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Aims: Currently, no head-to-head data are available comparing semaglutide 2.0 mg with dulaglutide 3.0 mg or 4.5 mg. We conducted an indirect treatment comparison (ITC) of their effects on glycated hemoglobin (HbA1c) and body weight in patients with type 2 diabetes., Materials and Methods: Multilevel network meta-regression was conducted, based on a connected evidence network of published results from the A Study of the Efficacy and Safety of Dulaglutide (LY2189265) in Participants With Type 2 Diabetes 11 trial and individual patient data from the A Research Study to Compare Two Doses of Semaglutide Taken Once Weekly in People With Type 2 Diabetes (SUSTAIN) and SUSTAIN 7 trials., Results: Semaglutide 2.0 mg significantly reduced HbA1c vs dulaglutide 3.0 mg and 4.5 mg, with estimated treatment differences (ETDs) of -0.44% points (95% credible interval [CrI], -0.68 to -0.19) and -0.28% points (95% CrI, -0.52 to -0.03), respectively. Semaglutide 2.0 mg also significantly reduced body weight vs dulaglutide 3.0 mg and 4.5 mg with ETDs of -3.29 kg (95% CrI, -4.62 to -1.96) and -2.57 kg (95% CrI, -3.90 to -1.24), respectively. Odds of achieving HbA1c < 7.0% were significantly greater for semaglutide 2.0 vs dulaglutide 3.0 mg (odds ratio [OR]: 2.23 [95% CrI, 1.15-3.90]), whereas this did not reach significance for semaglutide 2.0 mg vs dulaglutide 4.5 mg (OR: 1.58 [95% CrI, 0.82-2.78]). Sensitivity analyses supported the main analysis findings., Conclusions: This ITC demonstrated significantly greater reductions from baseline in HbA1c and body weight with semaglutide 2.0 mg vs dulaglutide 3.0 mg and 4.5 mg. The findings of this study provide important comparative effectiveness information until randomized head-to-head studies become available., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss., Objective: Assess plasma metabolome changes mediated by tirzepatide., Design: Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed., Setting: Post hoc analysis., Participants: 259 subjects with T2D., Intervention(s): Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo., Main Outcome Measure(s): Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction., Results: At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species., Conclusions: Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Possible dulaglutide-induced cholecystitis, with successful resumption of dulaglutide after cholecystectomy, is discussed., Summary: A 72-year-old White man was started on dulaglutide for outpatient management of type 2 diabetes, in addition to his existing antihyperglycemic regimen of metformin, glipizide, pioglitazone, and insulin glargine. His glycated hemoglobin (HbA1c) concentration improved from 8.2% to 7.2% with the addition of dulaglutide. Furthermore, the use of dulaglutide did not lead to weight loss. After 16 months of treatment with dulaglutide, he presented to the emergency room with nausea, loss of appetite, and progressive sharp, nonradiating right upper quadrant pain. Based on symptom presentation, laboratory workup, and computed tomography scan results, acute cholecystitis was diagnosed. He underwent a cholecystectomy to remove what was found to be a gangrenous gallbladder. Per documented surgical dictation from the cholecystectomy, the gallbladder was removed, but portions of the biliary tree were left intact. The patient was continued on dulaglutide postoperatively without recurrence of bile stones, biliary tree disease, or abdominal symptoms at 8 months after initial cholecystitis incident., Conclusion: A male patient with possible dulaglutide-induced cholecystitis was successfully continued on dulaglutide therapy post cholecystectomy without recurrent complications within the biliary tract., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Recent findings from animal and human studies indicate that glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) modulate stress response by activating the hypothalamic-pituitary-adrenal (HPA) axis, which may have relevant clinical implications., Objective: To investigate the influence of GLP-1 RA treatment on HPA axis activity compared with placebo in healthy volunteers., Design: Double-blind, randomized, crossover study., Setting: University Hospital Basel, Switzerland., Participants: Twenty healthy volunteers., Intervention: Dulaglutide (Trulicity®) 1.5 mg and placebo (0.9% sodium chloride) were given subcutaneously once weekly for 3 weeks., Main Outcome Measures: Twenty-four-hour urinary free cortisol, circadian rhythm of serum and salivary cortisol, cortisol after 1 mg dexamethasone suppression test, and cortisol levels before and after stimulation with ACTH., Results: Urinary free cortisol levels were similar under dulaglutide [median (interquartile range) 240 nmol/L (164, 324)] vs placebo [188 nmol/L (133, 338), P = 0.131]. The circadian rhythm of serum and salivary cortisol were comparable in both groups as were cortisol levels after dexamethasone [dulaglutide 28 nmol/L (22, 47.5) vs placebo 26.5 nmol/L (15.8, 45.5), P = 0.4]. Serum cortisol levels in dulaglutide and placebo treated participants were 522 nmol (388, 710) and 530 nmol/L (394, 747), before (P = 0.6), and 658 nmol/L (604, 810) and 636 nmol/L (512, 910) after ACTH stimulation (P = 0.87)., Conclusion: Our results suggest that there is no activation of the HPA axis by long-term GLP-1 RA exposure, particularly dulaglutide, at the medically approved dosage of 1.5 mg once weekly.

Context: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat, and currently available therapies have limited efficacy to treat this complication. The antimyostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice., Objective: The objective of the study was to evaluate the safety, pharmacokinetics, and muscle efficacy of AMG 745 in men undergoing ADT for nonmetastatic prostate cancer., Methods: This was a randomized, blinded, placebo-controlled, multiple-dose, phase 1 study of AMG 745 given for 28 days. The end point of percentage change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry was prespecified., Results: Rates of adverse events (AMG 745 vs placebo) were the following: diarrhea (13% vs 9%), fatigue (13% vs 4%), contusion (10% vs 0%), and injection site bruising (6% vs 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg vs the placebo groups on day 29 by 2.2% (±0.8% SE, P = 0.008); in exploratory fat mass analysis, a decrease of -2.5% (±1.0% SE, P = 0.021) was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after day 29., Conclusion: Four weekly s.c. doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for nonmetastatic prostate cancer. RESULTS support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.