Background The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days. Methods In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase–polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183. Results A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19–related deaths occurred, all in the placebo group. Conclusions A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725 .)

No abstract

Background COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness.Methods DARE-19 was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19 and with at least one cardiometabolic risk factor (ie, hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease). Patients critically ill at screening were excluded. Patients were randomly assigned 1:1 to dapagliflozin (10 mg daily orally) or matched placebo for 30 days. Dual primary outcomes were assessed in the intention-to-treat population: the outcome of prevention (time to new or worsened organ dysfunction or death), and the hierarchial composite outcome of recovery (change in clinical status by day 30). Safety outcomes, in patients who received at least one study medication dose, included serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This study is registered with ClinicalTrials.gov, NCT04350593.

Cotadutide, a dual GLP-1 and glucagon receptor agonist, is under development for nonalcoholic steatohepatitis (NASH) and chronic kidney disease with type 2 diabetes. The effects of cotadutide on hepatic and metabolic parameters were evaluated in participants with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODSIn this phase 2b study, 834 adults with BMI $25 kg/m 2 and type 2 diabetes inadequately controlled with metformin (glycated hemoglobin A 1c [HbA 1c ]of 7.0%-10.5% [53-91 mmol/mol]) were randomized to double-blind cotadutide 100 μg(n = 100), 200 μg(n =256), or 300 μg(n = 256); placebo (n = 110); or open-label liraglutide 1.8 mg (n = 110)-all administered subcutaneously. Coprimary end points were changes in HbA 1c and body weight at week 14. The originally randomized interventions were continued to week 54. Liver damage biomarkers and liver fibrosis algorithms were assessed. RESULTSCotadutide significantly decreased HbA 1c and body weight at weeks 14 and 54 versus placebo (all P < 0.001). Improvements in lipid profile, AST and ALT levels, propeptide of type III collagen level, fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score were observed with cotadutide 300 μg versus placebo, but not with liraglutide. Weight loss with cotadutide 200 μg was similar to that with liraglutide 1.8 mg and greater with cotadutide 300 μg versus liraglutide 1.8 mg. The most common adverse events with cotadutide (nausea, 35%; vomiting, 17%) decreased over time. CONCLUSIONSCotadutide treatment for 54 weeks improved glycemic control and weight loss in participants with overweight/obesity and type 2 diabetes. Ad hoc analyses demonstrated improvements in hepatic parameters and support further evaluation of cotadutide in NASH.Approximately 70% of people with type 2 diabetes, and 93% of people with severe obesity who are candidates for weight reduction procedures or surgeries, have

Context Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity. Objective To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects. Design/setting Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites. Patients Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs. Intervention Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50–300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2). Main outcome measures Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC0–4h]) post–mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2). Results Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0–4h post MMTT (least squares mean [90% CI], −21.52% [−25.68, −17.37] vs 6.32% [0.45, 12.20]; P &lt; 0.001) and body weight (−3.41% [−4.37, −2.44] vs −0.08% [−1.45, 1.28]; P = 0.002). A significant increase in insulin AUC0–4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs −42.9 minutes; P = 0.0392). Conclusion These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying. Trial Registration ClinicalTrials.gov, NCT03244800.

In this single-dose, Phase 1 study in healthy subjects, the safety and pharmacokinetic profiles of MEDI0382 support once-daily dosing and further clinical development of MEDI0382.

Aims Coronavirus disease 2019 (COVID‐19) is caused by a novel severe acute respiratory syndrome coronavirus 2. It can lead to multiorgan failure, including respiratory and cardiovascular decompensation, and kidney injury, with significant associated morbidity and mortality, particularly in patients with underlying metabolic, cardiovascular, respiratory or kidney disease. Dapagliflozin, a sodium‐glucose cotransporter‐2 inhibitor, has shown significant cardio‐ and renoprotective benefits in patients with type 2 diabetes (with and without atherosclerotic cardiovascular disease), heart failure and chronic kidney disease, and may provide similar organ protection in high‐risk patients with COVID‐19. Materials and methods DARE‐19 (NCT04350593) is an investigator‐initiated, collaborative, international, multicentre, randomized, double‐blind, placebo‐controlled study testing the dual hypotheses that dapagliflozin can reduce the incidence of cardiovascular, kidney and/or respiratory complications or all‐cause mortality, or improve clinical recovery, in adult patients hospitalized with COVID‐19 but not critically ill on admission. Eligible patients will have ≥1 cardiometabolic risk factor for COVID‐19 complications. Patients will be randomized 1:1 to dapagliflozin 10 mg or placebo. Primary efficacy endpoints are time to development of new or worsened organ dysfunction during index hospitalization, or all‐cause mortality, and the hierarchical composite endpoint of change in clinical status through day 30 of treatment. Safety of dapagliflozin in individuals with COVID‐19 will be assessed. Conclusions DARE‐19 will evaluate whether dapagliflozin can prevent COVID‐19‐related complications and all‐cause mortality, or improve clinical recovery, and assess the safety profile of dapagliflozin in this patient population. Currently, DARE‐19 is the first large randomized controlled trial investigating use of sodium‐glucose cotransporter 2 inhibitors in patients with COVID‐19.

Follicular helper T cells (Tfh) are implicated in type 1 diabetes (T1D) and their development has been linked to CD28 costimulation. We tested whether Tfh were decreased by costimulation blockade using the CTLA-4-Ig fusion protein (Abatacept) in a mouse model of diabetes and in individuals with new onset T1D. Unbiased bioinformatic analysis identified that ICOS + Tfh, and other ICOS + populations including T-peripheral helper cells, were highly sensitive to costimulation blockade. We were able to use pre-treatment Tfh profiles to derive a model that could predict clinical response to Abatacept in individuals with T1D. Using two independent approaches we demonstrated that higher frequencies of ICOS + Tfh at baseline were associated with a poor clinical response following Abatacept administration. Tfh analysis may therefore represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade.