2024 Fall Think Tank

New blockbuster drugs are transforming obesity treatment,¹ pervading popular culture,¹ and – at a cost of approximately $1000 a month – wreaking havoc on employer health plan costs and influencing global stocks and economies.

Initially developed to treat diabetes, glucagon-like peptide-1 (GLP-1) receptor agonists have skyrocketed in popularity since the once weekly injectable semaglutide (i.e., Wegovy) was approved for weight loss in 2021. Tirzetpatide, a drug targeting both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors can produce even more dramatic weight loss² and was approved by the FDA in 2023. Drugs targeting triple-hormone receptors are being tested now.³ Science named GLP1s the breakthrough of the year in 2023.¹

GLP-1s are naturally occurring hormones released after eating that signal GLP-1 receptors to produce insulin, which helps regulate blood sugar. These hormones also slow how fast the stomach empties, which creates feelings of satiety. GLP-1 receptor agonists mimic these effects.⁴ Studies demonstrate that these drugs can produce dramatic weight loss⁵ and may confer benefits and improve health outcomes in people living with chronic diseases,^4,6–8 including heart failure⁹ and cardiovascular disease.¹⁰

A crucial element being overlooked in the media frenzy about these pharmacological agents is the critical role of comprehensive lifestyle as medicine interventions. Obesity is a complex chronic condition with multiple intersecting contributing factors, including biology, genetics, social determinants of health, psychosocial variables, and behaviors.¹¹ The prescribing guidelines for Wegovy state that “WEGOVY is indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adults.” The often-cited seminal trials of these drugs paired them with lifestyle interventions. While some have argued that the intensity of these interventions is unclear, there has been little discussion about the success that some participants in the control group had. In the tirzepatide trial, for example, more than 1/3 of those on placebo lost 5% or more of their body weight, nearly 20% lost 10% or more, and more than 8% lost 15% or more. Lifestyle interventions can improve outcomes when introduced prior to the pharmacological agents and/or paired with them. Increasing fiber intake through a whole-food plant-forward diet, for example, may increase our production of naturally occurring GLP1s and other hormones that decrease appetite (e.g., peptide YY).¹² Lifestyle as medicine interventions can also contribute to the maintenance of weight loss¹³ and could help mitigate side effects.

This Think Tank will explore the benefits and drawbacks of GLP-1s and similar drugs, illustrate how employers are integrating them into their health benefit offerings (or not), and delve into the opportunities to more systematically integrate lifestyle as medicine into benefit strategies as a precursor of, adjunct to, or substitute for pharmacological interventions. Hearty dialogue and debate will center on key questions, such as:

• What role can organizations play in attenuating obesogenic environments and/or amplifying Lifestyle as Medicine efforts? Are there steps employers can take to facilitate lifestyle as medicine to potentially reduce the need for GLP-1s and/or support GLP1s when they are covered?
• What are the implications of the various approaches to benefit design employers have or can implement for GLP-1s? Some employers are electing not to cover this class of medication or are using a phased approach to care by instituting requirements for lifestyle interventions prior to the prescription. Other organizations are creating formal relationships with virtual telehealth providers to act as gatekeepers to the tsunami of costs associated with the increasing demand for these drugs.¹⁴
• Might even better results be possible if we invested a fraction of the resources being spent on pharmacologic agents in Lifestyle as Medicine (e.g., innovative Food is Medicine solutions, personalized gut microbiome assessments to identify optimal dietary intake, addressing unmet social needs)? Can employers collectively pressure “big pharma” to reinvest in some of these initiatives?
• How can we ensure GLP1s don’t exacerbate existing health disparities?
• Do the potential health benefits of GLP1s and similar drugs warrant the costs? What is the cost effectiveness?
• How does the evidence for intensive therapeutic lifestyle change compare to that for GLP1s in the short and long-term?
• How can we do a better job conveying the potential power of intensive, individually tailored Lifestyle as Medicine interventions when many are cynical about the role of lifestyle as medicine? One diabetes clinician researcher said, “The era of ‘just go out and diet and exercise’ is now gone. Now clinicians have tools to address obesity.”

Learning Objectives

After attending this Think Tank, participants will be able to:

1. Define GLP-1s and name three benefits and three drawbacks to their use.
2. List four reasons why lifestyle as medicine interventions should be used as a foundational aspect of any comprehensive employer-sponsored program to address obesity.
3. Describe the health equity challenges presented by GLP-1s.

Additional Aspect of GLP-1s We’ll Discuss…

Forecasters predict that the market for these drugs could be $100 billion in 10 years,¹⁵ in part because the agents currently approved appear to be just the beginning of this class of drugs. Beyond the headlines, social media frenzy, and relentless direct-to-consumer ads, however, the story is much more complicated.

• Side Effects. These drugs commonly have side effects, including gastrointestinal symptoms, that can lead to discontinuation. There are a black box warning about the risk of thyroid C-cell tumors,⁴ questions about links to suicidal ideation,¹⁵ and many unknowns about potential long-term risks. One troubling finding to date is that 40% of the weight loss on these drugs appears to be lean muscle mass. Dietary modifications to prioritize protein and resistance training will be essential to mitigate lean mass loss.¹¹
• Stability of Treatment Effect. A year following the withdrawal of Wegovy, two-thirds of weight was regained and improvements in cardiometabolic outcomes were lost.¹⁶ That raises important questions about how long people will have to continue to take the drugs.
• Health Equity. There are also already equity concerns and early indications that individuals disproportionately burdened by diabetes and obesity (i.e., Black and Hispanic Americans) are experiencing inequities in access to these medications.¹⁷

References

1. Couzin-Frankel J. 2023 Breakthrough of the Year. Science. 2023;382(6676):1226-1227.
2. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038
3. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972
4. Michos ED, Lopez‐Jimenez F, Gulati M. Role of Glucagon‐Like Peptide‐1 Receptor Agonists in Achieving Weight Loss and Improving Cardiovascular Outcomes in People With Overweight and Obesity. J Am Heart Assoc. 2023;12(11):e029282. doi:10.1161/JAHA.122.029282
5. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183
6. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653-662. doi:10.1016/S2213-8587(21)00203-5
7. Yu JH, Park SY, Lee DY, Kim NH, Seo JA. GLP-1 receptor agonists in diabetic kidney disease: current evidence and future directions. Kidney Res Clin Pract. 2022;41(2):136-149. doi:10.23876/j.krcp.22.001
8. Peng ZY, Yang CT, Lin WH, Yao WY, Ou HT, Kuo S. Chronic kidney outcomes associated with GLP-1 receptor agonists versus long-acting insulins among type 2 diabetes patients requiring intensive glycemic control: a nationwide cohort study. Cardiovasc Diabetol. 2023;22(1):272. doi:10.1186/s12933-023-01991-5
9. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069-1084. doi:10.1056/NEJMoa2306963
10. 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
11. Lifestyle Medicine & GLP-1-RA Medications for Weight Loss.; 2024. Accessed February 17, 2024. https://static1.squarespace.com/static/5d38ca4174e198000123709a/t/65cbdd3bb35cf818d5804ad0/1707859265845/Diet+ID+GLP-1+Webinar+Feb+9.final.pdf
12. Less snacking, more satisfaction: Some foods boost levels of an Ozempic-like hormone. Published online October 30, 2023. Accessed February 17, 2024. https://www.npr.org/sections/health-shots/2023/10/30/1208883691/diet-ozempic-wegovy-weight-loss-fiber-glp-1-diabetes-barley
13. Mayo Clinic. Considering GLP-1 medications? What they are and why lifestyle change is key to sustained weight loss. Mayo Clinic Diet. Accessed February 17, 2024. https://diet.mayoclinic.org/us/blog/2023/considering-glp-1-medications-what-they-are-and-why-lifestyle-change-is-key-to-sustained-weight-loss/
14. Wingrove P. US employers hire virtual providers as weight-loss drug gatekeepers. Reuters. Published online December 13, 2023. Accessed February 17, 2024. https://www.reuters.com/business/healthcare-pharmaceuticals/us-employers-hire-virtual-providers-weight-loss-drug-gatekeepers-2023-12-13/
15. Gershberg M. Weight-loss drugs: Who, and what, are they good for? Reuters. Published online January 2, 2024. Accessed February 17, 2024. https://www.reuters.com/business/healthcare-pharmaceuticals/weight-loss-drugs-who-what-are-they-good-2024-01-02/
16. 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
17. Eberly LA, Yang L, Essien UR, et al. Racial, Ethnic, and Socioeconomic Inequities in Glucagon-Like Peptide-1 Receptor Agonist Use Among Patients With Diabetes in the US. JAMA Health Forum. 2021;2(12):e214182. doi:10.1001/jamahealthforum.2021.4182