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GLP-1 Receptor Agonists for Obesity
Future Treatment of Obesity: GLP-1 Receptor Agonists

Released: February 09, 2023

Expiration: February 08, 2024

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Key Takeaways
  • The classic approach to addressing obesity—caloric restriction and exercise—may be thwarted by gut hormones that protect the body from starvation.
  • Glucagon-like peptide-1 (GLP-1) receptor agonists are appetite suppressants designed to create a situation where the body receives satiety signals with less food.
  • With newer incretin-based therapies, weight loss results can be achieved approaching those achieved with bariatric surgery.

The National Institutes of Health has recognized obesity as a chronic disease since the 1990s. Prevalence of obesity in American adults was 42% in 2017-2020; this was an increase of >10% over that seen in 1999-2000. The estimated annual medical cost of obesity in the United States was nearly $173 billion in 2019 dollars. Medical costs for adults who had obesity were $1,861 higher than medical costs for people with healthy weight.

The classic approach to weight loss is caloric restriction and exercise. The goal is to change one’s body weight set point. However, what we haven’t understood until recently is that it is very difficult to reset the body weight set point because that set point is dependent on the secretion of gut hormones whose goal is to protect body fat in the face of starvation. Therefore, food restriction to accomplish weight loss may end up being a temporary fix because gut hormone secretion creates a situation in which it’s very difficult not to regain the weight. 

Glucagon-like peptide-1 (GLP-1) receptor agonists have allowed us to be able to treat obesity with a more physiologic-based approach. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are hormones involved in blood sugar control. After a person has eaten, these hormones are secreted by cells of the intestines and, in turn, cause the secretion of insulin. This response can become blunted in diabetes and GLP-1 receptor agonists help to restore it.

GLP-1 receptor agonists can also act as appetite suppressants, and they play on the appetite and satiety patterns that physiologically occur after one eats a meal. GLP-1 receptor agonists are designed, however, to create a situation where the body receives satiety signals with less food. 

Weight Loss With GLP-1 Receptor Agonists

Our understanding of the importance of gut hormones on weight loss was gained through experience with bariatric surgery. We have seen with bariatric surgery that GLP-1 levels certainly increase. Ghrelin levels, on the other hand, decrease and there are also alterations in in GIP, leptin, insulin, and amylin. Bariatric surgery typically produces a 25% to 35% weight loss. This is much higher than even the best of the incretin-based medications now. The best that we have seen with incretin-based therapies is a 22% weight loss, which has been achieved with tirzepatide, a new GLP-1/GIP receptor agonist approved for the treatment of type 2 diabetes (T2D) and which has been submitted for approval for the treatment of obesity to the FDA. With semaglutide, we might expect a 16% to 17% weight loss after 68 weeks on a 2.4-mg once-weekly injection. With liraglutide 3.5 mg for 56 weeks, only a 9.2% loss was achieved, similar to other pharmacologic therapies for weight loss. The reason why we think that the sleeve gastrectomy and the Roux-en-Y gastric bypass give us better weight loss is because these procedures may affect more than one gut hormone.

I think of GLP-1 receptor agonists as a medical gastric bypass, that is, achieving the degree of weight loss from medications that we can see with the Roux-en-Y gastric bypass. In addition, there is real evidence that these drugs reduce cardiovascular mortality in patients with T2D. We are looking expectantly for the data on cardiovascular risk reduction in the ongoing trial of semaglutide in patients with obesity alone without T2D.

Recommendations for Primary Care Providers Who Want to Treat Obesity

Primary care providers who wish to use GLP-1 receptor agonists in their patients without T2D for the purposes of weight loss can benefit from having a dietitian on staff to give nutrition and exercise advice to the patients. Then, if primary care providers plan to prescribe one of the GLP-1 receptor agonist medications for weight loss (ie, in a patient without T2D), they should be aware that insurance authorizations must be obtained to do so, and it may be helpful to have someone in their office assist with the required paperwork.

Each agent has specific dosing and titration recommendations from the manufacturer. These should be followed to minimize adverse effects. They also must be aware that patients must be taught how to self-inject and about common adverse events and their management. Ideally, these patients should also be seen more frequently at first (perhaps every 1-2 months) to be sure they are losing weight and not having untoward adverse effects.

By improving processes for treating obesity, we can ensure that more patients get the treatment that they need. Ideally, we should consider treating obesity first before treating other chronic issues stemming from obesity, since we know that the downstream effects of weight loss are beneficial in many other metabolic disease states.

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