Our Stance on GLP-1 Drugs

You would have to be completely cut off from society to not have heard about GLP-1 drugs.  Conversations, and advertisements, promoting these drugs are everywhere and their popularity continues to grow as they have been touted as the latest and greatest quick fix for weight management.  You can now pay out of pocket to have off label and compounded medications shipped directly to your home.  But, what are they, how do they actually work, and who are they intended for?  And, what is our stance on these drugs here at Untamed Nutrition Therapy?  

What are GLP-1 drugs?

To answer this question, let’s first get a better understanding of what GLP-1 is.  GLP-1 or glucagon-like peptide-1 is a natural-occurring peptide hormone that regulates blood sugar and appetite in humans and other animals.  GLP-1 is secreted by the intestinal tract during eating, which enhances insulin release, inhibits glucagon secretion, and delays gastric emptying to reduce the amount of food eaten through central appetite suppression.  Due to the mechanism of blood glucose control, researchers and chemists began working on the development of exogenous drugs that can mimic GLP-1, called GLP-1 receptor agonists (GLP-1R agonists) in hopes of enhancing current pharmaceuticals available for the management of diabetes.  GLP-1R agonists are a class of medications that were developed to help lower blood sugar.  Some have also been shown to cause weight loss.  There are many different types of GLP-1 drugs, including dulaglutides, liraglutides, exanatides, semaglutide tablets, and semaglutide injectables.  There is also a similar class of medications called GLP-1/GIP receptor agonists, with the one medication on the market called Mounjaro.  

How far back does GLP-1 research go? 

GLP-1 research dates back several decades. In 1987 in a study of seven human volunteers, Bloom et al. showed that an infusion of GLP-1 increased plasma insulin and reduced plasma glucose in patients that received a glucose load but not in patients who were fasted (1).  In 1992 and 1993, several reports confirmed a clinical response in diabetic patients, including a study by David Nathans, Mojsov, and Habener, who showed that a 30-min intravenous infusion of GLP-1 significantly increased insulin levels and lowered glucose levels in diabetic patients, the latter of whom showed a 3-fold increase in insulin (2). Similar findings were reported by groups led by Efendic et al. (3) and Nauck et al (4). These pivotal results established the potential of this new hormone as a therapy for diabetes. The formidable challenge was now to engineer a stable version of GLP-1 to be used as a medication.  At this point, Lotte Knudsen, a young scientist at Novo Nordisk, entered the scene.  Since its founding, Novo Nordisk has focused on making different forms of insulin, ultimately becoming the world's largest producer. In the early 1990s, Novo formed an innovation team to explore new approaches. Knudsen, who was working in the chemical division, was invited to join this new group and by 1995 she was leading it. One of their priorities was to develop GLP-1 into a drug for the treatment of diabetes.  

Who are GLP-1 medications intended for? 

The continued work by Knudsen and chemists at Novo led to the development of semaglutide, an ultrastable receptor agonist, which resulted in an extension of its half-life to 7 days and weekly subcutaneous administration led to an HBA1c reduction of 1.9%; therefore indicating its effectiveness in blood sugar control (1).  The original development of GLP-1R agonists was for the purposes of blood glucose control in type II diabetes; although there is also some research that suggests these medications may also be effective in type I diabetes as well.  Through the development of these medications, there was a surprise effect.  Diabetic patients treated with semaglutide (Ozempic) showed dose-dependent weight loss with an average of about 6 kg at a 2 mg dose, with 40% of patients losing more than 10% of their body weight (5). This was followed by clinical trials for the treatment of obesity using higher, escalating doses of the drug (Wegovy). Treated patients lost an average of 12.4% of their initial body weight compared to individuals who received placebo (5).  In diabetic patients, semaglutide significantly reduced the incidence of cardiovascular events by 26% vs. placebo (6). Weekly semaglutide also reduced the incidence of cardiovascular events in overweight patients with pre-existing cardiovascular disease but without diabetes and also in obese patients without diabetes (7).  While these medications were originally developed for the treatment of diabetes, there are also now three types of GLP-1 receptor agonists that are FDA approved for the use of weight loss, including semaglutide (Wegovy), liraglutide (Saxenda), and tirzepatide (Zepbound).  

How do they work?

GLP-1R agonists mimic the effects of the natural hormone GLP-1, discussed above.  GLP-1R agonists stimulate the pancreas to release more insulin when glucose is high after eating.  This suppresses glucagon secretion.  Glucagon is a hormone that raises blood sugar and is often elevated in individuals that have diabetes. GLP-1R agonists reduce the amount of glucagon released and inhibits glucose released from the liver, ultimately leading to lower blood sugar levels and better management of blood glucose for people with diabetes.  The reason weight loss occurs is because GLP-1R agonists also slow gastric emptying, or the rate at which food leaves the stomach, leading to a feeling of fullness and reduced appetite.  In addition, research suggests that in the central nervous system, GLP-1R agonists suppress appetite via the hypothalamus (8).  Other research also suggests that GLP-1R agonists were found to alter reward-related behaviors, leading to less cravings for energy-dense foods (8). 

What are the risks and side effects? 

Gastrointestinal problems, including nausea, vomiting, diarrhea and constipation are the most common side effects of GLP-1R agonists.  While GLP-1R agonists thus far appear to be safe, the nausea that it causes is clinically significant, leading many patients to discontinue treatment (1).  As mentioned previously, GLP-1R agonists also delay gastric emptying and there have been reports of severe gastroparesis symptoms, including stomach pain, nausea, constipation, and bloating.  Other patients experience severe diarrhea when using these medications. In addition, animal studies have suggested that there is a potentially harmful effect of these drugs on pancreatic tissue (9), including inflammation and pancreatitis. Less common, but more serious side effects have included bowel obstructions, gallstone attacks and bile duct blockages.  Another problem is that GLP-1R agonists need to be taken continuously to be effective and treatment results in loss of both fat and muscle mass, which appears to be equivalent to that seen after weight loss by dieting (1). However, muscle mass does not appear to recover when the drug is stopped and is of potential concern especially for older patients, where muscle mass is a protective component for longevity. 

Our stance at Untamed Nutrition Therapy 

From day one, the dietitians at Untamed have been supportive of the use of GLP-1 drugs for their intended purpose - blood sugar control.  These medications are truly a ground breaking invention for diabetes management and treatment.  On the other hand, we have concerns with these drugs as well.  Our biggest worry is the current lack of data or research assessing the safety of these drugs when used long term.  There has been a large increase in the number of people using these drugs, with a lack of research on their safety and efficacy, especially given that these drugs need to be used for a longer duration of time when used for weight loss.  Additionally, when used for weight loss purposes, these medications are prescribed in larger doses, with little research or information on how these larger doses are effecting the body long term.  Importantly, the surge in these drugs being prescribed by health professionals for weight loss continues to give the message that our bodies are wrong and need to be changed.  The use of these drugs for weight loss adds to the already trillion dollar weight loss industry and the toxicity of diet culture.  Our stance is that weight loss is not the answer to weight stigma.  A more informed healthcare system and understanding of the complexities of our bodies, in all different sizes, is what is needed.  We hold zero judgment towards anyone who decides to use these drugs; we understand that it is hard to live in this world in certain size bodies.  Our criticism lies in the system that created weight stigma in the first place and a society that continues to come up with more solutions for people to conform and shrink their bodies.  

References: 

1. Friedman, J. M. (2024). The discovery and development of GLP-1 based drugs that have revolutionized the treatment of obesity. Proceedings of the National Academy of Sciences, 121(39), e2415550121.

2. D. M. Nathan, E. Schreiber, H. Fogel, S. Mojsov, J. F. Habener, Insulinotropic action of glucagonlike peptide-I-(7–37) in diabetic and nondiabetic subjects. Diabetes Care 15, 270–276 (1992).

3. M. Gutniak, C. Orskov, J. J. Holst, B. Ahren, S. Efendic, Antidiabetogenic effect of glucagon-like peptide-1 (7–36)amide in normal subjects and patients with diabetes mellitus. N. Engl. J. Med. 326, 1316–1322 (1992).

4. M. A. Nauck et al., Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36, 741–744 (1993).

5. M. H. Tschop, J. M. Friedman, Seeking satiety: From signals to solutions. Sci. Transl. Med. 15, eadh4453 (2023).

6. S. P. Marso et al., Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl. J. Med. 375, 1834–1844 (2016).

7. M. Lincoff et al., Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl. J. Med. 389, 2221–2232 (2023).

8. Kooij, K. L., Koster, D. I., Eeltink, E., Luijendijk, M., Drost, L., Ducrocq, F., & Adan, R. A. (2024). GLP-1 receptor agonist semaglutide reduces appetite while increasing dopamine reward signaling. Neuroscience Applied, 3, 103925.

9. Filippatos, T. D., Panagiotopoulou, T. V., & Elisaf, M. S. (2015). Adverse effects of GLP-1 receptor agonists. The review of diabetic studies: RDS, 11(3), 202.