Efficacy and safety of cotadutide, a dual glucagon-like peptide-1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease.

AIM: To assess the efficacy, safety and tolerability of cotadutide in patients with type 2 diabetes mellitus and chronic kidney disease. MATERIALS AND METHODS: In this phase 2a study (NCT03550378), patients with body mass index 25-45 kg/m2 , estimated glomerular filtration rate 30-59 ml/min/1.73 m2 and type 2 diabetes [glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)] controlled with insulin and/or oral therapy combination, were randomized 1:1 to once-daily subcutaneous cotadutide (50-300 µg) or placebo for 32 days. The primary endpoint was plasma glucose concentration assessed using a mixed-meal tolerance test. RESULTS: Participants receiving cotadutide (n = 21) had significant reductions in the mixed-meal tolerance test area under the glucose concentration-time curve (-26.71% vs. +3.68%, p < .001), more time in target glucose range on continuous glucose monitoring (+14.79% vs. -21.23%, p = .001) and significant reductions in absolute bodyweight (-3.41 kg vs. -0.13 kg, p < .001) versus placebo (n = 20). In patients with baseline micro- or macroalbuminuria (n = 18), urinary albumin-to-creatinine ratios decreased by 51% at day 32 with cotadutide versus placebo (p = .0504). No statistically significant difference was observed in mean change in estimated glomerular filtration rate between treatments. Mild/moderate adverse events occurred in 71.4% of participants receiving cotadutide and 35.0% receiving placebo. CONCLUSIONS: We established the efficacy of cotadutide in this patient population, with significantly improved postprandial glucose control and reduced bodyweight versus placebo. Reductions in urinary albumin-to-creatinine ratios suggest potential benefits of cotadutide on kidney function, supporting further evaluation in larger, longer-term clinical trials.

MEDI0382, a GLP-1/glucagon receptor dual agonist, meets safety and tolerability endpoints in a single-dose, healthy-subject, randomized, Phase 1 study.

AIMS: MEDI0382 is a balanced glucagon-like peptide-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus and non-alcoholic steatohepatitis. The primary objective was to assess the safety of MEDI0382 in healthy subjects. METHODS: In this placebo-controlled, double-blind, Phase 1 study, healthy subjects (aged 18-45 years) were randomized (3:1) to receive a single subcutaneous dose of MEDI0382 or placebo after ≥8 h of fasting. The study consisted of six cohorts that received study drug at 5 µg, 10 µg, 30 µg, 100 µg, 150 µg or 300 µg. The primary objective was safety and tolerability. Secondary endpoints included assessments of pharmacokinetics and immunogenicity. All subjects were followed for up to 28 days. RESULTS: A total of 36 subjects received MEDI0382 (n = 6 per cohort) and 12 subjects received placebo (n = 2 per cohort). Treatment-emergent adverse events (TEAEs) occurred more frequently with MEDI0382 vs. placebo, which was mostly due to an increased occurrence at MEDI0382 doses ≥150 µg. All TEAEs were mild or moderate in severity. The most common TEAEs were vomiting, nausea and dizziness. There appeared to be a dose-dependent increase in heart rate with MEDI0382 treatment. MEDI0382 showed linear pharmacokinetic profile (time to maximum plasma concentration: 4.50-9.00 h; elimination half-life: 9.54-12.07 h). No immunogenicity was observed in the study. CONCLUSIONS: 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.

Recurrent in-stent restenosis is not associated with the angiotensin-converting enzyme D/I, angiotensinogen Thr174Met and Met235Thr, and the angiotensin-II receptor 1 A1166C polymorphism.

Although great progress has been made in reducing renarrowing of the lumen after stenting of coronary arteries, a considerable number of patients develop recurrent in-stent stenosis. Several studies suggest that neointimal proliferation is the crucial pathophysiological process underlying restenosis after stenting. The renin-angiotensin-aldosterone system (RAS) has been implicated in the development of neointimal hyperplasia. We tested the hypothesis that polymorphisms of the RAS genes are associated with recurrent in-stent restenosis (ISR). Coronary stent implantation was performed in 272 patients with clinical symptoms or objective signs of ischemia. At follow-up angiography 6 months after stenting, 81 patients (29.8%) revealed in-stent restenosis. These patients underwent balloon angioplasty and were scheduled for a further 6 months of follow up. One year after initial stenting of the coronary artery, 39 patients displayed no significant angiographic ISR, whereas 42 patients developed recurrent in-stent restenosis (RISR). The survey of specific functional polymorphisms of the RAS, namely the angiotensin-I converting enzyme (ACE) D/I, the angiotensinogen (AGT) T174M and M235T, and A1166C of the angiotensin-II receptor 1 (AGTR1), revealed that the incidence RISR in the high-risk cohort was not associated with any of the polymorphisms examined in this study.

End-stage heart failure with multiple intracardiac thrombi: a rescue strategy.

The use of ventricular assist devices as a bridge to transplantation has become a widely used option for patients with end-stage heart failure. In contrast to total artificial hearts, ventricular assist devices support the failing heart by bypassing one or both ventricles. In certain cases (myocardial tumors, graft failure, transplant rejection, endocarditis, intracardiac thrombus formation), however, it may be advantageous to excise the heart and replace it with an artificial device. Total artificial hearts are intracorporeal devices designed for this purpose. Unfortunately, some patients are too small or are, for other reasons, ineligible for a total artificial heart. We describe the case of a 55-year-old woman who had ischemic cardiomyopathy and thrombus formation in all 4 cardiac chambers. To reduce the risk of thromboembolic events, we elected to replace her heart completely with 2 extracorporeal ventricular assist devices. The heart was excised via a median stemotomy approach, and the outflow cannulae (from device to patient) were connected to both atrial remnants. The 2 inflow cannulae (from patient to device) were anastomosed end-to-end to the aorta and the pulmonary artery, respectively. After attaining a flow of more than 5 L, the 2 extracorporeal assist devices effectively and efficiently performed the work of the native heart. Thus re-established, organ perfusion was improved by this mechanically driven circulation, as signified by an initial decrease in creatinine and blood urea nitrogen levels. The patient, however, did not recover from postoperative neurological dysfunction and died of respiratory insufficiency and multiple-organ failure on the 26th postoperative day.