Unanswered Questions in the Research of Weight Loss Medications

The buzz around GLP-1 agonists, such as Ozempic and Wegovy, has increased exponentially in the last couple of years. GLP-1 medications are not new, but they are relatively new to being used as treatment for obesity. However, there are a few concerns when looking at these medications. They aren't treating the root cause of the obesity epidemic and the longest studies completed only have people taking these medications for 3-4 years, what happens when they come off of the medications? This also leads to the problem of changes to body composition and whether people should be on these medications for life? The side effects to the GI tract also beg to question, can people safely and comfortably stay on these medications for 20-30 years? There are so many unknowns in this discussion and yet so many people seem comfortable accepting that risk, it makes us question whether they are getting the full story or not.

Peter Attia discusses the moral dilemmas in the boom of weight loss drugs with David Allison, a leading expert in obesity and nutrition research, on his podcast, The Drive. The risk versus benefit analysis was completed for those taking weight loss medications for medical necessity to reduce high excess of weight and the chronic disease risk factors that come with severe obesity. The risk versus benefit analysis was not done for those looking to take the medications for aesthetics that don't have as much excess weight or medical reason to lose weight. These medications have many GI side effects to include gastroparesis, diarrhea, constipation, nausea, and vomiting. This can lead to major discomfort and potentially dangerous consequences.

Another factor into the risk versus benefit analysis is weight regain. If someone does not have as much weight to lose when they start and they regain 6% of their weight back after stopping, was it really worth the side effects? The studies to look at weight and body composition for both long term users and after coming off the medications are quite limited. However, a recent study did look at the weight regain in three different groups; placebo, a combination of GLP and exercise or GLP alone. The study found that weight regain after 1 year was 6kg (13.2 lb) more for folks just taking the GLP medication rather than those in the GLP plus exercise group. The study helped to show that GLP medications alone are not enough to help improve health and weight loss. There needs to be an interdisciplinary team working together to make the most impact.

Body composition is another big factor to consider in GLP-1 medications. Again, the studies looking at body composition before, during, and after weight loss medications is limited as this was not a requirement the FDAs guidelines for assessing weight management therapies. However, a study in 2021 did complete DEXA scans for body composition analysis and found that lean mass accounted for 39% of total weight loss and additional study found an average of 40% lean mass loss in people taking a lower dose of GLP-1 agonists. For reference, in normal weight loss it is estimated that lean body mass usually accounts for about 25% of total weight loss. The benefits of overall weight loss may outweigh the risk of losing lean body mass in individuals that have obesity, but the same can not confidently be said about those that are normal weight or just slightly overweight. The loss of lean body mass can lead to increased risk of osteoporosis, falls due to loss of muscle strength for balance and coordination, slower metabolism, and more.

Overall there are many open questions about the use of weight loss medications and if their benefits outweigh the risks, especially in folks that are motivated by different factors. There is much more research needed on these medications as well as better interdisciplinary care teams to help reap the most benefit and minimize the risks.