Weight Management Drugs

Popular weight loss drugs like semaglutide, liraglutide, and tirzepatide have been taking the media by storm due to their “miracle drug” status. Celebrities are regularly reported to use drugs like Ozempic or Wegovy to lose weight, and a host of articles have been published about these drugs, ranging from their effects on weight loss to theories that it may be increasing the rate of unintended pregnancies. Recently, discussion of “Ozempic Face” a condition where those taking the drug appear suddenly gaunt and aged due to weight loss has been dominating headlines.  Countless telehealth services are offering weight-loss drug treatments, and weight-loss coaches, doctors, dietitians, and body-positivity activists are all rushing to give their takes on the physical, psychological, and social health benefits or drawbacks of these drugs.

So, what does the research say? Here’s what I found:

Currently, the FDA has approved 9 drugs for weight loss indications. They include Semaglutide (Wegovy, Ozempic), Liraglutide (Saxenda), Tirzepatide (Mounjaro, Zepbound), Phentermine (Adipex, Suprensa), Phentermine-topiramate (Qsymia), Naltrexone-bupropion (Contrave), Setmelanotide (Imcivree), Orlistat (Xenical and Alli), and Hydrogel (Plenity). (1) Today we will focus on semaglutide, liraglutide, and tirzepatide, as they have been most recently approved by the FDA and are receiving the most attention in the media. 

Initially, semaglutide was approved only for those with diabetes as Ozempic,  but has gained approval for use in patients with obesity as Wegovy. (2) Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA), meaning that it is a synthetic version of a hormone found in the body.  It is typically delivered through injections under the skin. (3) Liraglutide is also a GLP-1 RA initially used to control blood sugar in diabetic patients. It has slightly different doses but is also typically delivered through subcutaneous injections. (4)

If you’re like me, you probably need a quick refresher on what a GLP-1 RA is. GLP-1 is a gut hormone, that is, a chemical the body creates in the gut that influences what happens in another part of the body.  The “RA” part of the labeling of these drugs mean that they are “receptor agonists” or that this class of medication can bind  to the same receptors and trigger the same effects as GLP-1.  Natural GLP-1 affects the regulation of blood sugar by causing the pancreas to release insulin, a hormone that allows sugar to be absorbed from the blood for use in other body tissues. It also blocks the secretion of glucagon, a hormone that releases  sugar in the bloodstream to help make energy available for the body. This function is why GLP-1 RA drugs have been so effective for the treatment of Type 2 Diabetes, because they increase this effect. Type 2 Diabetes is typically associated with the body responding less well to the insulin it can produce on its own, so having a boost means that the body can manage blood sugar better. 

Like GLP-1, these drugs also tell the brain to reduce the feeling of hunger as well as increasing the time it takes for the stomach to empty. These two effects help people feel fuller for longer and makes them less prone to overeating, which often results in weight loss. The combination of improving blood sugar control and making people feel fuller longer means that these drugs are pretty effective in treating a lot of concerns typically associated with Type 2 diabetes, overweight, and obesity. 

Tirzepatide is both a GLP-1 RA and a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. It is also indicated both for the treatment of diabetes and for weight loss. (5) As of now, it isn’t well understood why GIP aids in the treatment of Type 2 Diabetes or aids in weight loss because it has very little effect on insulin or food intake. However, when used in combination with a GLP-1 RA, it appears to have a synergistic effect, improving how GLP-1 RA functions.  The two medications  together are even more effective for blood sugar control than either one on its own.(6)

Population and Benefits:
All of the  studies examining these drugs that I reviewed required participants to have a weight status of obesity or overweight, usually defined by  a BMI at or over 30 or at 27 with at least one weight-related comorbidity. These comorbidities could include high blood pressure, high blood lipids, or other markers of disease typically associated with carrying excess body fat. As of now, there are no approvals for drugs to be used for those with lower body weight, so the “off label” use of weight loss drugs is not recommended. EliLilly, maker of Mounjaro and  Zepbound has written an open letter discouraging the use of these medications for “cosmetic” reasons, stating that they should only be used in accordance with the FDA’s approved indication. That is, for people who have an  overweight status with weight-related comorbidities or have an obese status. (7)

To understand the benefits of these drugs , let’s use an example person, “Joe.” Joe is 55 years old, 6 feet tall, weighs 260 pounds, and has a BMI of 35, which would put him in an obese BMI category. In addition, Joe’s doctor has told him that he has hypertension, high blood lipids, and prediabetes. Currently, recommendations for the treatment of an obese status with an adverse metabolic condition suggest  that if Joe were able to lose 3-5% of his body weight and keep it off, the loss is likely to lead to clinically meaningful reductions in his triglyceride levels and risk of developing Type 2 diabetes. If he were able to lose more weight and keep it off, he may also see improvements in his blood lipid profiles and reduce his need for medication to control his blood pressure. (8)  With all this in mind, Joe decides to look into weight loss drugs. 

If Joe entered a study and took Semaglutide 2.4 mg, he would expect to  lose about 11.85% of his body weight or ~31 pounds, reducing his BMI to 31 (9). If Joe entered a study and took Liraglutide 3.0 mg, he would expect to lose about 4.81% of his body weight or 12.5 pounds, reducing his BMI to 33.6. (10) If Joe entered a study and took Tirzepatide 5 mg, he would expect to  lose about 12.47 kg or ~27.5 pounds,  reducing his BMI to 31.5. If he could tolerate Tirzepatide 10 mg or 15 mg without serious side effects, he would lose even more weight. (11) 

On all three drugs, he would still have an obese weight status after his weight loss based on his BMI,  but he could also expect to see improvements in his blood glucose control. He would also reach the moderate 3-5% body weight loss recommended to see some improvements in his blood glucose, and on Semaglutide and Tirzepatide would probably see some improvements in his blood lipids and blood pressure. So these drugs could be a really useful tool for Joe to use to reduce his risk of diseases related to high blood pressure and high blood lipids later in his life. 

As for how these drugs would change Joe’s appearance, not much research has yet been conducted on how weight loss drugs influence body composition. So far, preliminary results suggest improvement in body composition  by reducing fat mass and improving the ratio of fat mass to lean mass among Type 2 diabetic patients while on Semaglutide. However, these patients still lost some of their lean mass, so weight loss drugs don’t just melt fat away, they take muscle with it. (12) Further research in this area for those with obesity is needed to understand exactly how that will affect people later in life. 

Side Effects:
Overall, the commonly reported side effects of weight loss drugs typically included nausea, vomiting, diarrhea, and constipation. All of the drugs were associated with statistically significant increases in these mild adverse events, with Liraglutide studies reporting the highest adverse event (AE) rate at 75.15%. Serious side effects varied by drug, with semaglutide being associated with gastrointestinal disorders and hepatobiliary disorders and tirzepatide associated with cardiovascular events. Liraglutide studies reported no difference in serious adverse events between the treatment groups and placebo groups. 

Although it was reported that the duration of these side effects was short and transient for all drugs, participants were roughly twice as likely to discontinue treatment due to adverse events in all drug treatment groups than those who were in the placebo group.(9,10,11) This means that the side effects were probably pretty uncomfortable compared to everyday life, since that’s what the placebo group would be comparable to. 

Withdrawal and Weight Maintenance:
Right now, it appears that these drugs are short-term fixes, and that if you want to keep the weight off, you have to stay on the drug. There aren’t many long-term studies that examine weight regain after stopping weight loss drugs yet. However, one study followed study participants for 68 weeks while on semaglutide, then continued to follow them for a year after discontinuing the drug. Participants who had received semaglutide regained approximately 11.6% of the weight they lost back over the course of the year. (13) Using our friend Joe for example again, that would mean that if he lost 31 pounds while on Semaglutide for 68 weeks, he would have gained back about 3.5 pounds after a year. That’s not a huge amount to regain, but it does show that the weight loss effects of the drug stop once you stop taking it. 

In a tirzepatide study, participants received the maximum tolerated dose (10 or 15 mg) for a 36 week lead in period, followed by half being randomized to switch to a placebo. The participants saw a mean reduction of 20.9% body weight during the lead in, but regained back 14% of their body weight after randomization to placebo. (14) So, if Joe started at 260 pounds and lost 54 pounds over 36 weeks, he would have a new body weight of 206 pounds. After stopping the drug, he would then gain back about 29 pounds over a year, putting him at 235 pounds. He would still see some weight loss, but not nearly as much as if he had stayed on the drug. 

Conflicts of Interest:
One thing I personally always check on when reading studies is who funded the study and for whom the researchers work. The reason I tend to look at this information is because if the people who are funding the study and working on the study stand to benefit a lot from the study going well, that creates a lot of room for bias. Bias is any tendency which prevents unprejudiced consideration of a question. I am particularly concerned about the bias in these studies because it has already been proven that effective weight loss drugs stand to make an enormous amount of money for the people and companies who provide them, which could introduce a lot of potential prejudice towards reporting positive things about these drugs. 

 The randomized controlled trials of these weight loss drugs  were typically supported by the companies who make the drugs.  Novo Nordisk funded many of the semaglutide and liraglutide studies, while Eli Lilly Funded many of  the tirzepatide studies. Additionally, many of the principal investigators in the randomized controlled trials were in a position to gain financially from the success of the weight loss drug, as they were frequently stakeholders or  employed by Novo Nordisk, Eli Lilly, and/or other pharmaceutical companies who are interested in weight loss. In some cases, the funding company had representatives involved in, “the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. Data was gathered by the site investigators, and the sponsor performed study site oversight, data collation, and analysis.” (15) 

While this was not the case for all studies, I would personally love to see some trials with a little less involvement from these companies, particularly when studies start to examine the long-term health consequences of this drug class. Although company involvement does not necessarily create bias, it tends to make me skeptical, and I would prefer to have more information from sources that I felt were less biased before recommending this drug as a first line of treatment.

Access:
The estimated cost of five years of treatment with GLP-1 RA drugs for weight loss  is $53,268. (16) Because people are expected to need to stay on these drugs indefinitely to maintain their weight loss, the cost of maintaining treatment will only climb higher the longer you stay on the medication. Medicare and Medicaid do not cover weight loss drugs, nor do many other commercial insurance companies, because right now  these drugs are largely considered cosmetic, not medical. In addition, Medicare is barred from covering weight loss medications because of previous safety concerns. (17) Because of this, weight loss drugs are not accessible to anyone who is unable to pay the steep price of staying on them, especially for the long term. Even if commercial insurance companies begin coverage, they will remain inaccessible to those on Medicare unless there is change in legislation. 

This is another big concern for the use of these drugs. Nobody ought to have to go bankrupt to take care of their health, and there are other forms of treatment for people with an overweight  or obese status that are covered by insurance and have similar results to treatment with weight loss medication. This is another reason why I would hesitate to recommend weight loss drugs as a first line of treatment. If there are other less expensive and equally effective treatments, why prescribe a new, more expensive treatment? Novelty, popularity, and media buzz should not be informing guidelines for medical practice, high-quality research should. 

Conclusion:
Weight loss drugs for the treatment of Obesity and Type 2 Diabetes are stunningly effective in these modalities. However, at this time, the research is preliminary, short-term, and likely to be significantly influenced by the funding sources.  With how short the research periods have been, how expensive long-term treatment is,  and my level of skepticism about the funding for the studies, I would hesitate to recommend GLP-1 RA/GIP drugs to a friend or family member unless they were severely obese and had complications from Type 2 Diabetes. I tend to err on the side of caution, and as everything stands,  I think caution is to be advised with these drugs, particularly if a person is already at a healthy weight. 

 What I would like to see before recommending these kinds of drugs to people I know would be further research on the health effects of long-term usage of these drugs, as it currently appears that people will need to stay on the drugs long-term if they want to keep the weight off. I also have significant concerns about the psychology involved with using these drugs. Are we setting people up to have disordered eating patterns and body dysmorphia as they lose weight? What about the psychological effect of weight regain after discontinuing the drug? 

Overall, I don’t feel that we know enough about weight loss drugs and their long-term effects to recommend them wholesale. But, these medications are remarkably popular and have been shown to be extremely effective in helping people lose weight. They show some really exciting innovation and are likely to be widely used for the foreseeable future, and will probably only get more effective as innovation continues. I am hopeful that this line of treatment will be proven to be safe and effective in the long term, and that as it becomes more mainstream, it will become more accessible. I look forward to seeing where medical innovation takes us! 

References: 

1. Top Weight Loss Medications. Obesity Medicine Association. https://obesitymedicine.org/blog/weight-loss-medications/
2. Semaglutide (Subcutaneous Route) Description and Brand Names - Mayo Clinic. www.mayoclinic.org. https://www.mayoclinic.org/drugs-supplements/semaglutide-subcutaneous-route/description/drg-20406730
3. Collins L, Costello RA. Glucagon-like Peptide-1 Receptor Agonists. PubMed. Published January 13, 2023. https://www.ncbi.nlm.nih.gov/books/NBK551568/
4. Liraglutide (Subcutaneous Route) Description and Brand Names - Mayo Clinic. www.mayoclinic.org. https://www.mayoclinic.org/drugs-supplements/liraglutide-subcutaneous-route/description/drg-20073828
5. Tirzepatide (Subcutaneous Route) Description and Brand Names - Mayo Clinic. www.mayoclinic.org. https://www.mayoclinic.org/drugs-supplements/tirzepatide-subcutaneous-route/description/drg-20534045
6. Pelle MC, Provenzano M, Zaffina I, et al. Role of a Dual Glucose-Dependent Insulinotropic Peptide (GIP)/Glucagon-like Peptide-1 Receptor Agonist (Twincretin) in Glycemic Control: From Pathophysiology to Treatment. Life (Basel). 2021;12(1):29. Published 2021 Dec 25. doi:10.3390/life12010029
7. Open Letter Regarding the Use of Mounjaro® (tirzepatide) and Zepbound® (tirzepatide) | Eli Lilly and Company. Eli Lilly and Company. Published 2022. https://lilly.gcs-web.com/node/50471
8. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society [published correction appears in J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):3029-3030]. J Am Coll Cardiol. 2014;63(25 Pt B):2985-3023. doi:10.1016/j.jacc.2013.11.004
9. Tan HC, Dampil OA, Marquez MM. Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis. J ASEAN Fed Endocr Soc. 2022;37(2):65-72. doi:10.15605/jafes.037.02.14
10. Lin Q, Xue Y, Zou H, Ruan Z, Ung COL, Hu H. Efficacy and safety of liraglutide for obesity and people who are overweight: a systematic review and meta-analysis of randomized controlled trials. Expert Rev Clin Pharmacol. 2022;15(12):1461-1469. doi:10.1080/17512433.2022.2130760
11. Tan B, Pan XH, Chew HSJ, et al. Efficacy and safety of tirzepatide for treatment of overweight or obesity. A systematic review and meta-analysis. Int J Obes (Lond). 2023;47(8):677-685. doi:10.1038/s41366-023-01321-5
12. Lazzaroni E, Ben Nasr M, Loretelli C, et al. Anti-diabetic drugs and weight loss in patients with type 2 diabetes. Pharmacol Res. 2021;171:105782. doi:10.1016/j.phrs.2021.105782
13. Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553-1564. doi:10.1111/dom.14725
14. Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024;331(1):38–48. doi:10.1001/jama.2023.24945
15. Wadden TA, Bailey TS, Billings LK, et al. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA. 2021;325(14):1403–1413. doi:10.1001/jama.2021.1831
16. gazetteterrymurphy. Excited about a new diet drug? This procedure may be better. Harvard Gazette. Published May 6, 2024. Accessed May 21, 2024. https://news.harvard.edu/gazette/story/2024/05/excited-about-new-diet-drug-this-procedure-seems-better-deal/
17. Does Insurance Cover Weight Loss Medication? Obesity Medicine Association. Published December 18, 2023. https://obesitymedicine.org/blog/does-insurance-cover-weight-loss-medication/

— Written by Jay Gendron, Edited by Oliver Gonzalez-Yoakum