Weight in vain?

According to the World Health Organization, 16% of adults aged 18 and over were living with obesity in 2022. This number has more than doubled since 1990.

As obesity rates climb, the health community has reacted with great concern, evident in the surge of obesity drugs flooding the market.

Broadly defined as excess weight that puts an individual at higher risk for adverse health outcomes, obesity is associated with negative implications for cardiovascular and metabolic health.

Increasingly, however, obesity is understood as an inflammatory disease.  Understanding and addressing the inflammatory impact of obesity is crucial for developing effective, beneficial therapies.

Here, we explore the connection of obesity and inflammation, the current treatment landscape and future treatment directions.

Adipose tissue is a metabolic and endocrine organ that secretes necessary hormones, such as leptin and adiponectin.

As fat tissue progresses into obesity, an increased number of immune cells are recruited into the tissue. These cells stimulate the production of pro-inflammatory cytokines, such as TNF-alpha and IL-6. These lead to toxic lipid accumulation and oxidative stress, increasing susceptibility to obesity-related complications.

Meanwhile, the production of anti-inflammatory factors, such as IL-10, decreases. Heightened levels of pro-inflammatory cytokines are associated with various health conditions.

Inflammation contributes to the narrowing of blood vessels in atherosclerosis. It can also lead to cardiovascular and pulmonary conditions, diabetes, chronic kidney disease, cancer, metabolic syndrome, and gastrointestinal and liver diseases.

The inflammation associated with obesity increases the risk of autoimmune diseases. Evidence suggests that obesity contributes to worse outcomes in conditions such as gout, rheumatoid arthritis, osteoarthritis, psoriasis, psoriatic arthritis and multisystem inflammatory syndrome in children.

Obesity can also impact the response to treatment for autoimmune diseases. The response to some forms of rheumatoid or psoriatic arthritis treatment is blunted in obese patients, with a lower likelihood of achieving low disease activity compared to non-obese counterparts.

Addressing obesity through weight-loss treatments can help improve inflammation-linked comorbidities. Weight loss has a positive impact on many such conditions.

For instance, a loss of at least 10% of body weight has been linked to a reduction in cardiovascular disease. For every pound of weight lost, there is a decrease of four pounds of pressure on the knee joint.

However, improvements in glucose, insulin and blood pressure, which come with weight loss, revert to baseline with even mild weight regain.

Current weight loss options consist of lifestyle changes, pharmacotherapy and bariatric surgery.

Only bariatric surgery has shown lasting effects on weight, with an average regain of under 5% of total weight lost after seven years. However, it is only recommended for a specific subset of patients.

The long-term benefits are not promising for other treatments. Within five years, patients are likely to regain up to 80% of weight lost through lifestyle changes.

Anti-diabetes and anti-obesity medication semaglutide – a glucagon-like peptide-1 (GLP-1) receptor agonist (RA) – can help maintain a total weight loss of 10% for more than four years. However, such drugs may be a lifetime commitment.

Patients discontinuing semaglutide can expect to regain two-thirds of weight initially lost through the drug within two years. In addition to their effect in weight loss, GLP-1 RAs have shown success in reducing inflammation and pain.

A recent study showed that weight loss with semaglutide led to improvements in pain and physical function scores in knee osteoarthritis patients. These drugs suppress the secretion of inflammatory cytokines, such as IL-6 and TNF-alpha, by interacting with receptors in immune cells and modulating immune signals.

This contributes to the ability of GLP-1 RAs to improve outcomes in inflammation-linked comorbidities such as major adverse cardiovascular events and chronic kidney disease, particularly in lupus.

While weight loss alone may improve some inflammation-linked comorbidities, its focus is on reducing obesity rather than targeting inflammation.

For patients who struggle to achieve or maintain weight loss, or who do not wish to take GLP-1 RAs in perpetuity, treating the cause of their conditions may seem out of reach.

As highly effective weight loss drugs have entered the market, we can focus on improving treatment for obesity-driven inflammation.

One potential route for future drug development is to evaluate a therapy’s impact on inflammatory markers, such as circulating concentrations of IL-6 and TNF-alpha.

These biomarkers can be used to evaluate the efficacy of an obesity therapeutic for addressing inflammation-linked comorbidities. There is promise in using immunotherapies that target the white adipose tissue microenvironment.

Immunotherapies can accomplish this through direct treatment that influences cells or signalling pathways or indirect treatment that targets cytokines after they have been secreted.

Research in this area is in early stages, but some clinical trials in humans have shown potential in moderating inflammatory responses and improving outcomes for comorbid diseases.

For example, empagliflozin, a sodium-glucose transport protein 2 inhibitor (SGLT2i), has had encouraging results in type 2 diabetes and atherosclerotic cardiovascular disease by interfering with the secretion of inflammatory cytokines. Patients receiving this treatment experienced greater weight loss than those on placebo.

In gout, SGLT2i use is associated with lower flare rates. More study is necessary to gather information on the safety, efficacy and long-term benefits of such immunotherapies.

This approach to mitigating inflammation may involve some toxicities and adverse events in patients. The immune landscape of adipose tissue is very complex.

Developers must ensure that therapies only impact the desired immune responses, without interfering with beneficial immune system function.

Current treatments, particularly incretin hormones such as GLP-1 RAs, have provided a powerful tool in addressing obesity and its comorbidities.

Yet there is still a long way to go. Developers are working towards obesity therapeutics that enable long-term maintenance of weight, do not reduce lean weight alongside fat and can be taken orally rather than as an injection.

Among all these avenues of research and development, the ability to treat the inflammation driven by obesity is central to improving health outcomes.

Christopher Mojcik is Senior Director, Therapeutic Area, Drug Development Solutions at ICON. Johnny Peppers is Executive Director, Global Drug Development, Therapeutic Expertise at ICON.
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