GLP-1 (Glucagon-like peptide 1) is a peptide hormone made by our intestines (distal ileum & colon). It is secreted about 30 minutes after a meal and has a short 2 minute half-life. GLP-1 relays satiety signals to the brain, delays gastric emptying, and improves insulin secretion and sensitivity. It was first identified in anglerfish in the 1980’s (1) and was isolated and synthesized from Gila monster venom (seriously!) in 1992 (2). Being an incretin (a hormone that raises insulin and thus lowers blood sugar), it drew pharmaceutical interest for diabetes. Because it raises insulin, it was initially postulated that it would cause weight gain. It was first FDA approved for diabetes in 2005- a drug called Byetta (3). A patient I was seeing around that time told me she was “prescribed Gila monster venom” for her diabetes. I noticed she lost weight while taking it.

Semaglutide

Semaglutide is the generic name for GLP-1 based drugs. Besides Byetta, other brand names include Ozempic, Wegovy, Trulicity, Victoza, Saxenda among others. Semaglutide is 94% identical to human GLP-1, so has the same actions, but has been modified to last much longer- 7 days as opposed to a 2-minute half-life.(4) It was approved for weight loss in 2021 (Wegovy), and as a result has become a financial blockbuster. In 2020, GLP-1 drugs yielded $5.1 billion in sales; in 2023 $12 billion; and in 2030 it is projected to reach $50.9 billion.(5) Despite costing less than $5 to make (for a 1-month supply) (6), Wegovy averages $1349.02 per month in the U.S. The price in all other first world countries ranges from $83 to 169.00. (7)

GLP-1 analogs have proven to be the most efficacious weight loss tools to date, rivaling gastric bypass surgery. Widespread data of their use show a 15-17% reduction in body weight over 68 weeks. (8) Unfortunately, the data shows an average gain of 2/3 of the lost weight within 52 weeks of discontinued use. (9) This is in line with follow up data with virtually all methods of weight loss. There is growing concern that most who use these drugs are having a significant percentage (39%) of their weight being lost as lean body mass (i.e. muscle). (10) A common scenario is a person is prescribed Semaglutide for 6 months. They make no dietary changes other than eating far less of the poor quality foods they normally eat due to a suppressed appetite. This leads to a 40 lb weight loss of which 30 is fat and 10 is muscle. Then 6 months after stopping the drug, they have regained the 40 lbs. and have not implemented any strength training, meaning all the weight gained is fat. So, 1 year after starting Semaglutide, their weight is the same, but with 10 lbs. less muscle and 10 lbs. more fat. In an attempt to prevent weight regain, some doctors are suggesting these drugs be used for life.(11) Few patients seem interested in doing this, plus can we afford $1349.02 per month for every man, woman and child who is 20+ lbs. overweight for life? And you think insurance premiums are expensive now, imagine that scenario!

GLP-1 drugs have been in use since 2005, so there is a lot of data to monitor for safety and side effects. Also, GLP-1 is a naturally occurring hormone that every one of us is exposed to endogenously.Despite the recent media attention of such cases, serious side effects are very rare. However, mild side effects are very common, particularly nausea and constipation. (12)

Tirzepatide

Tirzepatide is the generic name for another drug which are dual agonists (brand names- Mounjaro and Zepbound). Mounjaro was FDA approved for diabetes in 2022, and Zepbound for weight loss in 2023. Like Semagultide, they have GLP-1 activity, though far weaker (5x less potent than human GLP-1). The other half is another peptide hormone called GIP (glucagon insulinotropic hormone). GIP is secreted by cells in our upper small intestine 30-60 minutes after a meal- especially from carbohydrates and protein intake. Like GLP-1, human GIP has a short half-life (5 minutes). The GIP in Tirzepatide has been altered to have a half-life of 7 days (the same as the GLP-1). (13) Much has yet to be learned about this hormone, but what is known is it has an anti-nausea effect, is neuroprotective, increases bone and fat synthesis, lowers stomach acid and is also an incretin (raises insulin/lowers blood glucose). (14) Due to GIPs function of increasing fat synthesis, scientists were surprised to discover GIP aids in weight loss. It turns out Tirzepatide is even more potent than Semaglutide in weight reduction. Data shows an average of 20% body weight reduction in 36 weeks. (15) Another advantage is the anti-nausea effects of GIP helps to negate the nausea inducing effects of GLP-1. Being more efficacious than Semagultide, the initial cost of Tirzepatide was even higher. Eli Lilly, the pharmaceutical maker of both Mounjaro and Zepbound, has recently sent cease and desist letters to all generic makers of Tirzepatide such as compounding pharmacies and research chemical companies who offer the generic drug at far cheaper prices. (16)

My opinion on these drugs

Being the most efficacious weight loss aid to date, Semaglutide and Tirzepatide can be game changers in turning the tidal scourge of obesity and improve the health of our society if used properly. However, the means in which most people are using them, they will suffer a net negative with yet another cycle of yo-yo dieting with more fat and less muscle in the end. GLP-1s are very potent in suppressing appetite and thus removing “food noise” and breaking food addictions. Regarding side effects, we now have 19 years of data which is not showing any major red flags (like Fen Phen), and I suspect the long-term side effects of obesity are far worse. There are effective strategies to minimize the more common mild side effects (nausea and constipation).  Three important questions for anyone considering starting one of these meds:

1. Do you plan to take these injections every week for the rest of your life? Most will say no. For those who would consider it, I would advise against it. These drugs elevate resting heart rate by 5-10 beats in every user. (17) In the short term this is not too big a concern and probably reflects a bit of a raised metabolism and thus caloric burn. Having this for one’s entire life however will most certainly shorten lifespan. All long-term users report a hard plateau in weight loss at 6-18 months, at which time the body finds homeostasis adapting to the elevated GLP-1 levels.(18)
2. How will you mitigate muscle loss? We have a plan where we coach patients on minimizing GLP-1 side effects, and the ideal calorie intake, macronutrient ratios, hormone balance and the best type of exercise to help you keep every ounce of muscle. The first few I have worked with have actually gained muscle while losing fat on GLP-1 drugs.
3. What is your plan when the injections stop? This is the most important question of all. Maintaining results is by far the hardest part of any weight loss endeavor, requiring more planning, expert guidance and discipline than the weight loss does. We call this the “post-diet” and have a plan to help push back against the body’s biological levers that promote weight regain.

On the horizon

Because of the huge financial windfall the GLP-1 discovery has brought to pharmaceutical companies, research for even better agents is fast unfolding. Here are a few currently in trials:

Retatrutide– a triple agonist (GLP-1, GIP and glucagon). This is Tirzepatide with the added effects of glucagon which stimulates increased caloric burn. So far it has outperformed all current drugs and is anticipating FDA approval in 2026. (19)

Mazdutide– a dual agonist (GLP-1 and glucagon); popular in China (20)

MariTide– a GLP-1 agonist and GIP antagonist (opposite of the GIP agonist of Tirzepatide)- interestingly showing better outcomes in early trials, and better weight maintenance (21)

CagriSema– a GLP-1 agonist and a hormone called amylin proving to be very effective. It is currently in a trial head-to-head with Tirzepatide (22, 23)

Bimagrumab– a biologic drug being used to cause muscle gain without exercising- being studied in conjunction with Semaglutide (24)

Mibavademab– an analog to the hormone leptin being combined with GLP-1. I am excited about this one because I think it holds great potential for weight maintenance. Time will tell! (25)

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707151/
2. https://www.sciencedirect.com/science/article/abs/pii/0167011596001358?via%3Dihub
3. https://en.wikipedia.org/wiki/Exenatide
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8736331/#:~:text=Semaglutide%20
5. https://www.midwesterndoctor.com/p/the-great-ozempic-scam-and-safer?utm_source=substack&utm_medium=email
6. https://www.cnbc.com/2024/03/27/novo-nordisk-ozempic-can-be-made-for-less-than-5-a-month-study.html
7. https://www.advisory.com/daily-briefing/2023/08/21/weight-loss-drug-cost
8. https://www.nejm.org/doi/10.1056/NEJMoa2032183
9. https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14725
10. https://www.drugdiscoverytrends.com/glp-1-impact-lean-mass/
11. https://www.reuters.com/business/healthcare-pharmaceuticals/novo-nordisk-says-stopping-obesity-drug-may-cause-full-weight-regain-5-years-2023-03-30/
12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294388/
13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526454/#:~:text=For%20GLP%2D1R%2C%20tirzepatide%20was,nM%20(1.86%2C%203)
14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020673/
15. https://jamanetwork.com/journals/jama/fullarticle/2812936
16. https://a4pc.org/2024-06/those-lilly-letters/
17. https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvae120/7687589
18. https://www.nytimes.com/2023/09/18/well/ozempic-weight-loss-plateau.html
19. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2301972
20. https://www.prnewswire.com/news-releases/innovents-first-new-drug-application-of-mazdutide-for-chronic-weight-management-has-been-accepted-by-the-nmpa-of-china-302055755.html
21. https://www.pharmexec.com/view/amgen-s-novel-weight-loss-drug-shows-potential-for-longer-lasting-effect-with-less-frequent-dosing-than-wegovy-zepbound
22. https://www.clinicaltrialsarena.com/analyst-comment/novo-nordisk-cagrisema-versus-zepbound/?cf-view
23. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01291-6/abstract
24. https://investor.lilly.com/news-releases/news-release-details/lilly-acquire-versanis-improve-patient-outcomes-cardiometabolic
25. https://clinicaltrials.gov/study/NCT06373146