13. Stephan Guyenet, PhD: GLP-1, Semaglutide, and the Big Future of Weight Loss Therapies

In this interview, Mitch Belkin and Daniel Belkin speak with Stephan Guyenet, PhD, about Glucagon-like peptide-1 (GLP-1) and Semaglutide. They discuss GLP-1’s mechanisms of action, Anthony Sclafoni’s experiments on food reinforcement and nutrient receptors in the small intestines. Finally, they touch on some exciting new weight loss drugs that may replace semaglutide and potentially even bariatric surgery.

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Who is Stephan Guyenet?

Dr. Stephan Guyenet received his PhD in Neurobiology and Behavior from the University of Washington. Afterward, he completed a postdoctoral fellowship in the neuroscience of obesity. He is the author of the book The Hungry Brain. Dr. Guyenet is the founder & director of Red Pen Reviews, which publishes expert reviews of popular nutrition books with structured semi-quantitative evaluations. In addition, he is a senior researcher at GiveWell where he conducts cost effectiveness analyses on water quality interventions and malnutrition treatments in low income countries.

What is GLP-1 ?

Glucagon-like peptide-1 is a hormone produced by the intestines. It is an incretin, meaning it signals the pancreas to increase insulin secretion in a glucose-dependent manner. Initially, GLP-1 agonists were developed for the treatment of diabetes. In both animal and human models, it was discovered that GLP-1 agonists suppress food intake, which led to weight loss. This discovery spurred its use in obesity trials, including STEP 1.

What is Semaglutide?

Semaglutide is a GLP-1 agonist that was used in the STEP trials.

What is STEP 1?

Semaglutide Treatment in People (STEP) 1 is a randomized double blind, placebo controlled trial that enrolled 1961 non-diabetic adults with a BMI over 30 (or a BMI of > 27 if the participants had other weight-related co-morbidities like hypertension, dyslipidemia, obstructive sleep apnea, etc). Participants were randomly assigned in a 2:1 ratio to 68 weeks of treatment with once weekly subcutaneous Semaglutide or placebo, plus lifestyle intervention. In the trial, the Semaglutide group lost an average of 14.9% of their body weight as compared to the placebo group which lost an average of 2.4%. Additionally, participants who received Semaglutide had greater improvement with respect to cardiometabolic risk factors (such as a decrease in waist circumference, lower blood pressure, and reduced glycated hemoglobin levels and lipid levels).

What are the common side effects of Semaglutide?

Nausea and diarrhea are the most commonly reported adverse events with Semaglutide. During the trial, these side effects were typically transient and mild-to-moderate in severity. Of note, more participants in the Semaglutide group than in the placebo group discontinued treatment due to gastrointestinal events (4.5% vs. 0.8%).

What are the strengths and weaknesses of the STEP 1 Trial?

Strengths of this trial include the relatively large sample size and the high rates of adherence to the treatment regimen. Limitations include that it was predominantly white (~75%) and had a relatively large percentage of women (~75%) so it may not be generalizable to other populations. Additional limitations were that it was a relatively short trial (only 68 weeks) and it excluded people with type 2 diabetes, who represent a large percentage of individuals who are obese. Furthermore, the participants who were enrolled may represent a subgroup in the population with a greater commitment to weight-loss efforts than the general population.

Are there any health benefits to Semaglutide besides weight loss and reductions in diabetes?

Taking Semaglutide lowers cardiovascular risk on par with statins – a 25% reduction in cardiovascular risk.

What are other theoretical concerns for Semaglutide?

1. Pancreatic and Thyroid Cancer. Animal models and case reports from other GLP-1 agonists demonstrate higher incidences of these types of cancer. However, these have not been borne out in human trials on Semaglutide thus far in the tens of thousands of patients who have used the medication for weight loss. Of course, it is possible these trials were insufficiently powered or too short to demonstrate potential rare effects.

2. Depression, suicidal ideation. A different weight loss medication — Rimonabant, which is a cannabinoid receptor antagonist — was taken off the market due to increases in suicidal ideation and a trend toward increases in suicide. Although Semaglutide has not been associated with increases in depression and suicidal ideation, individuals taking the medication do report decreased pleasure-seeking behaviors (e.g., alcohol consumption, recreational drug use, sex). This is similar to the effects of other centrally-acting weight loss drugs because of their effects on the dopaminergic pathways. While this could be considered a positive effect of the drug, theoretically decreases in the dopaminergic pathway could cause depressive type symptoms.