Obesity is a significant public health crisis. It is associated with multiple metabolic conditions including type 2 diabetes (T2DM), hypertension, cardiovascular disease (CVD), and fatty liver as well as sleep apnea, arthritis, and various cancers. In the US approximately 70% of adults struggle with excess weight. Newer drug therapies are changing not only how we treat obesity, but how the condition is understood and described—not simply a lack of willpower or poor habits, but rather a complex chronic disease rooted in genetics, biology, and hormonal factors.
I feel that one of the most exciting areas of endocrinology is the evolution of the GLP-1 (glucagon-like peptide-1) class. These medications mimic the action of a naturally-occurring gut hormone. They cause the pancreas to release insulin following meals, and cause suppression of glucacon (which reduces the liver’s tendency to over-produce glucose). Most importantly, they work on the brain to reduce appetite and the so-called “food noise.” These medications have been available for years for the treatment of T2DM, and more recently have also been indicated for the treatment of obesity. The first GLP-1 drug was exenatide (Byetta), which was actually derived from Gila monster venom. It was approved way back in 2005 for the treatment of T2DM. The next derivative was liraglutide (Victoza), made as a replica of human GLP-1. In 2004, liraglutide was also authorized for the treatment of obesity (Saxenda). The next generation of these drugs was the once-weekly injectible form, beginning with exenatide (Bydureon), semaglutide (Ozempic), and tirzepatide (Mounjaro). An oral form of semaglutide (Rebelsys) is also available in a once-daily pill form.
The field really “caught on fire” more recently when semaglutide was approved for the treatment of obesity (Wegovy). A major trial showed that people taking this lost 15% of body weight in a little more than a year. Recently tirzepatide was also approved for obesity (Zepbound). Slightly different, this is a combination hormone targeting both the GLP-1 and GIP receptors. A large clinical trial showed that people taking tirzepatide lost up to 21% of body weight.
And the benefits extend beyond glycemic control and weight loss. A large trial of people with obesity and heart disease showed that those taking semaglutide had a 20% lower risk of heart attack and stroke. Another important trial showed a significant delay in the progression of chronic kidney disease with semaglutide. Clinical studies are currently underway testing GLP-1 drugs in the treatment of Parkinson’s and Alzheimer’s disease related to reduction in brain inflammation. Also clinical trials are underway using these drugs to treat drug addition, as GLP-1 users have reported a decreased craving for alcohol and tobacco.
So is there a downside? There is always a concern for potential long-term adverse effects and complications. Warnings have been raised about uncommon but potentially severe GI complications including pancreatitis and gastroparesis. It remains unclear how long people should take these medications, and studies have demonstrated a significant weight re-gain following discontinuation. Obesity is a chronic disease and ideally should be managed as such. There have been reports of people using these drugs for “quick-fix” weight loss despite having normal body mass index, and these complaints tended to become more prevalent as a shortage of these drugs developed. These medications are also extremely expensive, and concerns regarding equitable access to newer medications continue to be raised.