Being involved in clinical research often feels like playing the long game. As we go about our day-to-day activities, we have the opportunity to see more immediate benefits for our participants when an investigational treatment has a positive impact on their disease/condition or quality of life. However, it can take many years or even decades to see those same effects for the larger population. At Headlands Research, we’ve been involved in a number of weight management trials over the years, including for glucagon-like peptide 1 (GLP-1) receptor agonists (RAs), and it was exciting to see, for the first time since 1999, a decrease in the rate of obesity in the United States.
Using data from the National Health and Nutrition Examination Survey (NHANES), the Centers for Disease Control and Prevention (CDC) reported that 40.3% of adults (20 years and older) were overweight in 2021-2023, a decrease from 41.9% in 2017-2020. Although a relatively small decline, it is noteworthy in the public health context, given the role of obesity in cardiovascular disease, kidney disease, some cancers, and physical function.
GLP-1 RAs are changing the weight management paradigm
GLP-1 RAs, which have demonstrated weight loss ranging from ~15% to 22%, have helped redefine the paradigm of weight management GLP-1 RAs and become an integral component of weight management for overweight and obesity. Not only is the range of weight loss much higher than the 6% achieved with previous drugs for weight management, it is also well above the 5% weight loss considered to be clinically meaningful to reduce the risk of developing obesity-related comorbidities such as cardiovascular disease, type 2 diabetes mellitus (T2DM), and kidney disease.
Studies following the first discovery of GLP-1 in 1987 showed that it stimulates insulin secretion from the pancreas, which is needed for glucose uptake by the body, thereby reducing blood glucose levels. These findings motivated development for the treatment of individuals with T2DM, and T2DM was the first FDA-approved indication for a GLP-1 RA in 2005. This approval was supported by further discoveries around its effect on decreasing glucagon secretion, increasing glycogen synthesis in peripheral tissues, delaying gastric emptying, and increasing satiety.
The development of GLP-1 RAs for weight management stemmed from a better understanding of the mechanisms of weight regulation and the role of the gut-brain axis on appetite, as well as potentially impaired GLP-1 secretion from the gastrointestinal system in obesity. This knowledge was supported by the observed effects on gastric emptying, satiety, and weight loss when prescribed for T2DM. Following additional studies of GLP-1 RAs specifically for weight management, the first approval of a GLP-1 RA to treat obesity was granted in 2014. Since then, scientific advances have addressed some of the limitations of the early medicines, such a short half-life that required frequent injections, as often as twice a day. Today’s GLP-1s offer more convenient once-weekly injections, and oral and monthly dosing options are in development.
Discoveries continue for other chronic diseases
During the use of GLP-1 RAs for T2DM and obesity, the scientific and healthcare community observed other positive effects such as decreases in cardiovascular events, strokes, and renal progression. The results of a meta-analysis presented at the European Society of Cardiology (ESC) Congress 2024 demonstrated the positive effects of GLP-1 RAs on cardiovascular outcomes in individuals with obesity. This is notable because the effects of these medications on cardiovascular outcomes in individuals with T2DM were demonstrated as early as 2016 and have been extensively studied since then, but evidence in the absence of T2DM had been lacking. In fact, the scientific support for the effects of GLP-1 RAs on cardiovascular health in the presence of T2DM is so established that the American Diabetes Association (ADA) updated its guidelines to include GLP01 RAs with demonstrated cardiovascular benefits as add-on treatment to metformin for individuals with atherosclerotic cardiovascular disease.
Although much of this could potentially be attributed to the lower risk of obesity-related comorbidities with decreasing weight, these cardiovascular findings prompted further research into whether these effects were related to the GLP-1 receptors themselves. As a result, we have since discovered that GLP-1 receptors are not only found on the pancreas and in the gut but also widely expressed in the autonomic nervous system, the brain, and other body systems. And promising clinical evidence has emerged for GLP-1 RAs to treat or prevent obstructive sleep apnea, metabolic dysfunction–associated steatohepatitis (MASH), obesity-related cancers, nicotine use disorder (NUD), and dementia, including Alzheimer’s disease.
In fact, it seems as if every week brings news about the potential additional applications for this drug type, and we have only started to scratch the surface of our understanding of the mechanism of action, which is an exciting place for the research community to be in!
However, obesity continues to be public health concern
A note of caution is also warranted, and we still have work ahead of us. Despite these exciting advancements in weight management pharmacology, the rates of obesity in 2021-2023 were still higher than previous NHANEs survey cycles (i.e., 39.6% in 2015-2016 and 37.7% in 2013-2014), and the prevalence of obesity in adults remains above the Healthy People 2030 goal of 36%. In 2023, obesity affected 35% of adults in 23 US states, compared with no states reaching that level before 2013, just 10 years earlier. Furthermore, the rate of severe obesity increased from 7.7% of adults in 2013–2014 to 9.7% of adults in 2021-2023, indicating that the population with the highest risk of weight-related comorbidities continues to grow.Therefore, research should continue pursuing additional promising weight management therapies (e.g., amylin, amycretin, acti-activin, melanocortin MC4 receptor agonists), whether on their own or in combination with GLP-1 RAs, particularly for individuals with obesity who haven’t seen the benefits of GLP-1 RAs; have discontinued them because of side effects such as nausea, vomiting, and diarrhea; experienced significant muscle loss; or have simply been unable to access them because of supply issues or high prices. Public and physician education about the important role of diet and physical activity is also needed, as GLP-1 RAs are not a magic cure or a lifelong therapy. Finally, we are still collecting data about the long-term safety and efficacy of the drugs that are currently available, which will help with decisions about their appropriateness for specific subsegments of the population.
One thing’s for sure, however: we are in a new, exciting era of pharmacological weight management that has the potential to positively impact the lives of a large part of our population. I’m proud to be a part of the research community forging this path and look forward to the next discovery we make in this space!
About the Author
Ryan Cady, Director of Endocrine/Metabolic/Pain Strategy at Headlands Research, brings over a decade of experience to the clinical research industry, with a career that began in 2013 at Clinvest Research in Springfield, MO. Stepping into leadership in 2016, Ryan successfully led the company until its integration with Headlands Research in May 2023. His academic background is solidly rooted in the sciences, holding an undergraduate degree in Neurobiology from the University of Wisconsin-Madison and a master’s degree in Biology from Missouri State University. Ryan has a passion for both Sponsor relationship-building and small biotech CRO interactions with a focus in Metabolic/Endocrine, Pain and Rheumatology.