Contributor: Treating Obesity by Breaking the GLP-1 Pattern

More than 1 billion people worldwide are obese.¹

It’s a staggering figure, which only grows more alarming when you consider the trendlines. Since 1990, obesity rates have more than doubled among adults and quadrupled among children and adolescents. In 2023, 43% of adults were classified as overweight.

Harith Rajagopalan, MD, PhD, cofounder and CEO of Fractyl Health | Image Credit: © Fractyl Health

Despite advances in treatment, obesity and type 2 diabetes (T2D) continue to drive up rates of conditions such as heart disease, stroke, fatty liver disease, and some cancers. It’s therefore no surprise that glucagon-like peptide 1 (GLP-1) weight loss drugs such as tirzepatide (Zepbound) and semaglutide (Wegovy) have made a seismic impact on the obesity and diabetes communities, with a 50-fold increase in their use from 2017 to 2024.² By the end of 2023, over 9.5 million GLP-1 prescriptions had been written, indicating that approximately 2.5% to 3% of the US population is now using these drugs.³

Disrupting the status quo

As exciting as these drugs are, we have to put them into context. While GLP-1 drugs effectively manage the symptoms of metabolic diseases, they don’t have lasting effect because they don’t fix what has gone wrong in the body that causes obesity in the first place. The quest for a true solution must address the root cause of obesity and metabolic disease.

Here’s my take on the current state of obesity and diabetes care and how recent advances can potentially cure obesity and T2D.

GLP drugs today do not offer a cure

GLP-1 drugs are remarkably effective at addressing obesity, cardiovascular, and metabolic conditions—as long as people keep taking them. However, as revolutionary as these treatments are, they’re limited by a kind of “Cinderella Effect.” They offer the possibility of an almost “magical” transformation—but only temporarily. The clock strikes midnight when patients stop taking the medication. All benefits disappear and most patients revert to baseline, as if the treatment never happened at all. These medicines demand a lifelong commitment, and can sometimes cause severe adverse effects, including fatigue, gastric disturbances, pancreatitis, intestinal obstruction, and more. Most people eventually stop taking these drugs, due to these effects, or the cost of treatment (more on that below). And when they do, the excess weight, T2D, cardiovascular threats, and metabolic diseases return, often more persistently and dangerously than before.

Patient financial burden, systemic economic challenges

A Reuters article from October 24, 2024, highlighted data from pharmacy benefits manager Prime Therapeutics, showing that the annual cost of care for patients using Wegovy or similar GLP-1 drugs has risen significantly—from $12,695 before starting therapy to $18,507 while on the drugs, representing nearly a 50% increase.⁴ Only 1 in 4 patients were still taking a GLP-1 drug at 2 years. Notably, this analysis found no decrease in obesity-related medical events, such as heart attacks, strokes, or new diagnoses of T2D, presumably due to drop off in utilization of the drugs.

So what we are seeing is that the real-world effectiveness of GLP-1 drugs is not matching the data shown in phase 3 trials of these drugs, and we believe it highlights the main unmet need in obesity today: weight maintenance.

A new treatment paradigm: reset the gut

Hippocrates, the father of modern medicine, famously stated, “All diseases begin in the gut.” We’re finally developing a better understanding of the huge impact gut health has on metabolic and overall health. Why? The gut is the body's largest hormone producing organ, its largest immune system, and its largest nervous system outside of the brain.

In fact, groundbreaking research reveals that our modern diets, which are typically high in fat and sugar, lead to changes in the lining of the gut. These changes, specifically in a section called the duodenum, appear to be the root cause of obesity and metabolic dysfunction.

Embracing a new treatment paradigm

The future of metabolic treatment lies not in chronic medication usage, but in targeted interventions that restore the body's natural balance. We need to demand more from therapies than chronic symptom management and focus more on actual cures to metabolic disease. Duodenal mucosal resurfacing (DMR) is an investigational, nondrug, endoscopic procedure that targets duodenal dysfunction by ablating the duodenal mucosa to improve metabolic health in patients with obesity and T2D. The procedure aims to reset the abnormal duodenal lining that can develop from high-fat or high-sugar diets, potentially improving insulin sensitivity and glycemic control. By challenging conventional wisdom and exploring innovative approaches like DMR as part of a comprehensive toolbox of solutions, we can revolutionize obesity treatment, offering patients hope for a healthier future, for the long term.

References

1. One in eight people are now living with obesity. News release. World Health Organization. March 1, 2024. Accessed December 19, 2024. https://www.who.int/news/item/01-03-2024-one-in-eight-people-are-now-living-with-obesity

2. Reardon S. How “miracle” weight-loss drugs will change the world. Nature. November 5, 2024. Accessed December 19, 2024. https://www.nature.com/articles/d41586-024-03589-7
3. Logan P. On the increase in use of GLP-1s. Indiana University School of Medicine. June 27, 2024. Accessed December 19, 2024. https://medicine.iu.edu/blogs/bioethics/on-the-increase-in-use-of-glp-1s

4. Terhune C. Weight-loss drugs didn’t curb health costs within two years. Reuters. October 24, 2024. Accessed December 19, 2024. https://www.reuters.com/business/healthcare-pharmaceuticals/weight-loss-drugs-didnt-curb-health-costs-within-two-years-data-show-2024-10-24/