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Aims: Sodium‐glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of hospitalization for heart failure (HHF) and composite kidney outcomes, but the mediators underlying these benefits are unknown. Materials and methods: Among participants from VERTIS CV, a trial of patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease randomized to ertugliflozin versus placebo, Cox proportional hazards regression models were used to evaluate the percentage mediation of ertugliflozin efficacy on the first HHF and kidney composite outcome in 26 potential mediators. Time‐dependent approaches were used to evaluate associations between early (change from baseline to the first post‐baseline measurement) and average (weighted average of change from baseline using all post‐baseline measurements) changes in covariates with clinical outcomes. Results: For the HHF analyses, early changes in four biomarkers (haemoglobin, haematocrit, serum albumin and urate) and average changes in seven biomarkers (early biomarkers + weight, chloride and serum protein) were identified as fulfilling the criteria as mediators of ertugliflozin effects on the risk of HHF. Similar results were observed for the composite kidney outcome, with early changes in four biomarkers (glycated haemoglobin, haemoglobin, haematocrit and urate), and average changes in five biomarkers [early biomarkers (not glycated haemoglobin) + weight, serum albumin] mediating the effects of ertugliflozin on the kidney outcome. Conclusions: In these analyses from the VERTIS CV trial, markers of volume status and haemoconcentration and/or haematopoiesis were the strongest mediators of the effect of ertugliflozin on reducing risk of HHF and composite kidney outcomes in the early and average change periods. ClinicalTrials.gov identifier: NCT01986881 [ABSTRACT FROM AUTHOR]

Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular death or worsening heart failure (HF), and improve symptom burden, physical function and quality of life in patients with HF and reduced ejection fraction. The mechanisms of the HF benefits of SGLT2 inhibitors, however, remain unclear. In this substudy of the DEFINE‐HF trial, patients randomized to dapagliflozin or placebo had lung fluid volumes (LFVs) measured by remote dieletric sensing at baseline and after 12 weeks of therapy. A significantly greater proportion of dapagliflozin‐treated patients (as compared with placebo) experienced improvement in LFVs and fewer dapagliflozin‐treated patients had no change or deterioration in LFVs after 12 weeks of treatment. To our knowledge, this is the first study to suggest a direct effect of dapagliflozin (or any SGLT2 inhibitor) on more effective "decongestion", contributing in a meaningful way to the ongoing debate regarding the mechanisms of SGLT2 inhibitor HF benefits. [ABSTRACT FROM AUTHOR]

In 2008, the US Food and Drug Administration (FDA) issued a guidance to industry statement concerning evaluation of the cardiovascular (CV) safety of new antihyperglycaemic therapies for type 2 diabetes. Fifteen CV outcome trials assessing three novel classes of antihyperglycaemic therapies, DPP‐4 inhibitors, GLP‐1 receptor agonists and SGLT‐2 inhibitors, were completed by the end of 2018 and several others are ongoing. In addition, one comparative insulin trial also has been completed. None of these trials reported an increase in risk for major adverse CV events (MACE), and six agents have demonstrated CV benefits. This experience has led to the first FDA‐approved indications for antihyperglycaemic medications to reduce the risk of CV death (empagliflozin) and to reduce the risk of MACE (liraglutide, canagliflozin), both indications specific to patients with established atherosclerotic cardiovascular disease (ASCVD). Because of the aggregate results from dedicated CV outcomes trials conducted in response to the FDA guidance statement, the contemporary paradigm for treatment of patients with type 2 diabetes has evolved substantially. However, the guidance has substantially increased the cost of developing new medications to address this important disease that afflicts hundreds of millions of adults worldwide, with reduction in quality of life as well as in life expectancy. The cost burden of drug development of medications proven effective that may directly impact cost to patients and to their insurers might be alleviated by modifications to the present guidance statement. These include areas of trial design, aspects of trial operation, expansion of composite outcomes to include broader component CV outcomes and continued evolution of analytic methodology. The guidance statement will benefit from consideration of a number of modifications to support continued innovation and, of course, the safety of marketed medications for type 2 diabetes. However, the requirement to assess each new antihyperglycaemic medication in at least one large‐scale standard randomized clinical outcomes trial should remain, so that clinicians can be reassured about the favourable efficacy/safety profiles of the medications they prescribe. [ABSTRACT FROM AUTHOR]

Aims: To compare the management of patients with diabetes and heart failure with reduced ejection fraction (HFrEF) in the United States and Asia to understand variations in treatment patterns across different healthcare systems. Materials and methods: Our cohort included patients with diabetes and HFrEF (ejection fraction <40%) from a US‐based registry of adults with diabetes (2013‐2016, electronic health records) and a multi‐national Asian registry of adults with heart failure (2010‐2016, prospective registry). Asian countries were categorized as high income (HI) or low income (LI), according to the United Nations classification. Rates of use of guideline‐directed medical therapies (determined through review of active medication lists) were compared across regions. Results: Patients with diabetes and HFrEF in the United States (n = 28 877) were older, had higher body mass indices, and were more likely to have coronary disease than those in Asia (n = 2235). Compared with US patients, the use of guideline‐directed medical therapy for HFrEF was lower in patients in LI Asian countries (angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers: patients in the United States, 77% vs. patients in HI Asian countries, 76% vs patients in LI Asian countries, 69%; β‐blockers: patients in the United States, 91% vs. patients in HI Asian countries, 87% vs. patients in LI Asian countries, 69%; P < 0.001 for both). Insulin was used more commonly in the United States (44% vs. 24% vs. 25%, respectively; P < 0.001), whereas sulphonylureas were more often prescribed in Asian countries (42% vs. 52% vs. 54%; respectively, P < 0.001). Thiazolidinediones were prescribed in 6% of US patients compared with <1% of patients in Asia. The use of newer diabetes medications was <5% in all. Conclusion: In both the United States and Asia, opportunities for improvement in the use of evidence‐based therapies exist for patients with both diabetes and HFrEF. Effective tools to guide medication choices for these complex, high‐risk patients could have substantial impact on quality and outcomes. [ABSTRACT FROM AUTHOR]