Ozempic and other GLP-1 Agonists: Are they safe?
Madison Martin, CNS
As with any health information and opinions based on evidence; the answer to the question of whether GLP-1 agonists are safe is extremely nuanced. The short answer is that it has its place and is incredibly helpful, even life-extending for some groups of people. For the majority of people, including those using it solely for weight loss absent applicable medical conditions, the risks most likely outweigh the benefits. Risks include things like GI distress, fatigue, headache, pancreatitis, gallbladder disease, acute kidney injury, suicidal ideation, ileus, and death.1,2,3 Many people regain weight that had been lost if they stop taking these medications and most people are unable to stay on these medications long-term.4 Because insurance companies do not cover weight loss drugs, out-of-pocket cost is also a consideration. Using this drug solely for weight loss is also perpetuating the high anti-fat bias that exists in medicine and society at large. It continues the pathologizing of people’s bodies. The shocking standard we see in medicine is weight loss at any cost, even health. The notion that thinness is synonymous with health and that a smaller version of you is a better version of you is false and dangerous albeit widely accepted. Being a weight-neutral practitioner, I certainly have my biases against weight loss medications (they have a fairly scary track record),5 but I will present the facts and evidence here so that the patient may make their own decision.
Before diving into the research, here is some information that might be helpful to know about the compounds that function as GLP-1 agonists. Ozempic is probably the most well known in this class of drugs and is used to treat type II diabetes mellitus (T2DM). Semaglutide is sold by Novo Nordisk under the names Wegovy and Rybelsus at a higher dose for weight loss. Novo Nordisk also sells Liraglutide under the name Victoza for T2DM. Tirzepatideis the generic name for the similar drug developed by Eli Lilly and is sold under the name Mounjaro for T2DM and Zepbound for weight loss. There are other versions of this drug with varying names so this is an incomplete list but includes the most common versions.
Mechanism of Action: These drugs mimic the effects of glucagon-like peptide-1 (GLP-1), a hormone responsible for regulating the production of insulin and glucagon.6 Together, these hormones control blood sugar levels. The central nervous system and gastrointestinal tract also have GLP-1 receptors and when acted upon, gastric emptying is slowed, having the effect of delayed glucose absorption and a reduced appetite.6 Essentially, you will feel fuller faster and longer and blood sugar will be better managed. All of this makes them an excellent intervention for those with type II diabetes mellitus (T2DM), for which they were developed. Those with poorly controlled blood glucose, poorly controlled blood pressure, and/or those at a higher risk of major cardiovascular events such as heart attack or stroke are good candidates for this intervention as this drug has shown to help with all of these conditions in a very substantial way.7
While these GLP-1 agonists were being studied for efficacy in treating diabetes, researchers noticed that many participants were seeing the side effect of weight loss. Since weight loss medications have traditionally been extremely lucrative, these pharmaceutical companies jumped to start trials to quickly get these approved for weight loss. The studies have been pretty consistent; most participants lose some amount of weight (5% of body weight), about half lose 10-15% of body weight, and about a third of participants lose more than 20% of body weight which is very rare with weight loss drugs.8 The issue is that while being used for T2DM, the goal is to use the smallest dose possible to get the intended effect of blood sugar management and improved lipid markers while minimizing negative side effects. When being used in a weight-loss application, the dose is much higher to maximize the side effect of weight loss. With this also comes the higher instance of negative side effects because side-effects are dose-dependent. We also do not have any data of long term use (more than two years) 8, 9 at this higher dose which is blatantly negligent and is a great example of a company putting profits above public safety.
Approval by the FDA does not necessarily mean these drugs are safe. The weight-loss industry has spent decades creating an enormous body of research that they publish in journals that they own showing correlations between high weight and poor health outcomes. The issue with that is that they are incentivized to show that being a higher weight is dangerous so they can sell a solution. Their studies fail to control for things like previous weight cycling, food insecurity, genetics, allostatic load, trauma, stigma, discrimination, and other social determinants of health.9 According to the world health organization, social determinants of health account for between 30-55% of health outcomes.10 The FDA uses this body of research that the industry has created to inform its approval decisions and since the overall theme is fat=bad, thin=good, even if the reality is far more complicated and nuanced than this, approval was granted, even with no long term data on safety and efficacy at this higher dose.8,9 A glaring problem here is that we know anti-fat bias in medicine and society leads to worse health outcomes.11 A lot of the health conditions that people in larger bodies deal with can be attributed to the stress that comes with being treated poorly almost all of the time yet they are told it’s solely due to their weight and that it’s only the individual’s fault.
The reported side effects of these drugs experienced commonly include gastrointestinal symptoms like nausea, diarrhea, vomiting, constipation, abdominal pain, and burping, as well as other more mild side effects like headache, fatigue, and dizziness.1,12 This drug is also known to cause fetal harm so those who are pregnant may not take the drug and those who are planning to become pregnant must stop months before planning to do so as this drug has a long half-life.1,9 Less common but more dangerous side effects seen are acute pancreatitis,13 acute gallbladder disease, acute kidney injury, increase in suicidal ideation/behaviors, ileus, and death.1,2,3,12,14 This drug also has a boxed warning for thyroid C-cell tumors7 which is “the highest safety-related warning that medications can have assigned by the Food and Drug Administration''15
A side effect often not discussed is the malnutrition that comes from eating far less food which is the general goal of taking this drug. Eating is how we fuel our bodies. Enough food is required to make energy, hormones, immune cells, and just to keep our bodies running. The nutrients that we need like vitamins, minerals, protein, fats, and carbohydrates come from eating enough food. I often tell my clients that feeding yourself properly is the ultimate act of self care. Anecdotal side effects include patients claiming to not enjoy food anymore and being disconnected from their bodies. If you can no longer hear the cues from your body asking for food, malnutrition is most likely not far off. If the side effects become too much to handle and the drug is no longer administered, many people regain the weight.4 There is no “jumpstarting weight loss.” This is a term created by diet culture and is not based in science. The very well known and understood biological compensatory mechanism after weight loss is weight gain. It is how your body protects itself as our biggest problem as a species has been famine. After weight loss, basal metabolic rate drops, hunger hormones increase, and you become more efficient at storing adipose tissue which gives you a higher chance of surviving famine. Weight cycling (also called yo-yo dieting; repeatedly losing and gaining weight) in and of itself is known to be an independent risk factor for mortality and adverse metabolic conditions.16 Essentially, losing and regaining weight is worse for your health than just existing in a larger body. We have known this for some time yet the weight loss industry continues to churn out the next “miracle” drug, plan, diet, etc which promises to solve fatness.
Since this drug was approved for weight loss and doctors are highly financially incentivized to sell this drug, those seeking weight loss without blood sugar issues caused a huge spike in use which made it extremely difficult to find. Approval of Wegovy happened in June 2021, and shortly after both Wegovy and Ozempic went into shortage as doctors were prescribing Ozempic off-label for weight loss.8 As of now, there is still a shortage of semaglutide.17 This shortage is presumably due to those who have the disposable income to pay these exorbitant out of pocket prices ($1,349.02 for a 28-day supply) since insurance companies no longer cover weight loss drugs. The effect is that those who need this drug for more medical reasons no longer have access. This elicits a larger conversation about healthcare as a business under capitalism but right now there are real world consequences for those with lesser means who need this drug to manage serious conditions.
When drugs such as these go into shortage, the FDA allows compounding pharmacies to mix up their own version of the drug without approval, testing, or screening.8,9,18 The problem is that Novo Nordisk has patents on the semaglutide molecule (only they can produce it until 2032) so when it’s in shortage, you are getting something different. These pharmacies, which are not regulated by any agency or department, often provide things like a watered down dose, “semaglutide sodium,” or something else entirely.8 Semaglutide sodium is not cleared for use in humans because it has not been studied and does not have the same mechanism of action.18 The problem has gotten so bad that the FDA has sent out warnings about using these pharmacies but unfortunately that’s the only authority they have; there is no enforcement mechanism. If you see an advertisement for something like heavily discounted Ozempic or Wegovy, it is most likely a compounding pharmacy startup. These pharmacies are, again, part of a larger conversation but they are playing a fairly dangerous role in the GLP-1 saga.
Above all, individual agency is important and people can make their own decisions. If you are someone who wants to use this drug for weight loss and has an extra $18,000 a year to do so, you have the right to make that decision for yourself. In this specific circumstance, it can be difficult to make a truly informed decision as many doctors were told by the pharmaceutical reps that there were no side effects or that they were not really a big deal.9 Novo Nordisk has been fined millions of dollars for influence peddling; downplaying the dangers and side effects of these drugs and providing financial incentive to doctors to push them.19 The GLP-1 agonists have been incredibly effective at treating dangerous metabolic conditions and are legitimately a net positive and life-changing for some people. For others without these conditions, scrutiny should be placed on the risk analysis and factors such as cost, availability, sustainability, long-term effects, and exit costs should be evaluated. When considering using a drug that changes the biochemical makeup of your body, it is prudent to do so with all the information possible and the ability to truly weigh the risks versus benefits.
Citations:
Keeping an eye on common side effects. (2024, April). Novo Nordisk. Retrieved from https://www.wegovy.com/dashboard/my-library/week-02-tips-for-managing-common-side-effects.html#:~:text=Common%20side%20effects%20of%20Wegovy,runny%20nose%20or%20sore%20throat.
Lu J, Liu H, Zhou Q, Wang MW, Li Z. A potentially serious adverse effect of GLP-1 receptor agonists. Acta Pharm Sin B. 2023 May;13(5):2291-2293. doi: 10.1016/j.apsb.2023.02.020. Epub 2023 Mar 2. PMID: 37250165; PMCID: PMC10213739.
Hyer, J. Deaths stalk GLP-1 agonist. Nat Biotechnol 26, 1204 (2008). https://doi.org/10.1038/nbt1108-1204b
Prillaman M. (2024, April 19). What Happens When You Quit Ozempic or Wegovy? Scientific American. Retrieved from https://www.scientificamerican.com/article/you-quit-ozempic-or-wegovy-what-happens-next/#:~:text=Research%20has%20shown%20what%20happens,to%20a%20taut%20rubber%20band.
O’Donnell J. Diet Drug Disaster: The Story of Redux and Fen-Phen*. Journal of Pharmacy Practice. 1998;11(2):81-86. doi:10.1177/089719009801100203
Shaefer CF Jr, Kushner P, Aguilar R. User's guide to mechanism of action and clinical use of GLP-1 receptor agonists. Postgrad Med. 2015;127(8):818-26. doi: 10.1080/00325481.2015.1090295. Epub 2015 Sep 15. PMID: 26371721.
Chun JH, Butts A. Long-acting GLP-1RAs: An overview of efficacy, safety, and their role in type 2 diabetes management. JAAPA. 2020 Aug;33(S8 Suppl 1):3-18. doi: 10.1097/01.JAA.0000669456.13763.bd. PMID: 32756220.
Gordon, A. (Host). Hobbes, M. (Host). (2023, October 10). Ozempic. [Audio Podcast]. Retrieved from https://maintenancephase.buzzsprout.com/1411126/13747346.
Harrison, C. (Host). Chastain, R. (Guest). (2024, May 6). The Dangers of Diet Drugs: Behind the GLP-1 Weight-Loss Hype with Ragen Chastain. [Audio podcast]. Retrieved from https://rethinkingwellness.substack.com/p/the-hidden-risks-of-weight-loss-drugs.
Social Determinants of Health. (n.d.). World Health Organization. Retrieved from https://www.who.int/health-topics/social-determinants-of-health#tab=tab_1
Puhl RM, Heuer CA. Obesity stigma: important considerations for public health. Am J Public Health. 2010 Jun;100(6):1019-28. doi: 10.2105/AJPH.2009.159491. Epub 2010 Jan 14. PMID: 20075322; PMCID: PMC2866597.
Smits MM, Van Raalte DH. Safety of Semaglutide. Frontiers in Endocrinology. 2021 July;12. https://doi.org/10.3389/fendo.2021.645563
Patel F, Gan A, Chang K, Vega KJ. Acute Pancreatitis in a Patient Taking Semaglutide. Cureus. 2023 Aug 19;15(8):e43773. doi: 10.7759/cureus.43773. PMID: 37731423; PMCID: PMC10506915.
Semaglutide Side Effects. (Updated 2023, Dec 24). Drugs.com Retrieved from https://www.drugs.com/sfx/semaglutide-side-effects.html#serious-side-effects
Delong C, Preuss CV. Box Warning. (Updated 2023 Jun 17). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK538521/
Oh TJ, Moon JH, Choi SH, Lim S, Park KS, Cho NH, Jang HC. Body-Weight Fluctuation and Incident Diabetes Mellitus, Cardiovascular Disease, and Mortality: A 16-Year Prospective Cohort Study. J Clin Endocrinol Metab. 2019 Mar 1;104(3):639-646. doi: 10.1210/jc.2018-01239. PMID: 30500906.
US Food and Drug Administration. (n.d.). FDA Drug Shortages. Retrieved from https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm
US Food and Drug Administration. (n.d.). Medications Containing Semaglutide Marketed for Type 2 Diabetes or Weight Loss. retrieved from https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss
Office of Public Affairs. (2017, Sept 5). Novo Nordisk Agrees to Pay $58 Million for Failure to Comply with FDA-Mandated Risk Program. US Department of Justice. Retrieved from https://www.justice.gov/opa/pr/novo-nordisk-agrees-pay-58-million-failure-comply-fda-mandated-risk-program
Madison Martin, CNS, is a highly-skilled clinical nutritionist who enjoys empowering clients with the knowledge and tools they need to take their health back into their hands. Madison’s expertise includes evidence-based methods as well as functional and intuitive eating, and emphasizes a whole-person approach to helping clients heal their health. If you are interested in working with Madison, you can book a free nutrition strategy consultation with her using the link below.
