GLP-2(TR)

How GLP-2(TR) is described to act.

GLP-2(TR) is a fatty-acid-modified synthetic peptide engineered to bind both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. Receptor-occupancy and signaling studies in cell lines reported imbalanced engagement favouring the GIP receptor, together with biased signaling at the GLP-1 receptor that favours cAMP generation over beta-arrestin recruitment and produces weaker receptor internalisation than native GLP-1. In primary islet preparations, beta-arrestin1 constrained the insulin response to GLP-1 but not to GIP or to GLP-2(TR), which the authors proposed as a basis for the compound's distinct pharmacology. In human adipocyte and diet-induced obese mouse models, long-acting GIP receptor agonism was reported to modulate adipocyte nutrient handling differentially according to insulin state.

Mechanistic descriptions summarize published in vitro and animal work. They are not a representation of efficacy or safety in any subject, and no administration guidance is given or implied.

Discovery-stage characterisation in vitro and in mice described activation of both incretin receptors with glucose-dependent insulin secretion and altered glucose tolerance, followed by a phase 1 programme in healthy participants and in participants with type 2 diabetes. The phase 3 SURPASS-1 trial measured mean change in glycated haemoglobin from baseline at 40 weeks in adults with type 2 diabetes inadequately controlled by diet and exercise. A post hoc analysis of a phase 2 dataset examined fasting biomarkers of beta-cell function and insulin resistance at 26 weeks, reporting changes in HOMA2-B, proinsulin ratios, HOMA2-IR, and adiponectin, IGFBP-1 and IGFBP-2. A review of the SURPASS 1-5 programme summarised the reported ranges of change in glycated haemoglobin and body weight and catalogued gastrointestinal events as the most commonly reported adverse events. Preclinical adipose tissue work attributed part of the observed metabolic profile to sustained GIP receptor activation rather than to GLP-1 receptor activity alone. A 112-week phase 3b trial at 20 US sites (SURMOUNT-MAINTAIN) followed a 60-week open-label weight-reduction period with a 52-week double-blind maintenance period, comparing continuation at the maximum tolerated dose, reduction to a lower dose, and a switch to placebo, with maintenance of the bodyweight reduction already achieved as the endpoint. A network meta-analysis of randomised trials of at least 12 weeks assessed 24 outcomes across obesity pharmacotherapies using GRADE and the Cochrane Risk of Bias 2 tool. Two population-based, new-user active-comparator cohort analyses examined severe gastrointestinal events including acute pancreatitis against dulaglutide and semaglutide, and major adverse cardiovascular events in adults with type 2 diabetes and atherosclerotic cardiovascular disease. A systematic review and meta-analysis of randomised placebo-controlled trials examined obesity-related cancer outcomes for GLP-1 receptor agonists and dual agonists as a class. A retrospective cohort drawn from electronic health records tracked fat-free mass, fat mass and their ratio over 24 months after bariatric surgery or GLP-1 receptor agonist treatment, an endpoint class the registration programme's weight and glycaemic outcomes did not capture.

Cited literature is provided for scientific reference only and does not constitute a representation of efficacy or safety in any subject. All research findings presented are sourced from peer-reviewed journals and are provided for educational reference only.