In this randomized clinical trial that included 611 adults with overweight or obesity, 68 weeks’ treatment with 2.4 mg once-weekly subcutaneous semaglutide vs placebo, combined with intensive behavioral therapy (and a low-calorie diet for the initial 8 weeks), resulted in reductions in body weight of 16.0% vs 5.7%.(1)
Drugs whose names end in “tide” are peptides. Peptides are little proteins but they are still big molecules when compared to most drugs. That means they have to be given by injection since they would be digested into their amino acid building blocks if you swallowed them. Semaglutide is classified as a glucagon-like peptide-1 (GLP-1). That makes it sound like it acts like glucagon but it doesn’t. Glucagon increases blood glucose in opposition to insulin. Rather GLP-1s are called that because they are made from a precursor they share with glucagon and instead decreases blood glucose by stimulating insulin production and secretion. Further confusing is that since insulin and other drugs that increase insulin secretion and sensitivity used for type 2 diabetes mostly increase weight while GLP-1s like semaglutide cause weight loss. That weight loss turns out to be pretty big, getting close to the weight loss achievable by gastric bypass surgery. The patients in this study did not have diabetes and were being treated for primary obesity instead with a higher dose than used for diabetes. Weight loss itself also goes a long way towards improvement in type 2 diabetes.
The stats from this trial are: comparing the patients who got semaglutide vs the placebo, wt loss greater than 5% happened in 86.6% vs. 47.6%, >10% was 75.3% vs 27%, >15% was 55.8% vs 13.2% and the biggy was that greater than 20% wt losers were 35.7% vs 3.7%. More than a third of the semaglutide customers got more than 20% weight loss. The other take away is the endlessly repeated fact that “intensive behavioral therapy” and “low-calorie diets” are pretty worthless on average but some people do manage to lose an important amount. Plus the durability of any weight loss is going to be much worse in the dieters. That weight lost durabilty in the semaglutide group, if they keep getting treatment, is not known yet.
How does it work? Well the most obvious explanation to me is that it reliably causes nausea and vomiting by slowing the emptying of your stomach and its actions in the brain. They tell me that that is not how it works but I don’t understand how you can be so sure. The proportion of participants experiencing nausea with semaglutide peaked at approximately 25% at week 20 and declined thereafter, remaining at approximately 15% for the duration of the study. At any given time during the study, the proportion of participants who experienced vomiting was less than 5% in both treatment groups. More participants discontinued treatment due to adverse events in the semaglutide group (5.9%) compared with placebo (2.9%), mainly because of gastrointestinal events. Another 20-week clinical study of participants with obesity found that treatment with once-weekly semaglutide, 2.4 mg, compared with placebo reduced self-reported hunger and food cravings and decreased food intake during an all you can eat lunch by 35%. So maybe it’s just a little nausea. Not enough to mention to the investigators or to make it not worthwhile to watch the weight go away. What would be a good placebo that just makes you a little bit nauseated to try and disprove my contention?
1. Wadden TA et al. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity The STEP 3 Randomized Clinical Trial. JAMA. Published online February 24, 2021. doi:10.1001/jama.2021.1831
John DiTraglia M.D. is a Pediatrician in Portsmouth. He can be reached by e-mail- firstname.lastname@example.org or phone-354-6605.