Obesity is commonly defined as excess fat accumulation that puts someone at a higher risk for adverse health outcomes.1 The simplicity of this definition can be misleading, because obesity’s pathophysiology is highly complex, and characterised by a multitude of interrelated factors, including metabolic and immune changes in response to energy surfeit; mechanisms such as oxidative stress, and local and systemic inflammatory responses; alterations in blood flow and perfusion; and the mechanical burden of weight. Together, these factors contribute to the morbidity and mortality of the many obesity-related conditions.
The interdependent pathophysiology of obesity and comorbid conditions are relevant to treatment efficacy and have informed an interdisciplinary approach to obesity treatment in recent years, including the development of single treatments for multiple indications and combination interventions. Indeed, in a 2023 ICON survey of more than 100 professionals engaged in obesity-related clinical research, only 37% reported studying obesity alone. The indications most commonly included in obesity-related research were reported to be diabetes (55%), metabolic disease (48%), mental health (39%) and cardiovascular disease (38%).
Multi-indication Trials
Historically, drug development proceeded one indication at a time, from diabetes to weight loss and MASH indications. But, encouraged by the recent approval of GLP-1 receptor agonists for obesity – in addition to type 2 diabetes, and an improved understanding of the shared pathophysiology of obesity and other comorbid conditions – that has begun to shift. In the ICON survey, 50% of respondents reported employing multi-indication studies in their obesity-related trials.
Innovative approaches to trial design are often needed to demonstrate a treatment’s efficacy for multiple indications. Here, sponsors may benefit from the use of master protocols, which are constructed to include multiple sub-studies, which have an overarching set of procedures to improve efficiency, such as inclusion of a common screening protocol or the sharing of control subjects. Master protocols with a basket trial design are well suited for multi-indication treatments across the obesity-related spectrum of diseases or for subtypes of a single disease, which have a common molecular characteristic.2
The Need for Long-term Follow-up
In the ICON survey, 44% of respondents reported that long-term follow-up was the biggest challenge in obesity-related clinical trials, Longer-term studies are needed to determine treatment effects on clinical events linked to obesity-related comorbidities, including major adverse cardiovascular events (MACE), chronic kidney disease and the onset of diabetes. This information is crucial for assessing the cost effectiveness of new treatments and will be required to compete with products that have proven outcome benefits.
