Glucagon-Like Peptide 1 Analogues as Adjunctive Therapy for Patients With Type 1 Diabetes: An Updated Systematic Review and Meta-analysis.

CONTEXT: Concomitant obesity is common among patients with type 1 diabetes mellitus (T1DM), yet adjunctive therapy options are scarce. OBJECTIVE: We assess the efficacy and adverse outcomes of glucagon-like peptide 1 (GLP-1) analogues when used as adjunctive therapy for T1DM. METHOD: PubMed, EMBASE, Cochrane Central, and Scopus databases were searched for randomized controlled trials up to December 2022. Efficacy outcomes were A1c level, body weight, and total daily insulin (TDI) after ≥12 weeks of GLP-1 therapy. We also assessed 12 different adverse outcomes. Subgroup analysis was done for newly diagnosed or C-peptide positive (C-pos) patients. We report the certainty of evidence based on the GRADE assessment tool. RESULTS: A total of 24 studies using 4 different GLP-1 analogues with a total of 3377 patients were included. Liraglutide had the most substantial evidence with effect sizes on A1c (-0.09%/mg), weight (-2.2 kg/mg), and TDI (-4.32 IU/mg). Liraglutide dose was the greatest predictor of greater average weight loss and TDI decrease but was associated with higher odds of nausea (OR 6.5; 95% CI, 5.0-8.4) and ketosis (OR 1.8; 95% CI, 1.1-2.8). Odds of severe (OR 0.67; 95% CI, 0.43-1.04) or symptomatic hypoglycemia (OR 0.89; 95% CI, 0.53-1.51) were not significantly elevated. Among C-pos patients, greater A1c decrease (-0.51% vs -0.28%) but similar weight loss and TDI were seen. Effect sizes for exenatide were similar, but studies had higher risk of bias and safety data were sparse. CONCLUSION: Our meta-analysis supports therapeutic benefits of liraglutide for patients with T1DM mainly for weight loss and insulin dose reduction. Newly diagnosed or C-pos patients do not appear to experience greater weight loss benefits.

In Situ Cross-linking Hydrogel as a Vehicle for Retinal Progenitor Cell Transplantation.

One of the current limitations of retinal transplantation of stem cells as well as other cell types is the dispersion of cells from the injection site (including loss of cells into the vitreous chamber) and low survival after transplantation. Gelatin-hydroxyphenyl propionic acid (Gtn-HPA) conjugate is a biodegradable polymer that can undergo covalent cross-linking in situ, allowing for injection of incorporated cells through a small caliber needle followed by gel formation in vivo. We tested the hypothesis that Gtn-HPA hydrogel supports survival and integration of retinal progenitor cells (RPCs) post-transplantation. In vitro compatibility and in vivo graft survival were assessed by mixing an equal volume of Gtn-HPA conjugate and RPC suspension and triggering enzyme-mediated gelation, using minute amounts of horseradish peroxidase and peroxide. Immunocytochemistry showed >80% survival of cells and minimal apoptosis for cells incorporated into Gtn-HPA, equivalent to controls grown on fibronectin-coated flasks. RPCs undergoing mitosis were seen within the three-dimensional Gtn-HPA hydrogel, but the percentage of Ki-67-positive cells was lower compared with the monolayer controls. For in vivo studies, gel-cell mixture or cell suspension in saline was trans-sclerally injected into the left eye of female Long Evans rats immunosuppressed with cyclosporine A. Grafts survived at the 1 week time point of the study, with Gtn-HPA-delivered grafts showing less inflammatory response demonstrated by anti-leukocyte staining. More eyes in the gel-cell mixture group showed surviving cells in the subretinal space compared with saline-delivered controls, while the number of cells surviving per graft was not significantly different between the two groups. This work demonstrates an injectable in situ cross-linking hydrogel as a potential vehicle for stem cell delivery in the retina.