Understanding GLP-1 Drugs: How They Work, Weight Loss, and the Emerging Pill

GLP-1 medications, once mainly for diabetes, have surged into weight loss fame through higher dosing and strong satiety effects. This episode explains how GLP-1 works in the body, why these drugs cause weight loss, and how the public conversation has evolved around injections versus pills. It also covers the emerging oral GLP-1 options, the latest entrants in the GLP-1 pipeline, safety concerns, costs, and the gray market around compounding pharmacies. The takeaway: GLP-1s offer real benefits but are not a universal or risk-free solution, and medical guidance remains essential.

GLP-1 Drugs: How They Work in the Body

GLP-1 is a hormone produced in the intestine after meals that stimulates insulin release, suppresses glucagon, slows gastric emptying, and promotes satiety. Bethany Brookshire explains that pharmaceutical GLP-1 receptor agonists mimic this natural signal but linger longer and at higher doses, producing stronger effects on blood sugar, weight, and appetite. The receptors are widespread, including in the brain, which helps explain appetite suppression beyond simple stomach fullness, but also contributes to potential side effects. "they linger a lot longer" - Bethany Brookshire.

From Diabetes Treatments to Weight Loss: Dosing and Public Attention

Initially these drugs were developed to improve glycemic control in type 2 diabetes by boosting insulin and slowing gastric emptying. Over time, higher doses were explored to induce weight loss, a shift that brought them into public view. Ozempic and Wegovi are the same drug, semaglutide, with Wegovi at a higher dose for weight loss. This transition coincided with rising use and scrutiny, including estimates that millions have tried GLP-1s in recent years. The pharmacology is remarkable: GLP-1 receptor activation improves blood sugar, helping people with and without diabetes, but the treatment is not a universal solution, and side effects or costs limit long-term use. "The effects of GLP-1 receptor agonists on blood sugar levels and on insulin are unparalleled." - Bethany Brookshire.

Oral GLP-1 Pills and the Pipeline

Making GLP-1 drugs as a pill has been challenging because enzymes and digestion degrade the peptide. Novo Nordisk finally released an oral semaglutide pill with meaningful weight loss, achieving about 16.6% mean weight loss over 64 weeks in trials. Other contenders include orfglapron and Ribelsis, both with strict dosing instructions to limit GI upset. Lilly’s retatrutide has shown striking weight loss in Phase 2 results, with reports of 24% weight loss or more in 48 weeks, while Caresema combines two drugs to push larger weight losses in adherent patients. "the pill has 16.6 mean weight loss percentage over 64 weeks." - Bethany Brookshire.

Ribelsis already exists as an oral GLP-1 for type 2 diabetes, but uptake remains to be proven for weight loss. The emergence of these pills changes patient experience, but they come with GI side effects and a practical burden, such as taking pills on a strict morning routine with limited water and a 30-minute fast. It is likely that oral therapies will be more widely used than injections, though injectables continue to dominate for now. "It is going to be a burden, but I also, if I were a betting person, I mean, a pill's going to be way more popular than having to take an injectable that needs to be kept in the fridge."

Potential Health Impacts Beyond Weight Loss

Beyond weight, GLP-1 drugs may affect cardiovascular risk, inflammation, and brain signaling, with potential implications for mood, addiction, and even fertility. Brookshire notes that GLP-1 activity in brain circuits linked to serotonin and dopamine could influence behaviors such as alcohol use and appetite in complex ways. There is evidence that GLP-1 drugs might help inflammatory conditions and metabolic dysfunction, and research has explored effects on polycystic ovarian syndrome and fertility in certain weight-related contexts. "There is evidence that it could help some of the effects of polycystic ovarian syndrome, which is a really nasty and far more common disorder than people realize." - Bethany Brookshire.

Risks, Side Effects, and the Gray Market

As with any potent weight loss strategy, rapid loss of weight raises safety concerns for the liver and gallbladder, and higher doses can increase psychiatric side effects such as depression or apathy. Side effects often center on the gut, including nausea, vomiting, heartburn, and sulfurous burps, especially with oral formulations. The presence of a brain region called the area postrema explains why vomiting is a common side effect, and overactivation of GLP-1 receptors can contribute to psychological symptoms. The rise of compounding pharmacies during shortages has created a gray market where people obtain formulations without standard dosing or oversight. Brookshire warns that self-medication, misdosing, and vulnerability in individuals with eating disorders can be dangerous. "This is an incredibly difficult disorder." - Bethany Brookshire.

Takeaways for Patients and Clinicians

GLP-1 therapies show real potential to improve glucose control and support weight management, but they are not a universal remedy. The ongoing development of oral formulations and combination drugs signals a shifting landscape, with important considerations around safety, access, and medical supervision. Patients should discuss risks, benefits, and long-term plans with healthcare providers, weighing cost, tolerance, and lifestyle factors when considering GLP-1 based treatments.