Obesity-Related Cancer Rates No Different With GLP-1s vs Bariatric Surgery

MALAGA, Spain—Among patients with obesity or diabetes, the long-term incidence of cancer related to excess body weight doesn’t differ between those treated with an early-generation glucagon-like peptide-1 (GLP-1) receptor agonist and those undergoing bariatric metabolic surgery, an observational analysis suggests.  

Given that patients treated with medication lost less weight than those who underwent surgery but had a similar rate of obesity-related cancer, it suggests that some other protective mechanism is at work with the GLP-1 receptor agonists.

“It’s not just the weight loss,” said lead investigator Dror Dicker, MD (Tel Aviv School of Medicine/Rabin Medical Center, Israel), during a media briefing this week at the European Congress on Obesity. “It’s something beyond weight loss.”  The mechanism might be an anti-inflammatory effect or a drug-induced alteration in apoptosis providing the additional benefit, but it is unknown at this stage, said Dror.

When investigators modeled weight loss with GLP-1 receptor to equal that achieved with bariatric surgery, there appeared to be an advantage for the drug class. In that analysis, there was a 40% larger relative reduction in the risk of obesity-related cancers with the medications compared with surgery.

Dror urged caution in interpreting the data, saying the GLP-1 drugs “may” better prevent cancer than bariatric surgery. As with all observational studies, there is the potential for confounding. “Future research will be needed to test whether GLP-1s can really prevent obesity-related cancer better than bariatric metabolic surgery,” he said.

Many Cancers Linked to Obesity

There is a large body of evidence linking obesity and different types of cancer. By some estimates, obesity plays a part in nearly 10% of the cancer burden in women in North America, Europe, and the Middle East. More than 20 years ago, the International Agency for Research on Cancer concluded that the evidence was strong enough to recommend avoiding weight gain to prevent cancers of the colon, esophagus, kidney, and breast, as well as endometrial cancer. In 2016, the group concluded that the “absence of excess body fatness lowers the risk of most cancers.”

Bariatric metabolic surgery has been shown to lower the risk of obesity-related cancer in several studies. In one recent meta-analysis, bariatric surgery was associated with a reduction in the incidence of cancer, obesity-related cancer, and cancer mortality. Overall, the reduction in the risk of obesity-related cancer with surgery ranges from 32% to 45%, the data suggest.

However, little is known about the potential cancer-related benefits of losing weight with GLP-1 receptor agonists, said Dror.

The new study, which was published simultaneously in eClinicalMedicine, included 3,976 patients with diabetes and obesity who underwent bariatric metabolic surgery as well as 27,685 patients with diabetes and obesity treated with a GLP-1 receptor agonist between 2010 and 2018.

Of these, 3,178 matched pairs (mean age 52.3 years; 61.1% female) were analyzed; mean body mass index (BMI) was 41 kg/m². Among those treated with surgery, 49% underwent sleeve gastrectomy, 40% gastric bypass, and 11% laparoscopic banding. Among those treated with medication, 73%, 13%, and 11% received liraglutide, exenatide, and dulaglutide, respectively. A small percentage were treated with lixisenatide or combinations of GLP-1 receptor agonists with insulin.

During a median follow-up of 7.5 years (maximum 12.9 years), there were 5.76 cases of obesity-related cancer per 1,000 person-years in the bariatric surgery group and 5.64 per 1,000 person-years in the medical therapy arm. Comparing GLP-1 therapy to surgery, the adjusted hazard of obesity-related cancer was not statistically different between the two arms.

There was a 31% reduction in BMI with bariatric surgery compared with a 14.3% reduction among those treated with the first-generation GLP-1 medications. The mean minimal BMI during follow-up was 28.7 kg/m²with surgery and 35.3 kg/m² with medications.

The maximal BMI change during follow-up was significantly associated with the incidence of obesity-related cancer. In the mediation analysis, which factored weight loss into the multivariable model, researchers estimated that GLP-1 receptor agonists could reduce the risk of obesity-related cancer by 41% compared with bariatric surgery. While the reduction in HbA1c levels was larger with the drugs, there was no significant mediation effect seen with changes in that measure.

In another presentation, Dror highlighted previously published data showing that bariatric metabolic surgery was associated with reduced all-cause mortality compared with first-generation GLP-1 receptor agonists among adults with a diabetes duration of 10 years or less (no difference was seen in those with longer diabetes duration). Once adjusted for weight loss, though, the surgical advantage disappeared. The observational study also found no difference in MACE between GLP-1s and bariatric surgery even after adjusting for weight loss.

Potential Effects of Newer Agents

The GLP-1 receptor agonist semaglutide (Wegovy; Novo Nordisk) and tirzepatide (Zepbound; Eli Lilly), which is a dual GLP-1 and glucagon-dependent insulinotropic polypeptide (GIP) receptor agonist, both result in larger body-weight reductions than the older-generation medications.

These newer versions, said Dror, are not only stronger weight-loss drugs, but they may have more powerful actions outside their effect on BMI. In the SELECT study of patients without diabetes but a history of cardiovascular disease, for example, the 20% reduction in MACE was only partially explained by weight loss, Dror told TCTMD. As such, he’s optimistic that the newer medications might be even more effective for preventing obesity-related cancers.

“[With a] more powerful drug, we have more potent pharmacologic effects,” he said. But while it’s possible these agents might be more effective for reducing obesity-related cancers, the field will have to wait and see.

Just a couple of weeks ago, the ESSENCE investigators showed that semaglutide improved liver function in patients with metabolic dysfunction-associated steatohepatitis, a liver condition associated with obesity, high blood lipids, and high blood sugar. Another observational study hinted the drugs might play a role in preventing atrial fibrillation in patients with obesity and type 2 diabetes.

Semaglutide and tirzepatide are currently US Food and Drug Administration-approved for treatment of diabetes and for chronic weight management in people with obesity or overweight with additional obesity-related comorbidities. Semaglutide gained an indication for reducing CVD events based on SELECT, while tirzepatide is approved for treating sleep apnea in adults with obesity.