New Optimism for Breaking the Obesity-Cancer Link

by Violet Kiesel, PhD

Obesity is a major problem. Having obesity increases risk of developing serious chronic diseases like cancer, which can reduce quality of life and lifespan. This risk becomes more striking when considering the growing number of people who are obese. Weight loss can effectively reduce or reverse some of the health risks that obesity poses, but losing weight through dieting can be challenging. A new class of drugs called antiobesity medications offers the potential for long-term weight loss without undergoing a major diet change or invasive procedures. In particular, the drug tirzepatide holds great promise as a weight loss intervention.

The Hursting lab at the UNC Nutrition Research Institute and Lineberger Comprehensive Cancer Center is conducting studies in mice and people to establish the mechanistic connections between obesity and cancer as well as ways to disrupt those connections. Previous work in the lab shows that weight loss through lifestyle (dietary calorie restriction and exercise) or surgical interventions can reduce risk of multiple types of cancer, and we are now beginning to explore the potential role of tirzepatide as an approach to prevent obesity-related cancers. Our aim is to determine if weight loss with tirzepatide will reduce cancer risk in the same way that we’ve seen with other weight loss interventions. If our data support that weight loss with tirzepatide reduces cancer risk, this may mean that tirzepatide use in humans with obesity could delay or prevent the development of cancer.

Obesity complications

To say that weight loss is challenging feels like an understatement. Eating is often about more than just nourishing our bodies; the decision to eat and choices about what we eat are tied to community environments, social contexts, economic factors, and more¹. Given the number of factors that can drive food consumption, it’s no wonder that so many adults in the US are obese or overweight; a recent estimate is that 42% of adults are obese and another 31% are overweight².

Having obesity is, unfortunately, not without consequence. Obesity causes major changes in the body, like narrowing of artery walls and disruption of blood sugar control^3,4. It also increases risk of at least twelve different types of cancer⁵. All these changes can have serious implications for overall health. Weight loss seems like the perfect solution, but it can also feel completely out of reach for anyone who has unsuccessfully tried to lose weight through dieting.

For those who have tried to lose weight through dieting and “failed” – be advised: it’s an uphill battle and you are not alone. Research has shown that the body fights weight loss in several ways; some scientists have referred to this as the body “defending” its weight”⁶. For example, one study showed that after people with obesity lost weight, levels of different hunger hormones were higher compared to before they lost weight⁷. This may mean that people feel hungrier after losing weight, making it harder to eat less, and contributing to weight regain.

One alternative to dieting for long-term weight loss is bariatric surgery⁸. In this procedure, the size of the stomach is reduced, and oftentimes part of the upper digestive tract is bypassed. Having a smaller stomach can make bariatric surgery patients feel full quickly after eating small meals and bypassing the digestive tract reduces absorption of macronutrients, like fat. Together, this results in effective, sustainable weight loss. These surgeries, however, are not trivial procedures – less than 1% of people with obesity are eligible for the surgery, they are expensive and come with risk of complications, and require plenty of preparation beforehand and recovery time afterwards.

With dieting being an uphill battle and bariatric surgery being invasive and risky, we’re right back where we started with the challenge of losing weight. Despite this challenge, weight loss is still an important goal! The risk that obesity poses for development of other chronic diseases, including those that can be deadly, means that we urgently need solutions to help people lose weight.

A fresh look at weight-loss drugs

One recent solution is a class of drugs called antiobesity medications, which are drugs that help people lose weight⁹. A handful of these drugs have garnered media attention for their potent effects on weight loss, including the drugs semaglutide (sold under the name Ozempic or Wegovy) and tirzepatide (sold under the name Mounjaro). Both drugs were originally developed for treatment of type 2 diabetes, and both help to reduce hemoglobin A1c (a measure of long-term blood sugar control)¹⁰. Excitingly, both also cause weight loss. While both drugs were effective at reducing A1c and body weight, a clinical trial comparing the two drugs showed that tirzepatide had a stronger effect on both outcomes. The same trial showed similar safety profiles between the two drugs, with nausea being the most common side effects, reported by about 20% of participants.

Semaglutide and tirzepatide both work by mimicking one or two different hormones which are naturally present in the body¹¹. Tirzepatide, despite being a single molecule, mimics two different hormones called GLP-1 and GIP. Semaglutide, on the other hand, only mimics GLP-1. GLP-1 and GIP are naturally produced by the body after eating, and their job is to signal the pancreas to release insulin. This means that eating increases the release of these hormones, causing an increase in insulin, which helps to bring blood sugar back down after a meal. This is why drugs that mimic GLP-1 and GIP like semaglutide and tirzepatide are effective at controlling type 2 diabetes.

It’s less clear how these drugs help people lose weight. Naturally occurring GLP-1 can stimulate cells in the brain, and some research links that simulation to decreased appetite¹². Right now, it’s not clear if either of these drugs directly affect the brain, but research shows that mice or rats treated with tirzepatide eat less^13,14. A trial assessing the effect of tirzepatide on appetite showed that people taking the drug ate less than people taking a placebo when presented with a buffet-style lunch, and that they had lower levels of hunger and higher satiety¹⁵. In addition, some participants taking tirzepatide in clinical trials report lower cravings for fatty or sweet foods¹⁶.

While researchers need to keep working to understand exactly how these drugs exert their effects, it seems like we may finally have a less invasive solution for long-term weight loss. Given what we know about obesity increasing risk of chronic disease, it’s tempting to speculate that weight loss with these new drugs will reduce that risk. In the Hursting lab, we’re working to determine definitively if this is true.

Obesity-cancer research in the Hursting lab

The Hursting lab has explored the links between obesity, weight loss, and cancer for years. Previous work from the lab showed that weight loss in obese mice reduced tumor size in several types of cancer. For example, weight loss through calorie restriction in mice decreased tumor size in breast and colon cancers^17,18,19. Earlier work in this lab also studied weight loss in mice through bariatric surgery and saw similar results: weight loss in obese mice before cancer development means smaller tumors²⁰.

This past research demonstrates that weight loss can reduce the risk of cancer development and slow down tumor progression. Work from the lab has strengthened the argument that weight loss is an important goal for cancer prevention. Weight loss with antiobesity medications, particularly tirzepatide, is the next piece of the puzzle.

Tirzepatide represents a new tool in our toolbox to achieve weight loss. We know from published clinical trials and from our own preliminary work with mice that tirzepatide causes weight loss. Based on this, we have several questions about what effects tirzepatide might have on cancer outcomes in mice. First, will weight loss with tirzepatide reduce tumor size as we’ve seen with other methods of weight loss? Next, we know that tumors in obese mice are larger than tumors in lean mice. Will tirzepatide treatment in obese mice be enough to make tumors as small as those in lean mice? Finally, we know that tirzepatide exerts its actions by mimicking GLP-1 and GIP. Is it possible that these hormones directly interact with cancer cells, and if so, would tirzepatide have direct effects on tumor cell growth?

We’ve carefully designed future studies to answer these questions and more, and we expect to see results by summer 2023. Right now, our efforts are focused on studying these questions in breast cancer and colon cancer, both of which can be driven by obesity, and we’re likely to expand these efforts to study other types of cancer in the coming months and years. We’re also completing studies in mice that will help us link specific genetic signatures with response to tirzepatide treatment.

Hope for tirzepatide

We’re eager to work through these research goals, but it’s important to note that our work with tirzepatide represents only a small piece of what needs to be done for this drug to be used in our society. For example, more work is needed from other researchers and companies to ensure that tirzepatide is accessible. Tirzepatide is currently approved for treatment of type 2 diabetes only. The drug manufacturer, Eli Lilly, submitted a request to the Food and Drug Administration (FDA) for tirzepatide to be approved for use solely as an antiobesity medication²¹. If approved, tirzepatide could be prescribed to individuals with obesity and without diabetes. Semaglutide, which was developed by Novo Nordisk four years before tirzepatide, already has FDA approval as either a type 2 diabetes or antiobesity medication. Another barrier limiting access to tirzepatide is its high financial cost. The estimated cost of a month’s supply of tirzepatide is more than $1,000²². We need solutions to ensure equitable access to this drug by those who will benefit from it the most.

In addition to these accessibility concerns, our picture of the long-term effects of tirzepatide is incomplete. The longest trial using tirzepatide was conducted for 72 weeks. During this time, participants taking the drug saw loss of about 20% of their body weight²³. As exciting as these findings are, there are few reports of what happens when participants stop taking the drug. For example, are there long-term benefits? Clinical trials that show what happens after drug discontinuation will be important in deciding whether people can take tirzepatide for a set period of time and then stop, or if they’ll need to take it for life.

This drug shows promise of improving health in multiple ways. While other researchers will need to explore different facets of its use to society by addressing its accessibility and guidance for usage, the focus in the Hursting lab remains on cancer prevention and improving response to cancer treatment. We’re excited to move forward with experiments that will assess the effects of tirzepatide on cancer outcomes, and we look forward to other researchers filling in other missing pieces of how this drug may fit into society. The idea of a drug being able to delay or prevent cancer development could have life-changing implications, and we’re eager to see if this may someday be true.

 

References

1. “Social Determinants of Health and Obesity.” Preventive Cardiovascular Nurses Association. 2022. https://pcna.net/social-determinants-of-health-and-obesity/
2. Fryar CD, Carroll MD, Afful J. Prevalence of overweight, obesity, and severe obesity among adults aged 20 and over: United States, 1960–1962 through 2017–2018. NCHS Health E-Stats. 2020. https://www.cdc.gov/nchs/data/hestat/obesity-adult-17-18/obesity-adult.htm
3. “Consequences of Obesity.” Centers for Disease Control and Prevention. 2022. https://www.cdc.gov/obesity/basics/consequences.html
4. “Health Effects of Overweight and Obesity.” Centers for Disease Control and Prevention. 2022. https://www.cdc.gov/healthyweight/effects/index.html
5. “What You Need to Know About Obesity and Cancer.” American Institute for Cancer Research. 2020. https://www.aicr.org/resources/media-library/what-you-need-to-know-about-obesity-and-cancer/
6. “Set Point Theory May Explain Why You’re Not Losing Weight.” Cleveland Clinic.  2023. https://health.clevelandclinic.org/set-point-theory/
7. Sumithran P, Prendergast LA, Delbridge ED, Purcell K, Shulkes A, Kriketos A, Proietto J. Long-term persistence of hormonal adaptations to weight loss. 2011. N Engl J Med. 17:1597.
8. “Bariatric Surgery.” Cleveland Clinic. 2022. https://my.clevelandclinic.org/health/treatments/17285-bariatric-obesity-surgery
9. Muller TD, Bluher M, Tschop MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. 2022. Nat Rev Drug Discov. 3:201.
10. Frias JP, Davies MJ, Rosenstock J, Perez Manghi FC, Fernandez Lando L, Bergman BK, Liu B, Cui X, Brown K, SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. 2021. N Engl J Med. 385:6.
11. Jepsen MM, Christensen MB. Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity. 2021. Expert Opin Emerg Drugs. 3:231.
12. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. 2013. Cell Metab. 6:819.
13. Geisler CE, Antonellis MP, Trumbauer W, Martin JA, Coskun T, Samms RJ, Hayes MR. Tirzepatide suppresses palatable food intake by selectively reducing preference for fat in rodents. 2023. Diabetes Obes Metab. 1:56.
14. Samms RJ, Christe MJ, Al Collins K, Pirro V, Droz BA, Holland AK, Friedrich JL, Wojnicki S, Konkol DL, et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. 2021. J Clin Invest. 12:e146353.
15. Heise T, Hans DeVries J, Urva S, Li J, Pratt EJ, Thomas MK, Mather KJ, Karanikas CA, Dunn J, Haupt A, Milicevic Z, Coskun T. Tirzepatide Reduces Appetite, Energy Intake, and Fat Mass in People With Type 2 Diabetes. 2023. Diabetes Care. Dc221710.
16. Matza LS, Stewart KD, Lando LF, Patel H, Boye KS. Exit Interviews Examining the Patient Experience in Clinical Trials of Tirzepatide for Treatment of Type 2 Diabetes. 2022. Patient. 3:367.
17. Bowers LW, Glenny EM, Punjala A, Lanman NA, Goldbaum A, Himbert C, Montgomery SA, Yang P, Roper J, Ulrich CM, Dannenberg AJ, Coleman MF, Hursting SD. Weight Loss and/or Sulindac Mitigate Obesity-associated Transcriptome, Microbiome, and Protumor Effects in a Murine Model of Colon Cancer. 2022. Cancer Prev Res (Phila). 8:481.
18. Rossi EL, Dunlap SM, Bowers LW, Khatib SA, Doerstling SS, Smith LA, Ford NA, Holley D, Brown PH, Estecio MR, Kusewitt DF, deGraffenried LA, Bultman SJ, Hursting SD. Energy Balance Modulation Impacts Epigenetic Reprogramming, ERα and ERβ Expression, and Mammary Tumor Development in MMTV-neu Transgenic Mice. 2017. Cancer Res. 9:2500.
19. Bowers LW, Doerstling SS, Shamsunder MG, Lineberger CG, Rossi EL, Montgomery SA, Coleman MF, Gong W, Parker JS, Howell A, Harvie M, Hursting SD. Reversing the Genomic, Epigenetic, and Triple-Negative Breast Cancer-Enhancing Effects of Obesity. 2022. Cancer Prev Res (Phila). 9:581.
20. Camp KK, et al. Manuscript under review in Cancer Research.
21. “Lilly receives U.S. FDA Fast Track designation for tirzepatide for the treatment of adults with obesity, or overweight with weight-related comorbidities.” Lilly. 2022. https://investor.lilly.com/news-releases/news-release-details/lilly-receives-us-fda-fast-track-designation-tirzepatide
22. “How much should I expect to pay for Mounjaro®?” Lilly. 2022. https://www.lillypricinginfo.com/mounjaro
23. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A, SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. 2022. N Engl J Med. 3:205.