Creating better health outcomes with a holistic approach towards weight management

It’s an exciting time within chronic weight management - an area where the science is quickly evolving and highlighting new pathways and mechanisms that show promise in helping patients to manage their excess weight. In recent years we’ve seen a new wave of innovation that has improved options for many, but this is coupled with a significant current and growing patient need, with the World Health Organization (WHO) recognising it as one of the most critical public health challenges today and in the future.^1-4

Obesity is a chronic disease that requires long-term effective solutions, and being overweight likewise poses a long-term risk of developing comorbidities.^1,5 Beyond the challenges of living with excess weight, cardiometabolic diseases are one of the most common complications for people living with obesity/overweight.^6-9 Approximately 60% of people diagnosed with obesity or overweight have at least one comorbidity, including type 2 diabetes (T2D), cardiovascular disease (CVD), heart failure, and chronic kidney disease (CKD).^10,11

As new options start to transform what healthcare professionals can offer to patients who struggle with excess weight, there remains a pressing need for proactive measures and next-generation therapeutic solutions to address this growing epidemic.^1,2

The current approach for managing excess weight

Diet and exercise remain the mainstay for management of excess weight and with the introduction of injectable glucagon-like peptide-1 (GLP-1) and GLP-1/glucose-dependent insulinotropic polypeptide (GLP-1/GIP) combination as adjunct therapies, options have increased to support patients with weight loss, but challenges persist.^3,4,12-14

GLP-1 released from the gut controls meal-related glycaemic excursions and inhibits gastric emptying and food intake.¹⁵ GLP-1 receptor agonists (GLP-1 RA) are a treatment option for people living with obesity and diabetes, with the potential to decrease haemoglobin A1c (HbA1c) in the blood, promote weight loss and reduce the risk of cardiovascular events.¹⁶ Most approved GLP-1 RAs are injectable peptides, requiring a cold chain supply and storage.^{3,13,14,17,18} There is a need for options that offer patient convenience, a simpler supply chain or that provide solutions for those that cannot tolerate or are ineligible for current therapies.^19-21

Re-defining standards to deliver a new future that will change the obesity/overweight treatment landscape

AstraZeneca has a leading Cardiovascular, Renal and Metabolism (CVRM) portfolio of therapies for organ protection in cardiorenal diseases.^19,22,23 We see obesity and overweight as a clear risk factor for these interconnected diseases, and better weight management is an important feature in managing interrelated cardiorenal and cardiometabolic diseases.

We are focused on the underlying causes and mechanisms of obesity, with our growing pipeline of novel treatments, with complementary (or synergistic) mechanisms that aim to provide durable weight loss benefit with mono- and combination-therapies, weight management with cardiorenal benefit.

Through our collaborations and research into the science of obesity, we are pursuing advances for:

• Patients living with obesity and additional comorbidities requiring durable weight loss while reducing their cardiorenal risk, through both incretin and non-incretin pathways and unique combinations.
• Patients who are overweight and have cardiorenal and/or cardiometabolic comorbidities requiring moderate weight loss with organ protection, through GLP-1 and combination therapies with our cardiorenal molecules.
• Patients with type 2 diabetes who are living with obesity that will benefit from HbA1C reduction and weight loss.

Exploring several mechanisms to deliver innovative solutions through mono- and combination therapies

The science in the obesity/overweight space is rapidly evolving and our understanding of the mechanism of disease is driving our exploration of new approaches. These approaches have the potential to deliver a step-change in weight management for patients that help to more appropriately realise weight management at the same time as achieving lean muscle preservation.

Small molecule GLP-1 RAs are currently in development following the rollout of injectable GLP-1s.^{3,4,13,14,17,18,22} The mechanism of action for GLP-1 RAs includes effects on facilitating weight loss via reduced appetite and energy intake, decreasing gastric emptying and increasing insulin secretion of the pancreas.²⁴ This approach can support patients with obesity/overweight as well as those with type 2 diabetes and as part of fixed-dose combinations to provide glycaemic control, weight loss and cardiometabolic protection.²² 

Long-acting amylin analogues have a differentiated mechanism of action and may provide an effective option as monotherapy, as an add-on to other weight loss therapies or as part of novel combination treatments for addressing cardiometabolic risk or organ protection.¹¹ The mechanism of action of this class is thought to decrease gastric emptying rate, decrease fat mass, and increase leptin sensitivity and satiation, according to preclinical studies.²⁵

GLP-1/glucagon (GCG) dual receptor agonists offer a potential way to target triple mechanisms which could have effects on multiple organs including lipolysis in adipose tissue, decreasing gastric emptying and increasing fatty acid oxidisation and glucose homeostasis.²⁴

Given the complexity of obesity/overweight, and the heterogeneity across the population, there is a vast unmet need for a variety of management options that are accessible, sustainable, meet patients’ individual goals, manage other long-term chronic conditions, reduce risk of complications, and improve quality of life.