Weight of expectation

Emerging evidence reveals a clinically significant rebound effect following the discontinuation of glucagon-like peptide-1 (GLP-1) agonists, characterised by weight regain, resurgence of cardiometabolic risk factors and relapse into maladaptive behaviours.

Yet there is no guarantee that patients living with obesity who gain access to GLP-1 medications during a clinical trial will remain engaged for the trial duration or be able to access the medications once the study ends.

This presents sponsors, sites, contract research organisations (CROs) and others in the clinical trial community with a unique opportunity to understand and proactively mitigate the effects of GLP-1 discontinuation.

After all, the patients living with obesity who participate in GLP-1 studies are not merely subjects or randomisation numbers’ they are people whose lives we may significantly change, often in unexpected ways.

Therefore, collaborative strategies to help patients navigate the complexities of GLP-1 use should be woven into clinical trial protocols and operational considerations from the very start. These strategies should include:

• Educating trial staff and participants about the physical, behavioural and emotional aspects of GLP-1 use
• Educating trial staff on combating obesity bias
• Supporting patients throughout their journey in the study to ensure they feel valued and informed, and well supported at every step.

Patients who take GLP-1 medications tend to see significant weight loss, in addition to positive changes in indicators such as blood pressure, cholesterol, haemoglobin A1c levels and others. GLP-1 drugs may also improve overall inflammation, as evidence suggests they decrease levels of C-reactive protein (CRP).

From a behavioural standpoint, GLP-1 therapies appear to quiet patients’ food cravings and food-related mental ‘noise’, which frees them to focus more on other aspects of their lives.

For example, a friend I’ve known for more than 30 years who started using a GLP-1 medication a year ago is now spending the time she previously spent thinking about food doing things she never did before, like riding her bicycle. She describes it as a space in her head that allows thoughts of other things that aren’t food.

However, research such as the STEP 1 Extension study suggests that many of the benefits generated by GLP-1 medications largely disappear once patients stop using them. The study found that one year after GLP-1 use, participants had regained two-thirds of the weight previously lost despite receiving lifestyle interventions during the initial clinical trial. Participants’ cardiometabolic benefits returned toward baseline, and their food-related “mental chatter” returned.

Most patients are aware that they may need to remain on GLP-1 medications for a long time – perhaps the rest of their lives – to retain the benefits. Still, many voluntarily stop taking them after a year or two for a variety of physical, financial, social and emotional reasons.

For example, they may disrupt patients’ normal household habits. Because eating is often tied to daily routines and social activities, even positive physical changes can create difficult emotional and behavioural consequences, affecting a patient’s self-view and relationships.

In fact, a recent New York Times article delves into some of the unforeseen ways GLP-1 drugs may negatively impact marriages. These may be some of the reasons why one recent study indicates 46.5% of patients with type 2 diabetes and 64.8% without type 2 diabetes discontinue use within one year.

To preserve patient engagement during GLP-1 clinical trials and more durable outcomes afterward, it is essential to educate investigators, clinical trial staff and clinical trial candidates about the benefits and risks associated not just with GLP-1 use but its discontinuance. Then, alongside the knowledge, we must build trust.

People living with obesity are already at high risk of dropping out of GLP-1 clinical trials because they often are uncomfortable seeking medical care. Sometimes, that is because weight stigma and unconscious bias are present within the provider community.

For example, most providers are surprised to learn that in the healthcare setting, patients living with obesity are touched less frequently than other patients.
As a nurse practitioner who spent years caring for patients with diabetes and endocrine conditions, I am acutely aware of the physical and emotional suffering often experienced by people living with obesity.

However, I have found that actively combatting obesity bias and ensuring truly informed patient consent are two ways the research community can build patient relationships, trust and engagement.

Fortunately, effective strategies for reducing bias and enhancing consent do not need to be exhaustive.

Steps researchers can take to improve how patients feel about study participation include:

• Identify and address obesity bias before launching GLP-1 studies. This can be accomplished by asking patient advocacy groups, CROs, or others to train principal investigators (PIs), clinical research associates, research coordinators and other site staff about obesity bias. While most PIs recognise the issue, obesity bias is not typically part of the research site onboarding process, even when diversity and inclusion education is part of it. Training should encourage all providers and staff members to honestly evaluate and challenge their own weight-based biases
• Examine how the study protocol reviews the disease process. While a protocol may already note the chronic nature of obesity as a disease, be sure it also describes the true challenge of obesity bias. Incorporating the concept of obesity bias presents opportunities to help patients with obesity feel welcomed and respected as clinical trial participants
• Promote inclusive language. Train everyone associated with a study to replace the word ‘obese’ (used as a judgmental label) with ‘people living with obesity’, just like describing people who live with heart disease or any other chronic disease. Use inclusive language without obesity bias throughout the patient-informed consent process, in study materials and in conversations. In all interactions, using patient-centred communication techniques will foster a more welcoming and comfortable experience
• Train staff to make informed consent truly ‘informed’. The full range of cardiometabolic, behavioural and other potential side effects of taking – as well as discontinuing – a GLP-1 should be clearly explained.
• Patients must understand precisely what they’re volunteering for, including the fact that they may not receive the study drug if the trial includes a placebo arm. Research sites with access to a simulation centre may want to create a simulated informed consent experience for their research coordinators based on their local SOPs and in collaboration with regulatory agency and published guidelines. The goal is for each person enrolled in the study to truly want to be there and remain engaged
• Embed lifestyle education as part of the protocol. Nutritional and exercise education should be an engaging and substantive part of the protocol. For example, teach patients how to prepare healthy meals, as well as how to begin and maintain an exercise programme. That way, patients who stop using a GLP-1 at their trial’s conclusion will be better equipped with the skills and resources necessary to adapt over the long run. Current prescribing information for GLP-1 RA drugs states these drugs should be used in combination with a reduced-calorie diet and increased physical activity
• Consider logistical factors in the protocol. Ensure sites have appropriately sized equipment, and that they can provide accessible parking spots near the door and wheelchairs for patients with mobility issues.

While enrolling patients in a GLP-1 clinical trial is seldom a problem, retaining them is often the challenge. Consequently, study designers must plan collaboratively and proactively to manage expectations, combat obesity bias, strengthen consent processes, and give patients skills and resources to adapt.

We must start viewing the disease of obesity like we do other chronic diseases and apply the lessons learned from other conditions that require long-standing or lifelong pharmaceutical treatment.

At the same time, we must remember that obesity involves clinical, behavioural and emotional complexities that may not exist with other conditions.

By addressing the complexities of GLP-1 discontinuation with empathy and proactive strategies, we can empower patients and redefine obesity care.

MarieElena Cordisco is Senior Director, Therapeutic Strategy Lead at Metabolic