What is the pipeline for future medications for obesity?

Abstract

Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.

Fig. 1. Secretion and main actions of the gut hormones used in the pipeline obesity treatments.

GLP-1 glucagon like peptide-1, GIP glucose-dependent insulinotropic polypeptide, PYY peptide YY, *data mainly from animal studies.

Fig. 2. Glucagon-like peptide-1 as the backbone of the pipeline for gut hormone-based obesity treatments.

GLP-1 glucagon like peptide-1, GIP glucose-dependent insulinotropic polypeptide, PYY peptide YY, NN: novo nordisk, *completed phase 3 trials for obesity.

Fig. 3. Weight loss with the obesity pharmacotherapies pipeline in people without diabetes.

A Mean % weight loss, B Proportion of people achieving ≥10% weight loss, C Proportion of people achieving ≥15% weight loss. OD once daily, OW once weekly, PO oral, SC subcutaneous, GLP-1 glucagon like peptide-1, GIP glucose-dependent insulinotropic polypeptide, GCG glucagon, PBO placebo, LIRA liraglutide, SEMA semaglutide, WL weight loss, NR not reported or not available. ^Afor efficacy estimand data, ^Bmain analysis presented, as efficacy estimand not available, ^Cunclear whether efficacy estimand or treatment-regimen estimand, *data from published abstract, presentation, clinicaltrial.gov or from press-release by the manufacturing company, **estimated treatment difference.

Fig. 4. HbA1c reduction and weight loss in people with type 2 diabetes with the pipeline molecules for obesity management.

A Mean HbA1c change, B Mean % weight loss, C Proportion of people achieving ≥10% weight loss. OD once daily, OW once weekly, BW twice weekly, PO oral, SC subcutaneous, IV intravenous, T2DM type 2 diabetes, GLP-1 glucagon like peptide-1, GIP glucose-dependent insulinotropic polypeptide, GCG glucagon, ACVR2B activin receptor type 2B, PBO: placebo, SEMA semaglutide, DULA dulaglutide, CAGR cagrilintide, WL weight loss, NA not available, NR not reported. ^Afor efficacy estimand data, ^Bmain analysis presented, as efficacy estimand not available, *data from published abstract, presentation, clinicaltrial.gov or from press-release by the manufacturing company.