NOT ONLY DIABETES AND OBESITY! The Potential Cancer-Preventive Effects Expected from GLP-1 Receptor Agonists
Masahiro Kami, M.D., Ph.D.
President, Medical Governance Research Institute, Tokyo, Japan
Table of Contents
Lowering Blood Glucose and Reducing Body Weight
GLP-1 Drugs Suppress Chronic Inflammation and Reduce Cancer Risk
Obesity-Related Cancer Risk Reduced by 40% Through Factors Beyond Weight Loss
Diet and Exercise Therapy Are Important, But…
I would like to write once again about GLP-1 receptor agonists—the drugs that have been in the spotlight as so-called “weight-loss drugs.”
GLP-1 refers to a hormone secreted from L cells in the small intestine, among other sites, when blood glucose rises after eating. Because it promotes the secretion of insulin—which lowers blood glucose—by pancreatic beta cells, GLP-1 receptor agonists that mimic GLP-1 attracted attention as candidate drugs for the treatment of diabetes.
Development proceeded smoothly, and in Japan as well, liraglutide (brand name: Victoza) by Denmark’s Novo Nordisk was approved in January 2010. Currently, five compounds are sold as seven products.
1. LOWERING BLOOD GLUCOSE AND REDUCING BODY WEIGHT
GLP-1 has many physiological effects beyond blood glucose regulation. One of them is appetite suppression. It delays gastric emptying to prolong the feeling of fullness and, at the same time, acts on the hypothalamus in the brain to reduce appetite. Because of this effect, GLP-1 drew attention as a “weight-loss drug.” Subsequent research showed that GLP-1 receptor agonists have weight-loss effects, and their use as drugs for the treatment of obesity has expanded rapidly.
GLP-1 receptor agonists lower blood glucose and reduce body weight. Both are risk factors for myocardial infarction and stroke. By using GLP-1 receptor agonists, it may be possible to prevent such complications.
On this point, results from several clinical studies have already been published. One of them is a study known as the “LEADER trial,” published in July 2016 in the New England Journal of Medicine (NEJM) (1). In this study, 9,340 patients with diabetes at high risk of cardiovascular disease were randomly assigned to a liraglutide group or a placebo group, and the frequency of death and the onset of cardiovascular disease and cerebrovascular disorders were compared. At a median observation period of 3.8 years, the study reported that risk was reduced with liraglutide administration.
In November 2016, similar results were reported in NEJM in the “SUSTAIN-6 trial” (2). In July 2019, the results of the “REWIND trial,” which targeted people without a history of cardiovascular disease and reported a 12% reduction in the risk of death, cardiovascular disease, and cerebrovascular disorders, were published in the UK journal The Lancet (3).
In this way, the cardioprotective effects of GLP-1 receptor agonists have become a medical consensus.
2. GLP-1 DRUGS SUPPRESS CHRONIC INFLAMMATION AND REDUCE CANCER RISK
The effects of GLP-1 receptor agonists are thought not to be limited to the treatment of diabetes and obesity; other mechanisms of action are also believed to be involved. Of particular note are anti-inflammatory effects such as suppression of inflammatory cytokine secretion and reduction of oxidative stress.
In recent years, it has become clear that chronic inflammation is deeply involved in the development of cardiovascular disease, cancer, and even dementia. Obesity is considered a health risk because enlarged fat cells secrete inflammatory substances, stimulate the immune system, and cause chronic inflammation.
GLP-1 receptor agonists not only produce weight loss but may also contribute to the prevention of various diseases through suppression of such chronic inflammation.
A representative disease driven by chronic inflammation is cancer. Gastric cancer develops due to Helicobacter pylori; cervical cancer is caused by human papillomavirus; and liver cancer develops due to inflammation from chronic infection with hepatitis B or C viruses. Obesity is considered a risk factor for carcinogenesis because obesity induces chronic inflammation. Administration of GLP-1 receptor agonists may also be able to prevent cancer.
On this issue, research findings have already been reported by multiple groups.
One is a large-scale observational study led by a research team centered at NYU Grossman School of Medicine in the United States, released on May 23 on the American Society of Clinical Oncology (ASCO) website (4).
In this study, among patients who had both diabetes and obesity, GLP-1 receptor agonists were shown to potentially reduce the risk of 14 types of obesity-related cancers (esophageal cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, gallbladder cancer, pancreatic cancer, kidney cancer, postmenopausal breast cancer, ovarian cancer, endometrial cancer, thyroid cancer, multiple myeloma, and meningioma).
The study conducted an average 3.9-year follow-up of more than 170,000 patients with a body mass index (BMI) of 30 or higher. Compared with a DPP-4 inhibitor group (DPP-4 inhibitors are standard diabetes drugs), the GLP-1 drug group had an approximately 7% lower cancer incidence and an 8% lower all-cause mortality risk. In women in particular, cancer risk was 8% lower and all-cause mortality risk was 20% lower. In addition, the incidence of colon cancer was 16% lower and rectal cancer 28% lower.
Similar research findings have been reported by other groups. In July of last year, the Journal of the American Medical Association (JAMA) introduced a study that followed 1.65 million Americans for 15 years and reported that the risk of developing 10 types of malignant tumors—including pancreatic cancer, colorectal cancer, ovarian cancer, and esophageal cancer—was reduced, indicating that researchers worldwide are interested in cancer prevention by GLP-1 receptor agonists (5).
3. OBESITY-RELATED CANCER RISK REDUCED BY 40% THROUGH FACTORS BEYOND WEIGHT LOSS
Then, how much of the cancer-preventive effect of GLP-1 receptor agonists is due to weight loss, and how much is due to drug effects such as anti-inflammatory action? If the latter accounts for a large share, we may need to reconsider treatment approaches that place diet and exercise therapy as the absolute top priority.
An interesting research result was reported on this point. The findings were presented at the European Congress on Obesity (ECO2025), held in Málaga, Spain, from May 11 to 14, and were simultaneously published in the medical journal eClinicalMedicine (6). eClinicalMedicine is a journal affiliated with The Lancet and has been drawing attention in recent years.
The study was led by a research team from Clalit Health Services, Israel’s largest health insurance organization. They followed 6,356 patients with type 2 diabetes and a BMI of 30 or higher (3,178 in each group) who, between 2010 and 2018, either began using GLP-1 receptor agonists or underwent obesity surgery, and they tracked them through the end of 2023, with a median follow-up of 7.5 years.
During the follow-up period, 298 people developed cancers considered related to obesity. The most common was postmenopausal breast cancer (77 people), followed by colorectal cancer (49 people) and endometrial cancer (45 people). The cancer incidence rates in the obesity surgery group and the GLP-1 receptor agonist group were 5.76 and 5.64 per 1,000 person-years, respectively, and there was no statistically significant difference.
What is noteworthy is that although the average weight loss rate in the obesity surgery group (31%) greatly exceeded that of the GLP-1 receptor agonist group (13%), there was no difference in cancer incidence rates among those with a BMI of 35 or higher.
As noted above, even if cancer is prevented by GLP-1 receptor agonists, it is not known how much is due to weight loss and how much is due to drug effects. The research team estimated the effect by comparing GLP-1 receptor agonist use with obesity surgery. While the detailed explanation of the statistical processing is omitted, the team estimated that GLP-1 receptor agonists have an effect of reducing the risk of obesity-related cancers by 41% through factors other than weight loss.
Of course, the effects of GLP-1 receptor agonists on cancer can hardly be called a medical consensus yet. It is unclear whether the results of studies targeting severely obese patients like this can be applied to Japanese people. Further research is needed.
Still, this study is good news for cancer patients and people with a family history of cancer, because it suggests that medication may lower cancer risk. At least for people with a BMI of 30 or higher (87 kg at a height of 170 cm), it is worth considering.
4. DIET AND EXERCISE THERAPY ARE IMPORTANT, BUT…
Fortunately, GLP-1 receptor agonists are “safe.” Diabetes drugs are often accompanied by the risk of hypoglycemia, but GLP-1 receptor agonists have the property of promoting insulin secretion only when blood glucose is high, so the risk of hypoglycemia is extremely low. Gastrointestinal side effects such as nausea and vomiting occur frequently, and very rarely serious complications such as pancreatitis or cholecystitis can occur, but these can be managed by consulting one’s primary physician. For obese patients at high cancer risk, those risks would be acceptable.
Even so, in Japan, the use of GLP-1 receptor agonists for obesity is strictly restricted. Under a Ministry of Health, Labour and Welfare notice issued in November 2023, semaglutide (brand name: Wegovy) can be prescribed under public health insurance only at educational training hospitals where board-certified specialists recognized by specific academic societies work full-time, making it difficult for ordinary clinics to prescribe it. In addition, patients must have a BMI of 27 or higher and at least two metabolic comorbidities, and they must undergo at least six months of lifestyle guidance under the management of an obesity specialist or diabetes specialist. Under these conditions, many patients cannot benefit from GLP-1 receptor agonists.
This situation contrasts with overseas. According to a survey of 1,479 U.S. adults published last May by the Kaiser Family Foundation, 12% had used some form of GLP-1 receptor agonist and 6% were currently using one (7). It is vastly different from Japan.
Regarding diet and exercise therapy, I do not intend to deny their importance, but emphasizing them too strongly does not help patients. In a study published in April 2019 in Annals of Internal Medicine by a U.S. multicenter research team (8), when metformin—a diabetes drug with a weight-loss effect—was used, 56.1% of the metformin group maintained weight loss over a 15-year observation period, whereas in the diet-and-exercise group it was 43.1%. If this is the case even among patients enrolled in a clinical trial, the real-world situation is likely worse. Diet and exercise therapy do not last.
Under Japan’s current circumstances, many patients cannot obtain prescriptions through insured medical care and are forced to rely on out-of-pocket treatment online and elsewhere. The internet is flooded with advertisements for “GLP-1 diets,” and some include content that a physician cannot overlook as improper. In that case, it is unclear what the regulations are for.
Research on GLP-1 receptor agonists is advancing day by day. In order for the results of medical research to be returned to the public, a more flexible, patient-centered approach should be adopted.
(1) Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. July 28, 2016. N Engl J Med.
(2) Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. November 10, 2016. N Engl J Med.
(8) Long-Term Weight Loss With Metformin or Lifestyle Intervention in the Diabetes Prevention Program Outcomes Study. Annals of Internal Medicine. 23 April 2019.
This article is an English translation of an article originally published in Mainichi Medical on June 10, 2025.
Comments