Mounting evidence that weight loss can reduce cancer risk is reinforcing the established causal link between obesity and cancer, prompting experts to call for greater awareness of an association that remains underestimated. 

"Our study serves as a call for action and a strong public health message to health care stakeholders to intensify efforts and resources to treat obesity as a chronic disease to help reduce the risk of developing cancer," wrote the authors of one of the latest studies, published in the journal Obesity, which highlighted reduced cancer risk with nonsurgical weight loss.

Obesity has been linked to at least 13 types of cancer, accounting for approximately 40% of all cancers diagnosed annually in the United States, according to the CDC. Excess body weight is the second leading preventable cause of cancer after cigarette smoking in both males and females.

Although prior studies demonstrated that weight loss can reduce cancer risk, the strongest evidence comes from bariatric surgery, where conditions are well controlled. Evidence for nonsurgical weight loss, by contrast, has been limited and conflicting.

A Real-World Analysis

To address this gap, senior author Daniel M. Rotroff, PhD, of the Department of Endocrinology and Metabolism, Medical Specialty Institute, Cleveland Clinic, and colleagues evaluated data from 143,630 adults with obesity (BMI > 30 kg/m²) treated within the Cleveland Clinic health system between January 2000 and December 2022. All patients had at least seven visits over 3 years.

Patients treated with bariatric surgery were excluded, as were those with alcohol or substance abuse and dependence, amputations, HIV, organ transplants, and thyroid disorders at baseline.

During the study period, 7703 patients had new cancer diagnoses, and the remaining 135,927 served as case controls without cancer. 

At baseline, type 2 diabetes was present in 32% of those with cancer and 23% of controls, and GLP-1 receptor agonist (RA) use was reported in 5.1% vs 8.6%, respectively, among those with up to 10 years of follow-up.

Each 1% reduction in BMI was significantly associated with a lower risk of obesity-related cancers at 3 years (odds ratio [OR], 0.990; P < .001), 5 years (OR, 0.989; P < .001), and 10 years (OR, 0.992; P = .057).

Weight loss was also associated with a reduced risk for other cancer types across all timepoints (OR < 1; P < .001).

Notably, weight loss was associated with lower odds of endometrial cancer at all follow-up points (P < .05) and renal cell carcinoma at 3 and 5 years (both P < .05). Reduced odds of developing multiple myeloma was only associated with weight loss over the 10-year interval (OR = 0.969).

Even weight loss over just 3 years was associated with lower odds of developing seven secondary endpoints in the study, including malignant neoplasms of the digestive system (OR < 0.989).

Mechanisms Behind the Association 

Multiple mechanisms are believed to underlie the increased cancer risk associated with obesity, varying by cancer type but including hormonal dysregulation, chronic inflammation, and adipokine imbalance.

"Increased adipose tissue mass disrupts the production of adiponectin, resistin, leptin, and free fatty acids, contributing to hyperinsulinemia and insulin resistance, both of which are implicated in cancer pathogenesis," the authors wrote.

Emerging Role of GLP-1 RAs

Although fewer than 10% of patients in the study used GLP-1 RAs, other research is beginning to suggest these agents may reduce cancer risk.

One recent study of more than 1.6 million patients in the United States with type 2 diabetes found GLP-1 RA use was significantly associated with reduced risks of 10 obesity-associated cancers, including gallbladder, pancreatic, hepatocellular, ovarian, colorectal, esophageal, and kidney cancers, compared with insulins or metformin.

"Together with our findings on real-world weight loss among individuals with obesity, these results highlight the importance of investigating the mediating role of GLP-1 RA-induced weight loss in cancer risk among individuals with obesity," the authors of the current study wrote.

They emphasized the need for prospective studies to determine whether antiobesity medications reduce cancer risk through weight loss alone or via independent mechanisms.

Nonsurgical and Bariatric Surgery Risk Reductions

A review of evidence on obesity and cancer risk, published online in JAMA in March, highlighted evidence supporting both pharmacologic and surgical approaches. 

In a study comparing two groups of over 43,000 individuals treated or not treated with GLP-1 RAs over 10 years (2014 to 2024), GLP-1 RA use was associated with a significantly lower overall cancer incidence (hazard ratio [HR], 0.83; P = .002). Reductions were primarily observed for endometrial (HR, 0.75), ovarian (HR, 0.53) and meningioma cancers (HR, 0.69). However, GLP-1 RA use was also linked to a marginal increase in kidney cancer risk (HR, 1.38).

Comparatively, an observational study of more than 30,000 patients with a BMI ≥ 35 reported that bariatric surgery was associated with a 32% reduction in obesity-associated cancer incidence over a median follow-up of 6.1 years. Patients undergoing bariatric surgery had a mean weight reduction of 27.5 kg over 10 years, compared with those not receiving the surgery (HR, 0.68; P = .002). Bariatric surgery was also associated with a significantly lower rate of cumulative incidence of cancer-related mortality (adjusted HR, 0.52; P = .01).

How Much Weight Loss Is Necessary to Reduce Cancer Risk?

Review senior author Neil M. Iyengar, MD, of the Winship Cancer Institute at Emory University in Atlanta, noted that weight loss doesn't necessarily have to be extreme to show a reduced cancer risk.

"The excess cancer risk is not confined to severe obesity," he told Medscape Medical News. "Overweight and obesity were both associated with higher cancer rates overall, and risk appeared especially elevated in people with metabolic dysfunction, such as having insulin resistance." 

While noting that GLP-1 RAs' ability to reduce cancer risk represents "one of the most important emerging questions in the field," Iyengar cautioned against overinterpretation.

"We do not yet have definitive evidence that widespread GLP-1-RA use will reduce population-level cancer incidence, and I have not seen a projection I would consider sufficiently robust to quote with confidence for future cancer rates."

However, "what we can say is that the hypothesis is very plausible," Iyengar added. 

"If safe, durable, and accessible treatments meaningfully reduce excess adiposity at scale, it would be reasonable to expect downstream reduction in global cancer burden," he said, noting the important caveat that "this will require sufficient access to these costly therapies."

Obesity-Cancer Link Remains Underrecognized

Despite a 2014 position statement from the American Society of Clinical Oncology identifying obesity as a major but unrecognized cancer risk factor, lack of awareness persists.

"Awareness is clearly improving, but I would not say it is yet where it should be," Iyengar said.

While guidelines address the link, "in day-to-day practice, I still think obesity is not addressed as consistently or as proactively as other modifiable cancer risk factors," he said.

"There is room for much more focus, particularly in people already at elevated cancer risk because of family history, premalignant conditions, metabolic disease, or prior cancer." 

Proposed Framework to Improve Risk Assessment

New clinical practice guidelines on this association from the European Society for Medical Oncology are in development. In the meantime, the proposed "PLUS" framework, outlined this month in a paper in JAMA Oncology, is calling for improved awareness of the "underestimated" issue.

With a mission to "synthesize current knowledge and advocate for obesity prevention and control as a critical, yet underutilized, strategy in cancer prevention," the proposal outlines four key components seen as necessary in addressing previous methodologies to improve the assessment of obesity-related cancer risk:

• P: Prediagnostic weight loss among patients with cancer, accounting for weight changes before cancer diagnosis
• L: Lifetime exposure to excess weight, rather than single timepoints
• U: Use of central obesity measures (eg, waist circumference and waist-to-hip ratio)
• S: Selection of risk-adapted thresholds beyond standard BMI thresholds, which may underestimate cancer risk

Overall, "the PLUS framework discloses a much stronger cancer-preventive potential of obesity prevention and control than previously established," the authors asserted.

"Given the ongoing obesity epidemic and its links to numerous adverse health outcomes, such as diabetes and cardiovascular disease, [the framework] underlines the urgency and expected rewards of enhanced efforts toward prevention and treatment of overweight and obesity," they concluded. 

Iyengar reported consulting fees and/or research funding from Novartis, Pfizer, AstraZeneca, Gilead, Genentech/Roche, Daiichi Sankyo, Puma, SynDevRx, BD Life Sciences, Menarini-Stemline, TerSera Therapeutics, Bayer, Boehringer Oncology, and Seattle Genetics, and equity ownership in Complement 1 and Roon.