THERAPEUTIC FOCUS - Targeting Chronic Inflammation in Obesity

Originally published and posted March 2025 in PharmaTimes

INTRODUCTION

According to the World Health Organization, 16% of adults aged 18 and over were living with obesity in 2022, a number that has more than doubled since 1990.¹ As obesity rates con­tinue to climb, the health community has reacted with great con­cern – a fact that is evident in the surge of obesity drugs now flooding the market.

Broadly defined as an excess of weight that puts an individ­ual at higher risk for adverse health outcomes, obesity is com­monly associated with negative implications for cardiovascular and metabolic health. Increasingly, however, obesity is becoming understood as an inflammatory disease, with impacts across a wide variety of systems. As we progress in treating obesity and its associated comorbidities, understanding and addressing the in­flammatory impact of obesity is going to be an important element of developing effective, beneficial therapies. Here, we’ll explore the connection of obesity and inflammation, the current treatment landscape, and directions for future treatment.

THE IMPACT OF OBESITY & INFLAMMATION

Adipose tissue plays an important role in the body as a meta­bolic and endocrine organ, which secretes necessary hormones, such as leptin, adiponectin, and omentin. As fat tissue progresses into obesity, an increased number of macrophages and other im­mune cells are recruited into the tissue, where they stimulate the production of pro-inflammatory cytokines, such as: tumour necro­sis factor (TNF)-alpha, which can signal necrosis or apoptosis; in­terleukin (IL)-6, which stimulates acute immune response and fever; and leptin, which impacts food intake and energy expen­diture. In addition to creating local inflammation, these lead to toxic lipid accumulation and oxidative stress, which can damage cellular structures and increase susceptibility to numerous obe­sity-related complications. Meanwhile, the production of anti-in­flammatory factors, such as IL-10, adiponectin and omentin, decreases.

Together, these heightened levels of pro-inflammatory cy­tokines have been associated with a variety of health conditions and outcomes. For example, inflammation contributes to the nar­rowing of blood vessels in atherosclerosis. It can also lead to other cardiovascular and pulmonary conditions – not to mention diabetes, chronic kidney disease, cancer, metabolic syndrome, and gastrointestinal and liver diseases.

The inflammation associated with obesity also increases the risk of autoimmune diseases and impacts their severity. Evidence suggests that obesity contributes to worse outcomes in inflamma­tory autoimmune conditions such as gout, rheumatoid arthritis, osteoarthritis, psoriasis, psoriatic arthritis, and multisystem inflam­matory syndrome in children. Indeed, the relative risk of gout in men increases stepwise with increasing body mass index. And obesity can also play a role in response to treatment for autoimmune diseases. For example, the response to some forms of rheumatoid or psoriatic arthritis treatment is blunted in obese pa­tients, with a much lower likelihood of achieving low disease activity compared to non-obese counterparts.^2,3

TODAY’S TREATMENT LANDSCAPE

In many cases, addressing obesity through weight-loss treatments can also help to improve inflammation-linked co­morbidities. Weight loss has been shown to have 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.⁴ And for every pound of weight lost, there is a decrease of four pounds of pressure on the knee joint, a reduction highly meaningful to patients with knee osteoarthritis.⁵ Nev­ertheless, improvements in glucose, insulin and blood pressure, which come with weight loss, have been shown to revert to the baseline with even mild weight regain.

Current weight loss options primarily consist of lifestyle changes, pharmacother­apy and bariatric surgery. Of these, only bariatric surgery has been shown to have lasting effects on weight, with an average regain of under 5% of total weight lost after seven years.⁶ But, it is only recom­mended for a specific subset of patients.

The long-term benefits are not so promising for other treatments. Within five years, patients are likely to regain up to 80% of weight lost through lifestyle changes.⁷ Anti-diabetes and anti-obesity medication semaglutide – a gluten-like peptide1 (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.⁸ Patients discontinuing semaglutide can expect to regain two thirds of weight initially lost through the drug within two years.⁹

However, in addition to their effect in weight loss, GLP-1 RAs have also shown notable success in reducing inflammation. 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 is thought to be a major con­tributing factor in the ability of GLP-1 RAs to improve outcomes in inflammation-linked comorbidities such as major ad­verse cardiovascular events and chronic kidney disease.

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

WHAT’S NEXT FOR TREATING INFLAMMATION IN OBESITY

As highly effective weight loss drugs have successfully entered the market, we can now focus on improving treatment for obesity-driven inflammation. One poten­tial route for future drug development is to specifically evaluate a potential therapy’s impact on inflammatory markers such as circulating concentrations of IL-6, TNF-alpha and other such cytokines. These biomarkers can be used as an additional dimension through which the efficacy of an obesity therapeutic can be evaluated for its abil­ity to address inflammation-linked comorbidities.

Additionally, there is a great deal of promise in using im­munotherapies that specifically target the white adipose tissue mi­croenvironment to improve inflammation-linked comorbidities. There are two ways that immunotherapies can accomplish this: (1) direct treatment that influences cells or signalling pathways; or (2) indirect treatment that targets cytokines after they have been secreted.

While research in this area is still in early stages, some clin­ical trials in humans have shown potential in moderating inflam­matory responses and improving outcomes for comorbid disease. For example, empagliflozin, a sodium-glucose transport protein 2 inhibitor, has had encouraging results in type 2 diabetes and atherosclerotic cardiovascular disease, by interfering with the se­cretion of inflammatory cytokines from obese white adipose tis­sue.¹⁰ As well as seeing health benefits due to the reduction of inflammation, patients receiving this treatment experienced greater weight loss than those on placebo.

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. Further, the immune landscape of adi­pose tissue is very complex. So, developers must be careful that any such therapies only impact the desired immune responses, or risk interfering with beneficial immune system function.

THE OBESITY TREATMENT OF TOMORROW

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 quite a long way to go. Many developers are working toward obesity therapeutics that enable long-term maintenance of weight, do not reduce lean weight alongside fat, and that can be taken orally rather than as an injection. Among all of these avenues of research and devel­opment, the ability to treat the inflammation, which is driven by obesity, is central to the improvement of health outcomes.

REFERENCES

1. Obesity and Overweight. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 13 June 2024.
2. Poudel, D, MDGeorge, and JF Baker. The impact of obesity on disease activity and treatment response in rheumatoid arthritis. Curr Rheumatol Rep: 2021;22(9):56
3. Daien CI and J Sellam. Obesity and inflammatory arthritis: Impact on occurrence, disease characteristics and therapeutic response. RMD Open 2015;1:e000012
4. Tahrani AA, Morton J. Benefits of weight loss of 10% or more in patients with overweight or obesity: A review. Obesity (Silver Spring). 2022 Apr;30(4):802-840. https://doi.org/10.1002/oby.23371.
5. Messier SP, Gutekunst DJ, Davis C and DeVita P. Weight loss reduces knee-joint loads in overweight and obese older adults with knee osteoarthritis. Arthritis Rheum. 2005 Jul;52(7):2026-32
6. “Long-Term Study of Bariatric Surgery for Obesity: LABS – NIDDK.” National Institute of Diabetes and Digestive and Kidney Diseases, https://www.niddk.nih.gov/about-niddk/research-areas/obesity/longitudinal-assessment-bariatric-surgery. Accessed 13 June 2024.
7. Hall, Kevin D., and Scott Kahan. “Maintenance of Lost Weight and Long-Term Management of Obesity.” The Medical Clinics of North America, vol. 102, no. 1, Jan. 2018, pp. 183–97, https://doi.org/10.1016/j.mcna.2017.08.012.
8. Weintraub, Michael A., et al. “Five-Year Weight Loss Maintenance With Obesity Pharmacotherapy.” The Journal of Clinical Endocrinology & Metabolism, Feb. 2023, p. dgad100, https://doi.org/10.1210/clinem/dgad100.
9. Wilding, John P. H., et al. “Weight Regain and Cardiometabolic Effects after Withdrawal of Semaglutide: The STEP 1 Trial Extension.” Diabetes, Obesity & Metabolism, vol. 24, no. 8, Aug. 2022, pp. 1553–64, https://doi.org/10.1111/dom.14725.
10. Priscilla, Lia, et al. “Immunotherapy Targeting the Obese White Adipose Tissue Microenvironment: Focus on Non-Communicable Diseases.” Bioactive Materials, vol. 35, Feb. 2024, pp. 461–76, https://doi.org/10.1016/j.bioactmat.2024.01.027.

Dr. Johnny Peppers is Executive Director, Global Drug Development, Therapeutic Expertise, at ICON, and has been involved in clinical drug development and medical affairs for over two decades. This experience includes designing and implementing phase 1-3 clinical trials, medical affairs, post-marketing clinical research, KOL interactions and regulatory agency (FDA/EMA/PMDA) interactions. His therapeutic expertise includes immunology and autoimmunity, dermatology, allergic conditions and infectious diseases. He holds a PhD in immunology, a Master’s Degree in biology and statistics and a mini MBA in pharmaceutical development. He is also an adjunct member of the CPCD and has a decade of paediatric clinical development experience, leading several clinical programs involving paediatric patients.

Dr. Christopher Mojcik is Senior Director, Therapeutic Area, Drug Development Solutions at ICON. He has over 25 years of experience in clinical research, including 14 years working with large and small pharma. He has worked with ICON for over six years. He is an MD with 12 years of experience in clinical and academic rheumatology, including seven years in private practice. His therapeutic expertise includes rheumatology, immunology, and autoimmunity. He also has experience with small molecules and biologics, Phases I-IV clinical trials, and in small (including orphan) to large indications. Christopher holds a PhD in immunology and was an instructor for seven years in Biology Sacred Heart University, Fairfield, CT.