'Can Popular Weight Loss Drugs Lower Cancer Risk?'

 Blockbuster weight loss and type 2 diabetes drugs, such as Ozempic, carry a growing list of benefits.

These drugs — known as glucagon-like peptide 1 (GLP-1) agonists — can control blood sugar, spur meaningful weight loss, and, in high-risk patients, help prevent heart attacks and strokes. US Food and Drug Administration approvals for these agents now span type 2 diabetes, weight loss, and cardiovascular problems.

A growing body of research is showing these popular drugs may do even more.

GLP-1 agonists can stall kidney disease progression and relieve sleep apnea, and early trials are exploring whether the drugs can treat Parkinson’s disease and prevent Alzheimer’s disease.

“They’re almost starting to look like wonder drugs,” said David Kaelber, MD, PhD, professor at Case Western Reserve University, Cleveland.

Now some experts are wondering: Can GLP-1 agonists help ward off cancer, particularly obesity-related cancers?

“Obviously, there’s a lot of excitement around these drugs,” said Laurent Azoulay, PhD, associate professor, Department of Oncology, McGill University, Montreal, Quebec, Canada. “They’re highly effective in controlling type 2 diabetes and reducing body weight, so people are interested in seeing whether that actually translates into reductions in cancer risk.”

But so far, only a handful of observational studies have dug into that question.

One of the largest to date, published in July in JAMA Network Open, came from Kaelber and colleagues. The study found that people taking GLP-1s for type 2 diabetes had lower risks for 10 obesity-related cancers than those taking insulin. For many of those cancers, the relative risk reductions were around 50% or more.

But Azoulay and other experts cautioned that while the JAMA study and other recent findings are intriguing, there are many limitations to the data that make it impossible to draw firm conclusions yet.

The main limitation: The findings are based on electronic health records and say nothing about cause and effect. In fact, even though obesity is associated with an increased risk for 13 cancers, there are limited data on whether weight loss interventions change that picture.

Still, whether GLP-1s can affect cancer risk “is a worthwhile question,” Azoulay said, “because more and more people are going to be taking these drugs.”

Wonder Drugs?

Although GLP-1s have only recently taken the world by storm, the first one — exenatide — was approved nearly 20 years ago for treating type 2 diabetes.

Today, the list includes semaglutide, sold as Ozempic for type 2 diabetes and Wegovy for weight loss, liraglutide (Victoza for type 2 diabetes and Saxenda for weight loss), and dulaglutide (Trulicity for type 2 diabetes). Tirzepatide, sold as Mounjaro for type 2 diabetes and Zepbound for weight loss, is considered a dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, which may enhance its effectiveness.

GLP-1 receptor agonists work by mimicking GLP-1, a gut hormone that plays a key role in controlling both blood sugar and appetite. The hormone tells the pancreas to release insulin and put the brakes on glucagon — a hormone that raises blood glucose, slows down digestion, and sends “fullness” signals to the brain. Most GLP-1s are taken by injection once a week, but liraglutide is taken daily.

Given the growing list of benefits for these popular drugs, some researchers are exploring the potential role GLP-1 agonists may play in reducing cancer risk, especially the risk for obesity-related cancers.

Trials from Kaelber and colleagues have linked GLP-1 use to markedly reduced risks for colorectal and liver cancers, and other trials have found links to reduced prostate and pancreatic cancer risk.

Most studies have focused on associations with single cancer types. In a large 2024 real-world study from Kaelber’s team, for instance, patients with type 2 diabetes who received a GLP-1 agonist had a lower risk for hepatocellular carcinoma than those who received other types of antidiabetic medications, particularly insulin.

The recent JAMA study expanded that GLP-1-cancer risk investigation, exploring the link between the drugs and cancer risk for 13 obesity-related cancers. In the analysis, Kaelber and colleagues examined electronic health records from 1.6 million patients with type 2 diabetes who were prescribed a GLP-1, insulin, or metformin. Over 15 years, the GLP-1 group had lower risks for 10 of 13 obesity-associated cancers — including gallbladder cancer (hazard ratio [HR], 0.35), pancreatic cancer (HR, 0.41), hepatocellular carcinoma (HR, 0.47), ovarian cancer (HR, 0.52), colorectal cancer (HR, 0.54), endometrial cancer (HR, 0.74), and kidney cancer (HR, 0.76) — than the insulin group.

That was not the case, however, when GLP-1s went up against metformin. Compared with metformin, GLP-1s were not associated with a lower risk for any cancers; in fact, the weight loss drugs were associated with a 54% increasedrisk for kidney cancer (HR, 1.54).

The reasons for the associations are unclear. The researchers controlled for the variables they could, such as patient demographics and coexisting medical conditions, but were limited to the information available on electronic health records.

“That’s the difficulty with real-world data,” Kaelber said. “You have to be very circumspect about what the findings really mean.”

An overarching issue with this type of study, Azoulay said, is that people who are prescribed GLP-1s are likely very different from those prescribed insulin, and it’s impossible to control for all of those differences.

“Insulin is essentially a last-line therapy for type 2 diabetes,” he noted. “So you’re comparing individuals who are at different stages of their disease.”

Insulin is sometimes prescribed earlier on, but that’s often in cases where people lack insurance coverage for the pricier options, said Rekha Kumar, MD, endocrinologist and obesity medicine specialist, Weill Cornell Medicine/NewYork-Presbyterian, New York City.

“From my perspective,” Kumar said, “people who are taking GLP-1 agonists tend to be pretty plugged in with the medical system. They may have better insurance coverage. They may be of higher socioeconomic status. There are a lot of potential confounders here.”

Azoulay noted that in the JAMA study, the differences in cancer incidence between GLP-1 users and insulin users were apparent from day 0.

“For an outcome like cancer, it’s biologically implausible that this would be due to the drug,” Azoulay said. “The fact that they diverge from day 0 usually points to a bias in the study.”

It’s reminiscent, he said, of the metformin story: 20 years ago, studies linked metformin use to reduced cancer risks among people with type 2 diabetes. But, Azoulay said, those studies were marred by “time-related biases” — metformin is a first-line medication prescribed much earlier than insulin — and subsequent clinical trials did not pan out.

Even with these caveats, Azoulay said, there’s still a case to be made for studying GLP-1s and cancer risk. For one, GLP-1s are not metformin — one big difference being the weight loss GLP-1s can achieve.

Understanding the Findings

In theory, any medication that causes sustained weight loss could lower the risk for obesity-related cancers, said Sonali Thosani, MD, associate professor, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston.

One question for future studies, Thosani said, is whether weight loss after starting a GLP-1 is associated with reduced cancer risks.

Kumar agreed but also said there could be additional mechanisms at play. In the SELECT trial, which led to Wegovy’s approval for preventing heart attacks, strokes, and cardiovascular death in patients with obesity and cardiovascular disease (CVD), it appeared that weight loss was not the whole story because risk reductions appeared early on, Kumar noted.

One theory is that the anti-inflammatory effects of GLP-1s were partly responsible. In the trial, p atients on semaglutide showed a drop in C-reactive protein — which indicates inflammation in the body — similar to what’s observed with statin therapy. Reductions in systemic inflammation could potentially affect cancer risk, Kumar said.

Other studies have delved into the possible cancer-fighting properties of GLP-1s — finding, for example, that they inhibit prostate cancer cell proliferation and might restore the normal natural killer cell functioning that tends to be disrupted in obesity. But there hasn’t been much work in this area.

Prescribing for Cancer Prevention?

Azoulay doubts it will be feasible to run clinical trials testing GLP-1s for cancer prevention among patients with type 2 diabetes or obesity because cancer is a relatively rare outcome that develops over a long period.

But Azoulay thinks it is possible to design observational studies that would zero in on any cancer benefit of GLP-1s. These studies, however, would have to account for cancers diagnosed early in the follow-up period, which would likely be unrelated to an obesity or type 2 diabetes treatment. Studies would also need to use a good comparator medication. Azoulay pointed to type 2 diabetes drugs called dipeptidyl peptidase 4 inhibitors because they are typically prescribed as second-line drugs and are “weight neutral.”

It’s also important to remember that GLP-1s are not without risks. The common side effects include nausea, vomiting, diarrhea, and constipation, and the drugs carry warnings about more serious conditions like pancreatitis, gallbladder stones, and acute kidney injury.

Plus, concerns have been raised about certain increasedcancer risks with GLP-1s, including the risk for thyroid tumors, which has been noted in animal research, as well as kidney cancer.

However, longer-term follow-up is needed to confirm any increased risks, Azoulay said.

Can Current Evidence Change Practice?

As a clinician, Kaelber said he would not start prescribing GLP-1 drugs in the hopes of changing patients’ cancer risks.

“If you’re my patient who has type 2 diabetes and obesity,” Kaelber said, “I’d say the main reason for you to be on one of these [GLP-1s] is that they’re going to do a good job of controlling your diabetes, and your obesity.”

It’s not clear how that might change if studies do ultimately show the drugs can move the needle on cancer risk, both Kumar and Thosani said. GLP-1s have already been bumped up in type 2 diabetes treatment guidelines to be first-line options for patients with obesity and those at a high risk for CVD.

And given how expensive GLP-1s are — with wholesale prices of over $1000 per month — cost is always a major prohibitive factor in prescribing.

While most insurance plans do cover the drugs when prescribed for type 2 diabetes, many do not cover them for obesity, Thosani said.

Then there’s access: Even when patients have insurance coverage, simply finding the drugs at a local pharmacy can be tough, she noted. Soaring demand has led to shortages of some GLP-1s.

Still, Thosani said, if future research shows the drugs can help prevent obesity-related cancers, it’s possible that would alter the insurance coverage picture.

For her part, Kumar wasn’t so sure. She noted that despite Wegovy’s approval for preventing heart attacks and strokes in people with obesity and CVD, insurance coverage has yet to change.

“We’re not seeing an expansion in coverage,” she said, “because the costs are just too high.”

The studies explored in this piece were not funded by industry. Kaelber and other experts interviewed did not have relevant conflicts of interest.

https://www.medscape.com/viewarticle/can-popular-weight-loss-drugs-lower-cancer-risk-2024a1000lg1