DKA), although rare, and genital infections were more common with dapagliflozin than placebo. Given its antihyperglycaemic, cardioprotective and possibly renoprotective properties and generally favourable tolerability profile, dapagliflozin provides an important option for the management of a broad patient population, regardless of the history of CVD.