The Evolution of GLP-1 Medications: A Clinical Perspective

My name is Dr. William Summers, and I have created an educational video series designed to help individuals better understand and manage weight gain. I hope you have had the opportunity to watch these videos. They are purely educational in nature—there is nothing being sold, and there is no request to enroll in any program. The purpose of this series is to simplify complex medical concepts and provide a clearer understanding of available options, so that individuals can make informed personal health decisions that support a higher quality of life.

As I discussed in the series, once a person becomes overweight, measurable biochemical and hormonal changes occur in the body that make additional weight gain more likely. In other words, after weight gain occurs, it becomes physiologically easier—and often unfairly easier—to gain even more. These changes can then further disrupt normal metabolic regulation, creating a cycle that promotes continued weight gain. This process reflects what we recognize clinically as the disease of obesity.

Understanding GLP-1

One important hormone involved in this process is Glucagon-Like Peptide-1 (GLP-1). GLP-1 is a peptide (a small protein-like molecule) produced in the intestines. After eating, GLP-1 is released and signals the brain to increase satiety (the feeling of fullness). It also acts in other parts of the body to help regulate blood sugar levels.

However, in individuals who are overweight, GLP-1 signaling becomes impaired. This dysfunction can reduce the feeling of satisfaction after meals, contributing to prolonged eating. In addition, impaired GLP-1 activity can reduce effective blood sugar regulation, which may increase fat storage. Over time, this pattern can contribute to worsening obesity and increase the risk of developing Type 2 diabetes.

Under normal physiology, GLP-1 travels from the intestines to the brain and binds to specific receptors—essentially "activating a button" that supports satiety. However, GLP-1 is rapidly broken down by an enzyme called DPP-4.

The First Generation

Years ago, researchers studying Type 2 diabetes observed that GLP-1 levels and activity were reduced. In response, medications known as DPP-4 inhibitors were developed to block the enzyme that degrades GLP-1, resulting in higher effective GLP-1 levels outside the brain. These medications improved glucose regulation; however, they did not consistently produce significant weight loss.

Subsequently, researchers asked a different question: rather than blocking the breakdown of GLP-1, what if we administered GLP-1 directly to increase its levels? This led to the development of GLP-1 receptor agonists. One of the first was exenatide (Byetta), introduced as a twice-daily injection for Type 2 diabetes. As expected, glucose control improved—but significant weight loss was also observed. At the time, many physicians began asking whether exenatide would be used primarily for weight management, as these results were unexpected.

The Liraglutide Era

Novo Nordisk later developed liraglutide, a once-daily GLP-1 receptor agonist, which was more convenient for patients than twice-daily injections. Having observed the significant weight loss associated with exenatide, Novo included obesity outcomes in liraglutide clinical trials—not solely Type 2 diabetes outcomes. As discussed in my videos, pharmaceutical companies are only permitted to market a medication for indications proven in FDA-reviewed clinical trials.

Liraglutide was released under two brand names: Victoza for Type 2 diabetes and Saxenda for obesity management. This marked a major shift in obesity treatment—Novo became the first pharmaceutical company to bring forward a medication specifically approved to treat the disease of obesity.

Because of FDA requirements, Novo was required to keep diabetes and obesity marketing entirely separate—even though Victoza and Saxenda contained the same active medication. Sales representatives for Victoza could only discuss diabetes treatment, while sales representatives for Saxenda could only discuss weight reduction. Although dosing structures were similar, higher doses were associated with greater weight loss without necessarily producing additional improvements in diabetes markers.

The Access Problem

Unfortunately, Saxenda launched at approximately $1,600 per month. Few patients were aware of it, insurance coverage was uncommon, and it became underutilized due to cost—even among those who recognized its benefits. By contrast, Victoza cost roughly $800 per month and was often covered by insurance. This created a predictable scenario: many clinicians began prescribing Victoza off-label for weight management due to accessibility and affordability.

It is important to clarify that off-label prescribing is legal and common in medicine; it refers simply to prescribing a medication for an indication other than the one specifically studied and approved by the FDA. In fact, up to 20% of prescriptions are written off-label. However, such prescribing must be evidence-based and done responsibly.

During this time, I became one of the top prescribers of Victoza in the United States, using it for weight management rather than Type 2 diabetes. This was during a period when off-label prescribing was not yet widespread. Although many questioned my approach, I was not doing anything illegal, nor did I ever misrepresent my intent. When documentation was requested by third-party payers—especially as insurers began restricting off-label use for cost containment—I remained fully transparent. Over time, it became increasingly difficult to use this approach, as pre-authorizations became universal and often required proof of Type 2 diabetes.

Nevertheless, it was this widespread off-label use of Victoza that brought broad public and clinical attention to GLP-1 therapy as a highly effective tool for weight management. That success helped drive further research into the overlapping metabolic disorders of obesity and Type 2 diabetes, leading to the development of newer medications with greater efficacy.

The Competition

During this period, Novo Nordisk benefited substantially from Victoza sales, but the company's obesity-related revenue remained limited due to the cost and limited coverage of Saxenda. Eventually, Novo faced major competition when another pharmaceutical company developed dulaglutide (Trulicity), a once-weekly GLP-1 injection. Weekly dosing dramatically improved convenience, adherence, and A1C outcomes. Trulicity quickly became the leading GLP-1 medication in the United States, largely because it was preferred by both patients and providers. Although Trulicity was not approved for weight loss, that limitation had little impact on revenue, since diabetes—rather than obesity—was the market driver.

The Semaglutide Breakthrough

Novo Nordisk needed to compete, and therefore developed semaglutide, another once-weekly GLP-1 injection. I have no affiliation with Novo Nordisk. Like many clinicians, I recognize the positive impact of their work, but I also have strong concerns about aspects of their practices. My priority is always whether a therapy benefits my patients.

Semaglutide demonstrated significant weight loss in clinical trials—unlike Trulicity—while providing comparable improvements in diabetes markers. One key scientific insight was that molecular size matters. The body naturally produces a very small GLP-1 peptide, and only smaller molecules can cross the protective blood-brain barrier. This is crucial, because satiety signaling occurs in the brain.

DPP-4 inhibitors raised GLP-1 levels outside the brain, which improved glucose control but had limited effect on satiety and weight. Some GLP-1 therapies were larger molecules and did not effectively pass into the brain, limiting their impact on weight reduction. Semaglutide's smaller molecular structure allowed more effective brain signaling while maintaining strong glucose-lowering benefits outside the brain.

Semaglutide was launched as Ozempic for Type 2 diabetes and Wegovy for obesity. However, because diabetes outcomes are tied to reimbursement structures and quality metrics (such as lowering A1C below 7), clinicians were not incentivized to change therapies solely for improved weight outcomes. Weight loss is not currently a key performance metric in many healthcare reimbursement models, despite the enormous long-term costs of obesity-related disease.

The Oral Revolution

In what I consider one of the most remarkable breakthroughs in modern pharmacology, Novo Nordisk also developed oral semaglutide—Rybelsus—which became the first peptide medication successfully delivered in pill form. Historically, peptides required injection because they are destroyed by stomach acid. Developing a way to protect semaglutide through digestion and deliver it through intestinal absorption was a scientific achievement of extraordinary significance.

Novo launched an aggressive program that temporarily made Rybelsus affordable (often $10–$25 per month), and because it was marketed for Type 2 diabetes, pre-authorizations were often not required. Although Novo could not and did not promote off-label use, the accessibility of Rybelsus made it possible for many clinicians to prescribe it off-label for obesity management. During this period, I became the number one prescriber in the country using Rybelsus off-label for obesity, because it was safe, effective, and, during that time, financially feasible for patients.

Oral semaglutide—previously marketed as Rybelsus for Type 2 diabetes—is now available under a new name as oral Wegovy. Although Novo is currently promoting improved self-pay pricing, the medication remains costly, and promotional pricing is typically temporary.

Looking Forward

I have much more to share about these medications and the broader issues surrounding obesity treatment. Even more importantly, we must improve public understanding of obesity as a medical disease and advocate for the same level of coverage and seriousness that exists for other chronic conditions.

At the same time, it is essential to emphasize that every individual is inherently valuable and deserving of respect, dignity, and equality. No one needs to lose weight in order to be worthy of respect or to be considered a better person. Our focus must be education, transparency, fairness, and ensuring that patients have access to informed choices—free from stigma, bias, and misinformation—so they can pursue personal health decisions that support their well-being and quality of life.