GLP-1s and Muscle Loss: Understanding the Potential Impact

Glucagon-like peptide 1 agonist (GLP-1) medications have become an incredibly popular treatment for diabetes and also weight loss for non-diabetics. Recent estimates conclude that 12% of US adults have used GLP-1 agonists. 

As a quick recap on how they work, glucagon-like peptides are naturally produced in the small intestine. They are released in response to increases in blood glucose that occur when we eat carbohydrates to stimulate the release of the hormone insulin. Insulin then lowers blood glucose levels by increasing glucose transport into cells, most prominently, skeletal muscle cells. GLP-1 agonists stay active longer than natural GLP and thus have stronger effects, namely increasing insulin, lowering blood glucose, reducing gastric emptying, and reducing appetite more than the natural hormone. Consequently, GLP-1 agonists are remarkably effective in helping patients achieve weight loss. As skeletal muscle is a primary target of GLP-1 agonists' downstream effects, medical providers generally recommend that patients exercise while on the prescription.

The Muscle Concern: Why GLP-1s Might Affect Muscle Mass

Weight loss following GLP-1 agonist is significant. Any time one loses large amounts of weight, the composition of that weight loss will consist of a mix of fat mass (the intended target of weight loss) and fat-free mass (muscle and connective tissue, which we would rather preserve). An ideal weight loss for health would consist of losing a high proportion of fat mass, which would translate into a greater loss in percent body fat. With the major weight loss that can occur with GLP-1 use, the possibility of losing large amounts of muscle mass is a pressing concern.

There is good evidence that combining exercise with GLP-1 agonists can do this. Over a one-year treatment period, the combination of exercise + GLP-1 agonists produced significantly greater losses in percent body fat (-3.9% vs. -1.9%) than the medication alone. So, exercise appears to be quite effective in reducing the loss of muscle mass while using GLP-1 agonists.

Exercise boosts the effectiveness of GLP-1 agonists.

In addition to its potential body composition-enhancing benefits, exercise can also help GLP-1 agonist medications work more effectively in your body. GLP-1 resistance is caused by a lack of effective receptors for the hormone to bind to the pancreas. Greater GLP-1 resistance would tend to negate the medication's effects. The major predictors of GLP-1 resistance are visceral body fat and gut microbiota dysbiosis. 

Visceral body fat is the fat that exists within and around internal organs. Exercise promotes the release of chemical messengers from contracting muscles that appear to target visceral fat and reduce inflammation specifically. 

Exercise also promotes greater diversity within the gut microbiome, which should further reduce GLP-1 resistance. For more information on how exercise impacts the gut microbiome, check out my previous work here.

Specific exercise recommendations

So, we can confidently state that exercise is a powerful adjutant for GLP-1 agonists. What is the best way to exercise? In truth – the best training plan is whatever way you enjoy and can stick with. But since you’ve made it this far, let me make some suggestions. A combination of aerobic and resistance training is key for overall health. Aerobic exercise has the best evidence supporting a positive effect on gut microbiota health. Strength training is key to maximizing muscle mass and improving body composition. Strength training should provide a powerful stimulus to reduce visceral body fat and retain/build muscle mass in the face of weight loss.

My ideal exercise plan consists of the following:

Aerobic exercise 4-5 days per week. I would recommend at least 2 of the days be “harder” intensity. This would include working at a pace that is at least 75% of your maximum heart rate.

• Any mode of aerobic exercise is good (running, walking, biking, rowing, elliptical, etc.)
• Try to shoot for at least 20 minutes of continuous exercise per workout

Strength training 2-3 days per week. To maximize muscle gain/fat loss:

• Focus on multi-joint/large muscle mass exercises such as squats, leg presses, bench presses, and rows – these are the most effective means of increasing/preserving muscle mass
• Perform 2-3 sets of 8-12 repetitions per exercise
• In the beginning, keep intensity at a subjective feeling of about 6-7/10 effort, but look to add weight/repetitions regularly. After strength training for ~6 months to a year, you will benefit from making one of your training days a light day, where you lift ~20% less weight for the same amount of repetitions as you do on your heavy days. 

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