Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD.

Key Points: Increasing doses of the endothelin receptor antagonist zibotentan and lower eGFR were associated with a higher risk of fluid retention. The higher risk of fluid retention could be attenuated by the combination of zibotentan with the sodium-glucose cotransporter 2 inhibitor dapagliflozin.

Background: Endothelin receptor antagonists (ERAs) reduce albuminuria but are limited by fluid retention risk, particularly in patients with CKD.

Targeting the endothelium by combining endothelin-1 antagonism and SGLT-2 inhibition: better together?

Endothelin A and B receptors, together with sodium-glucose cotransporter-2 (SGLT-2) channels are important targets in improving endothelial function and intervention with inhibitors has been the subject of multiple mechanistic and clinical outcome trials over recent years. Notable successes include the treatment of pulmonary hypertension with endothelin receptor antagonists, and the treatment of heart failure and chronic kidney disease with SGLT-2 inhibitors. With distinct and complementary mechanisms, in this review, we explore the logic of combination therapy for a number of diseases which have endothelial dysfunction at their heart.

Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial.

Background: In patients with chronic kidney disease, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) can reduce albuminuria and glomerular filtration rate (GFR) decline. We assessed the albuminuria-lowering efficacy and safety of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin.

Methods: ZENITH-CKD was a multicentre, randomised, double-blind, active-controlled clinical trial, done in 170 clinical practice sites in 18 countries.

Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver.

The principle pathological drivers of metabolic dysfunction-associated steatohepatitis (MASH) are obesity and associated insulin resistance, rendering them key therapeutic targets. As glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been licensed for the treatment of diabetes and obesity, they were one of the first drug types to be evaluated in patients with MASH, and successful phase IIa and IIb studies have resulted in progression to phase III clinical trials. Alongside GLP-1RAs, newer combinations with glucagon agonists and/or glucose-dependent insulinotropic peptide (GIP) agonists have been explored in related patient groups, with evidence of improvements in weight, insulin resistance and non-invasive liver parameters.

Totality of evidence of the effectiveness of repurposed therapies for COVID-19: Can we use real-world studies alongside randomized controlled trials?

Rapid and robust strategies to evaluate the efficacy and effectiveness of novel and existing pharmacotherapeutic interventions (repurposed treatments) in future pandemics are required. Observational "real-world studies" (RWS) can report more quickly than randomized controlled trials (RCTs) and would have value were they to yield reliable results. Both RCTs and RWS were deployed during the coronavirus disease 2019 (COVID-19) pandemic.

The new rosiglitazone story: its place today in type 2 diabetes management.

ADOPT suggests that rosiglitazone, ahead of traditional therapies, can meet patient needs with respect to long-term glycaemic control, yet the recent safety debate, stimulated by retrospective meta-analysis, has seriously affected physician confidence to use it. Other recent evidence, including from a number of long-term outcome studies, does not confirm or exclude a cardiovascular risk signal for rosiglitazone, and evaluation of this data has led EMEA to support continued use of rosiglitazone, albeit with a recommendation not to use in patients with a previous cardiovascular history. Where does this leave us? Rosiglitazone remains the only oral blood glucose lowering agent to have demonstrated nearly 5 years of blood glucose control.

Specific associations of insulin resistance with impaired health-related quality of life in the Hertfordshire Cohort Study.

Insulin resistance is a metabolic abnormality that underlies Type 2 diabetes, the metabolic syndrome and cardiovascular disease, but it may also be associated with more global health deficits. This study assessed associations of insulin resistance with health-related quality of life (HRQoL) in different domains of physical and mental health in a large elderly population study. Cross-sectional data of 1212 participants from the Hertfordshire Cohort Study were analysed.