Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults With Overweight or Obesity and Type 2 Diabetes: A 54-Week Randomized Phase 2b Study.

OBJECTIVE: 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 METHODS: In this phase 2b study, 834 adults with BMI ≥25 kg/m2 and type 2 diabetes inadequately controlled with metformin (glycated hemoglobin A1c [HbA1c] 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 HbA1c and body weight at week 14. The originally randomized interventions were continued to week 54. Liver damage biomarkers and liver fibrosis algorithms were assessed. RESULTS: Cotadutide significantly decreased HbA1c 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. CONCLUSIONS: Cotadutide 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.

Emergency Potassium Normalization Treatment Including Sodium Zirconium Cyclosilicate: A Phase II, Randomized, Double-blind, Placebo-controlled Study (ENERGIZE).

OBJECTIVES: Sodium zirconium cyclosilicate (SZC) is a novel, highly selective potassium binder currently approved in the United States and European Union for treatment of hyperkalemia. This pilot evaluation explored the efficacy of SZC with insulin and glucose as hyperkalemia treatment in the emergency department (ED). METHODS: This exploratory, phase II, multicenter, randomized, double-blind, placebo-controlled study (NCT03337477) enrolled adult ED patients with blood potassium ≥ 5.8 mmol/L. Patients were randomized 1:1 to receive SZC 10 g or placebo, up to three times during a 10-hour period, with insulin and glucose. The primary efficacy outcome was the mean change in serum potassium (sK+ ) from baseline until 4 hours after start of dosing. RESULTS: Overall, 70 patients were randomized (SZC n = 33, placebo n = 37), of whom 50.0% were male. Their mean (± standard deviation [±SD]) age was 59.0 (±13.8) years and mean initial sK+ was similar between groups (SZC 6.4 mmol/L, placebo 6.5 mmol/L). The least squares mean (±SD) sK+ change from baseline to 4 hours was -0.41 (±0.11) mmol/L and -0.27 (±0.10) mmol/L with SZC and placebo, respectively (difference = -0.13 mmol/L, 95% confidence interval [CI] = -0.44 to 0.17). A greater reduction in mean (±SD) sK+ from baseline occurred with SZC compared with placebo at 2 hours: -0.72 (±0.12) versus -0.36 (±0.11) mmol/L (LSM difference = -0.35 mmol/L, 95% CI = -0.68 to -0.02), respectively. A numerically lower proportion of patients in the SZC group required additional potassium-lowering therapy due to hyperkalemia at 0 to 4 hours versus placebo (15.6% vs. 30.6%, respectively; odds ratio = 0.40, 95% CI = 0.09 to 1.77). Comparable proportions of patients experienced adverse events in both treatment groups at 0 to 24 hours. CONCLUSIONS: This pilot study suggested that SZC with insulin and glucose may provide an incremental benefit in the emergency treatment of hyperkalemia over insulin and glucose alone.

Control of Postprandial Hyperglycemia in Type 1 Diabetes by 24-Hour Fixed-Dose Coadministration of Pramlintide and Regular Human Insulin: A Randomized, Two-Way Crossover Study.

OBJECTIVE: Healthy pancreatic ß-cells secrete the hormones insulin and amylin in a fixed ratio. Both hormones are lacking in type 1 diabetes, and postprandial glucose control using insulin therapy alone is difficult. This study tested the pharmacodynamic effects of the amylin analog pramlintide and insulin delivered in a fixed ratio over a 24-h period. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes were stabilized on insulin pump therapy with insulin lispro before a randomized, single-masked, two-way crossover, 24-h inpatient study in which regular human insulin was administered with pramlintide or placebo using separate infusion pumps in a fixed ratio (9 µg/unit). Meal content and timing and patient-specific insulin doses were the same with each treatment. The primary outcome measure was change in mean glucose by continuous glucose monitoring (CGM). Profiles of laboratory-measured glucose, insulin, glucagon, and triglycerides were also compared. RESULTS: Mean 24-h glucose measured by CGM was lower with pramlintide versus placebo (8.5 vs. 9.7 mmol/L, respectively; P = 0.012) due to a marked reduction of postprandial increments. Glycemic variability was reduced, and postprandial glucagon and triglycerides were also lower with pramlintide versus placebo. Gastrointestinal side effects were more frequent during use of pramlintide; no major hypoglycemic events occurred with pramlintide or placebo. CONCLUSIONS: Coadministration of fixed-ratio pramlintide and regular human insulin for 24 h improved postprandial hyperglycemia and glycemic variability in patients with type 1 diabetes. Longer studies including dose titration under daily conditions are needed to determine whether this regimen could provide long-term improvement of glycemic control.