Concerns Linger About GLP-1 Inhibitors Despite Their Popularity

Since the television health guru Dr Oz promoted semaglutide injection (Ozempic; Novo Nordisk, Inc) for its weight loss properties in February 2021,¹ hopeful questions from patients are common and often difficult to answer. In the ensuing 3 years, evidence has grown showing that glucagon- like peptide-1 (GLP-1) receptor agonists can lead to significant and sustained weight loss.^2,3 News coverage includes phrases such as medical milestone, miracle drug, and game changer. In March 2024, the FDA approved the expansion of semaglutide’s indications to include reduction of cardiovascular risk in adults who are overweight, creating additional interest.⁴

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GLP-1 is a hormone with broad effects and numerous metabolic functions. Researchers are studying these drugs in chronic kidney disease, Alzheimer disease, liver disease, sleep apnea, alcohol use disorder, and polycystic ovary syndrome.^5-10 Both semaglutide and tirzepatide (Mounjaro, Zepbound; Eli Lilly and Company) mimic GLP-1 to stimulate insulin production in the pancreas. Their weight loss actions stem from their ability to slow stomach emptying, making patients feel fuller faster and stay satiated longer.¹¹ They also possess central nervous system effects, suppressing hunger signals and silencing obsessive thoughts about food, commonly called food noise.¹²

When this type of media exposure occurs through traditional or social media, the impact can ripple throughout entire systems. Pharmacy staff are well aware of the drug shortages with GLP-1 inhibitors and concerns from patients who rely on these drugs to treat diabetes. The media are also quick to report problems and challenges, and sorting the misinformation from the truth can be challenging. Pharmacists have a significant role to play in helping patients navigate these questions.

THE BASICS

Patients are always concerned about safety and particularly adverse effects. GLP-1 agonists are not for everyone. In clinical trials of semaglutide, 16.6% of patients discontinued treatment because of adverse effects.¹³ Over 4 years, patients who responded to treatment lost an average of 10% of their body weight.² Data from a large trial showed that those who took the highest dose of tirzepatide lost an average of approximately 18% of their body weight after 72 weeks, yet more than 10% of participants discontinued treatment due to adverse effects.³

Adverse effects are most likely when patients first start the medications and gradually increase their doses over the first few months.2,3 The most common issues are associated with the mechanism of action in the gastrointestinal tract (eg, nausea, vomiting, diarrhea, constipation, acid reflux, stomach pain, and discomfort). Some patients report dizziness, fatigue, and headaches. In patients who have type 2 diabetes, hypoglycemia is possible, although it does not occur in patients who do not have diabetes.

Pancreatitis, gallbladder, or kidney issues rarely occur.^2,3

A whole vernacular has developed around these drugs in weight loss communities. The saggy skin that sometimes results from rapid wieight loss has been dubbed Ozempic face, or Ozempic butt in some cases, but weight loss occurs throughout the body, and it is impossible to target specific areas. In older adults, loss of muscle mass can cause or contribute to frailty.

WHO’S PAYING?

Currently, it appears that these drugs cost around $1000 per month.¹⁴ Insurer coverage varies, and patients may need to meet prior authorization criteria. Self-pay patients do not typically pay list price, and some patients qualify for discount cards from pharmaceutical companies. The cost has driven some people to seek less expensive compounded semaglutide and tirzepatide.¹⁵ Compounded versions are not permissible under FDA regulations unless the medication is in short supply, and some versions have been linked to adverse reactions. The FDA has received reports that some compounders may be preparing semaglutide sodium and semaglutide acetate. These salt forms differ from the approved base form of semaglutide. Compounding the salt forms does not meet the requirements for types of active ingredients that can be compounded.¹⁵

A GLP-1 IS FOREVER

Patients need to understand they will inevitably hit a weight loss plateau (usually around the 18-month mark), and when they stop taking GLP-1 agonists, they will typically regain some weight.¹⁶ As with all new drugs, the long-term effects are unknown. For that reason, the decision to use these drugs is not a trivial one.

THE LATEST BUZZ

Comments about unintended pregnancy while taking GLP-1 agonists are trending, and there is a large Facebook group called “I got pregnant on Ozempic.”¹⁷ Very little evidence exists concerning this issue because pregnant women or those intending to become pregnant were excluded from early clinical trials. Research is ongoing, and pharmacy staff can refer patients to these trials.¹⁸ The product labeling recommends discontinuing GLP-1 agonists 2 months before attempting to become pregnant.^19,20 Some experts indicate that the increased pregnancy rate may be related to weight loss because obesity is associated with difficulty conceiving.

CONCLUSION

With so many patients beginning to use GLP-1 agonists in such a short period, it is hard to keep up. The information overload can stymie busy practitioners. Pharmacists need to look at all information, trust but verify, and indicate when the evidence is weak when patients ask.

REFERENCES

1. Could a diabetes drug cure obesity? Oz Health YouTube page. February 16, 2021. Accessed September 12, 2024. https://www.youtube.com/watch?v=E9BsGVQ7MSU

2. Ryan DH, Lingvay I, Deanfield J, et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med. 2024;30(7):2049-2057. doi:10.1038/s41591-024-02996-7

3. Wadden TA, Chao AM, Machineni S, et al. Author correction: tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med. 2024;30(6):1784. doi:10.1038/s41591-024-02883-1

4. FDA approves first treatment to reduce risk of serious heart problems specifically in adults with obesity or overweight. News release. FDA. March 8, 2024. Accessed September 12, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-reduce-risk-serious-heart-problems-specifically-adults-obesity-or

5. Meca AD, Boboc IKS, Mititelu-Tartau L, Bogdan M. Unlocking the potential:semaglutide’s impact on Alzheimer’s and Parkinson’s disease in animal models. Curr Issues Mol Biol. 2024;46(6):5929-5949. doi:10.3390/cimb46060354

6. Zhao M, Liao B, Yun C, Qi X, Pang Y. Liraglutide improves follicle development in polycystic ovary syndrome by inhibiting CXCL10 secretion. Reprod Biol Endocrinol. 2024;22(1):98. doi:10.1186/s12958-024-01269-9

7. Lian K, Zhang K, Kan C, et al. Emerging therapeutic landscape: incretin agonists in chronic kidney disease management. Life Sci. 2024;351:122801.doi:10.1016/j.lfs.2024.122801

8. O’Donnell C, Ryan O, Hogan AE, et al. GLP-1 therapy increases visceral adipose tissue metabolic activity: lessons from a randomized controlled trial in obstructive sleep apnea. Obesity (Silver Spring). Published online August 22, 2024. doi:10.1002/oby.24126

9. Vi NB, Tressler EH, Vendruscolo LF, Leggio L, Farokhnia M. IUPHAR review– glucagon-like peptide-1 (GLP-1) and substance use disorders: an emerging pharmacotherapeutic target. Pharmacol Res. 2024;207:107312. doi:10.1016/j.phrs.2024.107312

10. Soresi M, Giannitrapani L. Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction–associated steatotic liverdisease. World J Gastroenterol. 2024;30(30):3541-3547.

11. Jalleh RJ, Rayner CK, Haysken T, Jones KL, Camilleri M, Horowitz M. Gastrointestinal effects of GLP-1 receptor agonists: mechanisms, management, and future directions. Lancet Gastroenterol Hepatol. 2024;9(10):957-964.doi:10.1016/S2468-1253(24):00188-2

12. Young L. Turning down the food noise: blockbuster weight-loss drugs are revealing secrets in the brain about appetite and satiety, as well as pleasure and addiction. Sci Am. 2024;331(1):36. doi:10.1038/scientificamerican072024-oPr5Gvp2GiG52cVWgx0tT

13. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med.2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563

14. Kolata G. Ozempic and Wegovy don’t cost what you think they do. The New York Times. October 22, 2023. Accessed September 12, 2024. https://www.nytimes.com/2023/10/22/health/ozempic-wegovy-price-cost.html?searchResult-Position=1

15. FDA alerts health care providers, compounders and patients of dosing errors associated with compounded injectable semaglutide products. FDA. July 26, 2024. Accessed September 12, 2024. https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-providers-compounders-and-patients-dosing-errors-associated-compounded

16. El Ansari W, Elhag W. Weight regain and insufficient weight loss after bariatric surgery: definitions, prevalence, mechanisms, predictors, prevention and management strategies, and knowledge gaps––a scoping review. Obes Surg.2021;31(4):1755-1766. doi:10.1007/s11695-020-05160-5

17. Klein A. An Ozempic baby boom? Some GLP-1 users report unexpected pregnancies. Washington Post. April 5, 2024. Accessed September 12, 2024.https://www.washingtonpost.com/wellness/2024/04/05/ozempic-babies-weight-loss-fertility/

18. A study to evaluate the safety of exposure to Wegovy during pregnancy. ClinicalTrials.gov. Updated September 11, 2024. Accessed September 20, 2024. https://clinicaltrials.gov/study/NCT05503927?term=NCT05503927&rank=1

19. Wegovy. Prescribing information. Novo Nordisk; 2022. Accessed September 3, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215256s005lbl.pdf

20. Mounjaro. Prescribing information. Lilly USA, LLC; 2023. Accessed September 3, 2024. https://pi.lilly.com/us/mounjaro-uspi.pdf