What You’ll Learn: 

• Glucagon-like peptide-1 receptor agonists a.k.a GLP-1 receptor agonists are a type of medication used primarily for diabetes management but are now being used for weight loss

• GLP-1 receptor agonists mimic the action of the hormone glucagon-like peptide 1, which is responsible for stimulating insulin release after a meal. 

• While GLP-1 are effective for weight loss, research shows that weight loss primarily comes from muscle, connective tissue, and bone loss

• There are some safety concerns associated with the use of GLP-1 agonists

• It is crucial for these medications to be used in conjunction with lifestyle support programs that emphasize metabolic health 

If you've been diagnosed with type 2 diabetes mellitus, your doctor may have spoken to you about glucagon-like peptide-1 receptor agonists or GLP-1 subcutaneous injections, which is a type of medication that differs in its physiological action from the commonly prescribed Metformin. 

More recently, GLP-1 agonists like Ozempic and Wegovy have started trending in the health space due to their increased use for weight loss and the widespread adoption from celebrities and health influencers. 

In this article, we'll look at what GLP-1 agonists are, how they work, their use as a weight loss drug, what the research says about the pros and cons of these medications, and our recommendations for these medications. 

What Is GLP-1 Receptor Agonists?

GLP-1 agonists are a class of drugs that originated as diabetes care due to their ability to help with blood sugar regulation.

While the American Diabetes Association still prefers Metformin as the first-line defense in treating diabetic patients, GLP-1 agonists are often prescribed when there's a reaction to Metformin or when target hemoglobin A1C (hba1c) levels aren't reached within a few months of using Metformin.

Some examples of GLP-1 agonists drugs include:

• Semaglutide (brand names Ozempic, Wegovy, and Rybelsus)

• Exenatide (brand names Byetta and Bydureon)

• Dulaglutide (brand name Trulicity)

• Liraglutide (brand names Victoza and Saxenda)

Semaglutide and high-dose liraglutide are also FDA approved as pharmacologic treatments for obesity and could be useful in the case of comorbidities such as heart failure and kidney disease[1][2].

How Does GLP-1 Work?

GLP-1 agonists are taken by subcutaneous injection, and are typically given on a daily or weekly basis. 

GLP-1 agonists work by mimicking the activity of a hormone called glucagon-like peptide 1 (GLP-1). GLP-1 is an incretin hormone, meaning that it's secreted from hormone-producing cells located in your gut in response to the food you eat. The primary role of GLP-1, and other incretin hormones, is to help stabilize blood sugar by regulating the amount of insulin secreted after meals[3]. 

Under normal circumstances, GLP-1 will automatically be secreted in your gut a few minutes after you begin your meal. This secretion stimulates the release of insulin, which in turn helps to regulate the glucose concentrations in your blood. 

In the case of prediabetes and type 2 diabetes, the process of GLP-1 secretion becomes diminished or entirely blunted. Thus, insulin is not properly secreted, and blood sugar chaos ensues driving up insulin resistance and hba1c. However, the administration of pharmacological doses of GLP-1 can help to revive insulin secretion and therefore assist in blood sugar management[4]. 

Furthermore, GLP-1 agonists can assist with glycemic control, glucose levels, and hba1c by[5][6]:

• Slowing gastric emptying (and therefore slowing down the amount of glucose entering circulation).

• Inhibiting the release of the hormone glucagon (a hormone that instigates the release of glucose into the blood). 

• Decreasing apoptosis (cell death) of the beta cells in your pancreas, which are responsible for insulin release. 

Potential Benefits of GLP-1

In addition to its role in diabetes care (due to glycemic control by regulating insulin release and blood sugar control), GLP-1 agonists may support risk factors and comorbidities related to diabetes, including weight loss, cardiovascular health, neurological health, and protection against kidney disease. 

Weight Loss

GLP-1 agonists, specifically medications in the form of liraglutide and semaglutide, have been shown to promote weight loss and lower body mass index (bmi) in several studies[7][8][9][10].

According to the Mayo Clinic, studies found that adding semaglutide drugs to healthy lifestyle changes can promote weight loss averaging about 33.7 pounds (15.3 kilograms) versus 5.7 pounds (2.6 kilograms) compared to baseline in those who just made lifestyle changes alone[2]. Keep reading to learn more about why that weight loss might not be ideal though.

In addition to the impact of stable blood sugar on weight management, these medications also promote delayed gastric emptying and improved feelings of satiety. By slowing down your digestive process and helping curb hunger, GLP-1 agonists may reduce your appetite and result in fewer calories consumed each day. 

Interestingly, the effect of GLP-1 agonists on satiety and appetite seems to be independent of gastric emptying and food intake. Therefore, the hormone itself may be responsible for reduced appetite due to its influence on the brain's satiety signals[11]. 

Improved Blood Lipids

Dyslipidemia (dysregulated blood lipids) can lead to various health complications that can increase cardiovascular risks. Many people with diabetes have dyslipidemia in the form of elevated fasting and post-meal triglycerides, low HDL cholesterol, and high LDL cholesterol[12]. 

Studies show that GLP-1 agonists can lead to significant reduction in fasting, as well as postprandial triglycerides, by modulating cholesterol transport and production, as well as lipoprotein production in the liver[13]. 

Furthermore, clinical studies shows these drugs may lower LDL cholesterol in people with high cholesterol levels[14]. 

Cardiovascular Disease

In addition to the impact on blood lipids mentioned above, there are a handful of other potential ways in which GLP-1 agonists may reduce cardiovascular disease risk and improve cardiovascular outcomes.

In animal research, these drugs have been shown to enhance endothelial function, sodium excretion, and recovery from ischemia (loss of oxygen). 

Furthermore, preliminary data indicates that GLP-1 agonists may help to reduce inflammatory markers such as C-reactive protein, which is associated with an increased risk of heart disease[15]. 

Studies also show that GLP-1 may reduce infarction size in the heart (injury resulting from inadequate blood supply) and therefore reduce overall mortality from cardiac events and improving cardiovascular outcomes[16]. 

Neuroprotection 

In people with diabetes, there is an increased risk of stroke due to the complication from hyperglycemia. GLP-1 agonists have displayed neuroprotective roles in ischemic stroke, particularly due to their ability to reduce tissue damage. Furthermore, research shows that the use of GLP-1 agonists may improve neurological symptoms and prognosis in stroke patients[17]. 

Studies also show that GLP-1 agonists may act as a promising therapy for Alzheimer's disease. Specifically, research indicates that GLP-1 agonists may reduce the dementia rate in people with diabetes[18]. 

Kidney Disease

Due to shared risk factors and complications, approximately one in three adults with diabetes also have chronic kidney disease (CKD)[19]. 

GLP-1 agonists may reduce the risk for diabetic kidney disease (DKD) by reducing blood glucose, blood pressure, and body weight. Furthermore, studies also show that GLP-1 agonists may directly impact the kidneys by helping to reduce oxidative stress and inflammation related to DKD and inducing sodium excretion[20]. 

Is GLP-1 Safe?

GLP-1 is approved by the food and drug administration but as with most pharmaceutical medications, GLP-1 agonists do come with some warning and potential side effects.

Common GLP-1 Side Effects

The most common side effects of GLP-1 agonists are gastrointestinal, including constipation, nausea, vomiting, and diarrhea. For this reason, it is recommended that anyone with severe GI diseases like gastroparesis and inflammatory bowel disease avoid these medications due to the impact on digestion. 

Other side effects may include:

• Dizziness

• Fatigue

• Tachycardia (increased heart rate)

• Infections

• Headaches

• Dyspepsia/Abdominal pain

• Heartburn

• Rash/Itching

• Swelling of eyes, face, mouth, tongue, or throat

Muscle Loss

Outside of the adverse events most people are talking about, one of the less talked about but concerning side effects of GLP-1 agonists is muscle loss. As Dr. Peter Attia has pointed out, muscle loss to some degree is expected when you are losing weight but retaining as much as you can is really important not only for long term health but also sustaining weight loss. Dr. Attia notes that, “Almost without exception, every patient we’ve put on this drug has lost muscle mass. And they have lost it at a rate that alarms me.”

A study published in 2021 called the STEP 1 trial was the first trial looking at semaglutide for obesity treatment. In this study, 140 patients did a DEXA scan pre and post intervention. The data demonstrated that 39% of the total weight loss from semaglutide came from muscle[21]. Another paper published from the SUSTAIN 8 trial demonstrated similar findings of 40% of weight loss coming from lean mass despite both lower doses of the drug and less total weight loss [22].

Weight Regain

On the opposite end of the spectrum, a very commonly discussed side effect of GLP-1 agonists is the rebound weight gain that occurs following drug discontinuation. Check out any forum or social media thread on the topic and you will see thousands of anecdotes from individuals who stopped taking the drug and either gained most of the weight back or in some cases even gained more weight. 

A good look at this comes from a trial extension of the STEP 1 trial discussed above[23]. This paper reported that one year after semaglutide injections were stopped, participants regained two-thirds of the weight they lost. Even worse is that the cardiometabolic improvements displayed while on the drug also returned to baseline.

The reason for the weight regain after discontinuation isn’t just that the drug is no longer exerting its effects. As mentioned briefly above, the loss of lean body mass is also a contributing factor. Muscle is our most metabolically active tissue, responsible for burning a ton of calories, including glucose. When we lose muscle we lose our capacity to burn calories and this is a big reason why its so hard to sustain the weight lost while on the drug. 

In addition to the common side effects associated with body composition, there are also a wide range of additional potential side effects that are seemingly less common but still worth noting.

Pancreatitis

While very rare, pancreatitis has been reported with semaglutide injections which is why it is suggested that you seek immediate medical attention if you develop severe stomach pain, nausea, or jaundice.

Thus, pregnant women or anyone who has experienced or is experiencing pancreatitis should avoid these medications[24]. 

Gallbladder Disease

Around 2% of patients taking semaglutide in clinical trials reported gallbladder impairment or gallstones. This is another reason to seek medical attention if you are experiencing stomach pain, jaundice, or strange colored stools. 

Kidney Damage

While some research suggests that GLP-1 agonists can provide benefit to the kidneys, there have been reports of kidney damage. This most likely affects people who already have damaged kidneys and is caused by fluctuations in fluid volume from some of the GI side effects discussed earlier. 

Cancer Risk

Animal studies on GLP-1 agonists have raised concerns about the development of thyroid tumors. The reason we see this in rodents is because rodent thyroids have high expression of GLP-1 receptors which when stimulated could lead to the risk of medullary adenomas and carcinomas[25]. 

There seems to be some discrepancy on whether or not human thyroid cells express GLP-1 receptors to the same degree. Initial studies said yes but further investigation has led to this research being refuted with the conclusion being that GLP-1 receptors are only “marginally” expressed in human thyroid cells [26][27].

During the SUSTAIN trials, there were three cases of adverse events resulting in malignant thyroid tumors reported with two coming from the semaglutide treated group and one from the control group. Another study called the PIONEER program reported four cases of thyroid malignancies in the semaglutide treated group and one in the control[28].

Researchers in both of these studies were unable to identify if it was the GLP-1 agonists that were responsible for tumor development but these instances have led to warnings being placed on the labels of GLP-1 medications and recommendations against taking these drugs for individuals with a family or personal history of thyroid cancer.

What Does GLP-1 Cost?

GLP-1 agonists can vary in price range depending on which type you use and what your insurance provider will cover. In some cases, these drugs can be as low as $25 per month with good coverage, but if your insurance carrier doesn't cover the cost (or at least a portion), it can get pretty expensive. Here is a snapshot of the out-of-pocket costs for some of the most popular GLP-1 Agonists:

• Ozempic around $900 per month 

• Wegovy around $1400 per month

• Trulicity around $770 per month

• Saxenda around $1350per month

• Victoza around $1100 per month

Do We Recommend GLP-1 Agonists?

As a whole, we are not huge fans of the GLP-1 agonists like semaglutide being used for weight loss because the long-term safety of these medications is unclear. From digging through the research, it is apparent that there is reason to be at least concerned about what additional health complications could come from using GLP-1 agonists, especially if you are already at a higher risk of these complications.

Additionally, the cost of GLP-1 agonists, as highlighted above, is another reason we don’t recommend these drugs. While insurance is starting to cover these treatments, most patients are paying out of pocket. We think you could put that money to better use. Here is a video we did showing you how much healthy food you could buy instead! 

Besides the safety concerns, another big reason we are not fans of these drugs is because the results are fleeting. As highlighted in the STEP 1 trial extension, most people regain the weight after they stop taking the medication. This is why we are now hearing more and more stories of doctors telling their patients that they will have to stay on these medications forever. Again, because of the long-term safety uncertainty, this concerns us. 

It’s important to point out the counter argument to our stance on GLP-1 agonists. Many will say that with proper lifestyle support and behavior change education, the concerns with muscle loss and weight regain could be mitigated. This might be true.

We agree that if someone is going to make the decision to use one of these drugs for weight loss, they need to be offered guidance that helps them know what to eat while taking the medication, encouragement to exercise, and behavior change strategies to help them maintain their weight after they get off the medication. This is a no-brainer but it is currently not being recommended by standard healthcare.

The problem with this solution is that it is far from practical due to the challenges these medications present. Good luck eating enough protein to maintain muscle mass if you find you are sick to your stomach if you eat more than 1,000 calories per day. Good luck having the energy to exercise and lift weights when only eating 1,000 calories per day. And good luck not overeating calories when you stop taking the medication after you have been eating only 1,000 calories per day. Especially after losing metabolically active tissue (muscle) that burns more calories. Lifestyle support combined with these drugs is a simple answer but it's far from easy to practically implement.

With that being said, we know that many individuals are still going to choose to take this drug. For many, the allure is too strong not to. If that's the case, we think a very specific metabolic support program needs to be put in place.

Metabolic Support Program for GLP-1 Agonists

At BioCoach, we are deeply concerned with the number of people choosing to take medications like Wegovy and Ozempic and the lack of support they are receiving. Thus, we have been doing our own research on medication doses and support programs to help the individuals choosing to use these medications limit side effects, see better results, and maintain those results.

In our early phases, we are already seeing success with using lower doses of GLP-1 agonists, implementing dietary protocols focusing on muscle preservation and growth, and teaching behavior change to allow individuals to learn how to take control of their weight and overall health without the continued use of these medications. 

Thus far, we have found promising results with individuals seeing better results while on the medications, being able to get off of them sooner, and maintaining their weight loss for longer after. As we continue to conduct this research, we will provide updates of our findings and in the near future will be rolling out a program in our subscription that is built specifically for supporting those who have decided to use GLP-1 agonists like Ozempic and Wegovy.

Conclusion

GLP-1 agonists like Ozempic and Wegovy are now being used for weight loss and while they can produce incredible weight loss while on the medications, maintaining that weight loss has proven to be difficult. Additionally, there are concerns about the long-term safety of these medications. At BioCoach, we recommend opting for solutions that provide more sustainable results without side effects, such as lifestyle interventions focusing on diet and exercise instead of opting for these medications. If one does choose to use a GLP-1 agonist, we highly recommend pairing it with a metabolic support program to help you get off of the medications sooner and continue seeing improvements in health after. 

References 

1. Burcelin, R., and P. Gourdy. "Harnessing glucagon‐like peptide‐1 receptor agonists for the pharmacological treatment of overweight and obesity." Obesity Reviews 18.1 (2017): 86-98.

2. https://www.mayoclinic.org/diseases-conditions/type-2-diabetes/expert-answers/byetta/faq-20057955

3. Kim, Wook, and Josephine M. Egan. "The role of incretins in glucose homeostasis and diabetes treatment." Pharmacological reviews 60.4 (2008): 470-512.

4. Collins, Logan, and Ryan A. Costello. "Glucagon-like peptide-1 receptor agonists." StatPearls [Internet]. StatPearls Publishing, 2022.

5. Gallwitz, Baptist. "GLP-1 agonists and dipeptidyl-peptidase IV inhibitors." Diabetes-Perspectives in Drug Therapy (2011): 53-74.

6. Garber, Alan J. "Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability." Diabetes care 34.Supplement_2 (2011): S279-S284.

7. Bergmann, Natasha Chidekel, et al. "Semaglutide for the treatment of overweight and obesity: A review." Diabetes, Obesity and Metabolism 25.1 (2023): 18-35.

8. Lau, David CW, Rachel L. Batterham, and Carel W. le Roux. "Pharmacological profile of once-weekly injectable semaglutide for chronic weight management." Expert Review of Clinical Pharmacology 15.3 (2022): 251-268.

9. Mehta, Anurag, Steven P. Marso, and IJ28392927 Neeland. "Liraglutide for weight management: a critical review of the evidence." Obesity science & practice 3.1 (2017): 3-14.

10. Lundgren, Julie R., et al. "Healthy weight loss maintenance with exercise, liraglutide, or both combined." New England Journal of Medicine 384.18 (2021): 1719-1730.

11. Shah, Meera, and Adrian Vella. "Effects of GLP-1 on appetite and weight." Reviews in Endocrine and Metabolic Disorders 15 (2014): 181-187.

12. Wu, Liya, and Klaus G. Parhofer. "Diabetic dyslipidemia." Metabolism 63.12 (2014): 1469-1479.

13. J Patel, Vishal, et al. "Effect of GLP-1 based therapies on diabetic dyslipidemia." Current Diabetes Reviews 10.4 (2014): 238-250.

14. Hasegawa, Yukiko, et al. "Glucagon-like peptide-1 receptor agonists reduced the low-density lipoprotein cholesterol in Japanese patients with type 2 diabetes mellitus treated with statins." Journal of clinical lipidology 12.1 (2018): 62-69.

15. Okerson, Theodore, and Robert J. Chilton. "The cardiovascular effects of GLP‐1 receptor agonists." Cardiovascular therapeutics 30.3 (2012): e146-e155.

16. Zheng, Sean L., et al. "Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis." Jama 319.15 (2018): 1580-1591.

17. Yang, Xiaoyan, et al. "Neuroprotective Mechanisms of Glucagon-Like Peptide-1-Based Therapies in Ischemic Stroke: An Update Based on Preclinical Research." Frontiers in Neurology 13 (2022): 457.

18. Nørgaard, Caroline Holm, et al. "Treatment with glucagon‐like peptide‐1 receptor agonists and incidence of dementia: Data from pooled double‐blind randomized controlled trials and nationwide disease and prescription registers." Alzheimer's & Dementia: Translational Research & Clinical Interventions 8.1 (2022): e12268.

19. https://www.cdc.gov/diabetes/managing/diabetes-kidney-disease.html

20. Yu, Ji Hee, et al. "GLP-1 receptor agonists in diabetic kidney disease: current evidence and future directions." Kidney Research and Clinical Practice 41.2 (2022): 136.

21. Wilding, John PH, et al. "Once-weekly semaglutide in adults with overweight or obesity." n engl j med (2021).

22. McCrimmon, Rory J., et al. "Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial." Diabetologia 63 (2020): 473-485.

23. Wilding, John PH, et al. "Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension." Diabetes, Obesity and Metabolism 24.8 (2022): 1553-1564.

24. Collins, Logan, and Ryan A. Costello. "Glucagon-like peptide-1 receptor agonists." StatPearls [Internet]. StatPearls Publishing, 2022.

25. Gier B, Butler PC, Lai CK, Kirakossian D, DeNicola MM, Yeh MW. Glucagon like peptide-1 receptor expression in the human thyroid gland. J Clin Endocrinology Metab. 2012 Jan;97(1):121-31. doi: 10.1210/jc.2011-2407. Epub 2011 Oct 26. PMID: 22031513; PMCID: PMC3412261.

26. Körner M, Stöckli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med. 2007 May;48(5):736-43. doi: 10.2967/jnumed.106.038679. PMID: 17475961.

27. Waser B, Blank A, Karamitopoulou E, Perren A, Reubi JC. Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas. Mod Pathol. 2015 Mar;28(3):391-402. doi: 10.1038/modpathol.2014.113. Epub 2014 Sep 12. PMID: 25216224.

28. Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, Jeppesen OK, Christiansen E, Hertz CL, Haluzík M; PIONEER 1 Investigators. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. 2019 Sep;42(9):1724-1732. doi: 10.2337/dc19-0749. Epub 2019 Jun 11. PMID: 31186300.