The SELECT trial (Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes) fundamentally redefined the treatment landscape for obesity. 1 In this large, event‐driven, randomized controlled trial (RCT) involving 17 604 adults with established cardiovascular disease and overweight or obesity [body mass index (BMI) ≥ 27 kg/m 2 ] but without diabetes, once‐weekly subcutaneous semaglutide 2.4 mg (a GLP‐1 receptor agonist, GLP‐1 RA) reduced the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) by 20% compared with placebo (hazard ratio 0.80; 95% CI: 0.72‐0.90; p < 0.001) over a median follow‐up of nearly 4 years. 1 This was the first demonstration that pharmacologic treatment of obesity can modify hard cardiovascular outcomes independent of glycaemic effects. SELECT provides perhaps the most compelling answer yet to the long‐standing debate over whether obesity should be regarded as a disease rather than merely a risk factor or lifestyle condition.
Cardiovascular disease represents only one aspect of obesity's clinical burden. Obesity is also a well‐established driver of both cancer incidence and cancer‐related mortality. 2 , 3 Epidemiologic and mechanistic evidence supports a causal association between excess adiposity and malignancy. 2 , 3 Obesity is linked to an increased risk for 13 cancer types that together account for more than 40% of new cancer diagnoses annually, including postmenopausal breast, colorectal, endometrial, kidney, esophageal adenocarcinoma, pancreatic, liver, gallbladder, gastric cardia, ovarian, thyroid, meningioma, and multiple myeloma. 2 , 4 These associations are mediated through interconnected pathways whereby obesity promotes carcinogenesis by stimulating anabolic and insulin‐dependent signalling, altering hormone regulation, inducing chronic inflammation, increasing oxidative DNA damage, and impairing DNA repair mechanisms. However, the precise molecular processes remain incompletely understood. 2
The global incidence of cancer continues to rise across both genders. 5 Although advances in screening, early detection, and treatment have reduced mortality for certain cancer types, cancer remains a leading cause of death worldwide. 5 In this context, the emergence of anti‐obesity agents that modify metabolic and hormonal homeostasis warrants careful examination of their potential impact on cancer risk and outcomes. The same GLP‐1‐based medicines that have demonstrated cardiovascular benefit and substantial weight reduction may also influence carcinogenic processes directly, through weight loss and consequent improvements in metabolic regulation, insulin signalling, inflammation, and immune modulation.
Evidence derived primarily from observational studies and, to a lesser extent, from RCTs, remains inconclusive. Some analyses have suggested that GLP‐1 RAs may lower the incidence of cancer, 6 whereas others have found neutral associations, 7 and some studies have raised concern for possible site‐specific risks. 7 , 8 Some researchers suggest that the modest signals of increased cancer incidence observed with long‐term GLP‐1‐based therapy may be attributable to greater longevity and intensified clinical surveillance among treated individuals, rather than to a direct carcinogenic effect of the agents themselves.
Concerns have also been raised regarding thyroid safety. In rodent models, GLP‐1 RAs can induce C‐cell hyperplasia and medullary thyroid carcinoma, reflecting high GLP‐1 receptor expression in rodent thyroid tissue. 9 By contrast, human data have not shown a consistent increase in thyroid C‐cell hyperplasia or medullary thyroid carcinoma with GLP‐1 RA therapy: large cohort studies and meta‐analyses of RCTs indicate that thyroid cancer is rare among GLP‐1 RA users, with no clear excess risk compared with other glucose‐lowering agents or placebo. 9 , 10 Nonetheless, in light of preclinical findings and regulatory guidance, GLP‐1 RAs remain contraindicated in individuals at high risk for medullary thyroid carcinoma, and cautious use is warranted in this context. 9
Dedicated, long‐term RCTs are therefore essential to elucidate the true effects of these agents on cancer incidence and progression. Such trials should enrol individuals with overweight or obesity and should extend well beyond the typical 52‐ to 72‐week duration of current weight‐loss studies. Ideally, they should adopt event‐driven designs, similar to SELECT, 1 with prespecified cancer outcomes.
Recruitment should focus on populations with an elevated baseline risk of malignancy, particularly individuals with obesity‐related conditions that are not managed surgically. These include individuals with monoclonal gammopathy of undetermined significance (MGUS), which can progress to multiple myeloma; those with metabolic dysfunction‐associated steatotic liver disease (MASLD), a precursor of hepatocellular carcinoma (HCC); and those with Barrett's oesophagus, a metaplastic disorder predisposing to oesophageal adenocarcinoma. Individuals at increased risk of colorectal cancer also represent a key target population.
Given the strong epidemiologic links between type 2 diabetes, obesity, MASLD/metabolic dysfunction‐associated steatohepatitis (MASH) (historically termed nonalcoholic steatohepatitis, NASH), and HCC, pharmacotherapies that both modify metabolic risk and improve liver histology are particularly attractive. 11 , 12 In this context, GLP‐1‐based therapies have shown promising effects on steatohepatitis and fibrosis, aligning with the concept of an “ideal” therapy that reduces liver fat content, improves chronic liver disease, and ultimately may lower the risk of hepatocellular carcinoma. 11 , 13 , 14 In a 72‐week, double‐blind phase 2 trial of 320 patients with biopsy‐confirmed NASH and fibrosis stage F1‐F3 (mean BMI: 35 kg/m 2 ), once‐daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) was compared with placebo. 13 Among patients with F2‐F3 fibrosis, the primary endpoint, NASH resolution without worsening of fibrosis at week 72, was achieved more frequently with semaglutide 0.4 mg than with placebo (59% vs. 17%; p < 0.001). 13 Similarly, in a 52‐week, double‐blind phase 2 trial of 190 participants with biopsy‐confirmed MASH and stage F2‐F3 fibrosis (mean BMI: 36 kg/m 2 ), once‐weekly subcutaneous tirzepatide (5, 10, or 15 mg) was compared with placebo. 14 At week 52, the primary endpoint of MASH resolution without worsening of fibrosis was achieved in 10% of placebo‐treated participants versus 44%, 56%, and 62% of those receiving tirzepatide 5, 10, and 15 mg, respectively ( p < 0.001 for all vs. placebo). These data suggest that MASLD/MASH is the “low‐hanging fruit” of preventive oncology. The pathway from disease modification, especially fibrosis regression, to the prevention of HCC is notably direct and potentially actionable. A recent meta‐analysis of five observational studies including 641 377 patients showed that GLP‐1 RA use was associated with a 58% lower risk of HCC, with the greatest benefit observed among those with cirrhosis. 15 Therefore, RCTs are needed to determine whether GLP‐1‐based therapies can causally reduce HCC incidence in this high‐risk population.
Building on the rationale in MASLD/MASH and HCC, a similar paradigm may apply to colorectal cancer. Obesity is a well‐established risk factor for colorectal cancer, and GLP‐1 RAs could plausibly modify both metabolic risk and neoplastic progression. 2 , 5 However, the existing data provide mixed signals. A large meta‐analysis of retrospective cohort studies involving 5 066 681 patients reported an increased risk of colorectal cancer with GLP‐1 agents use. 16 Nevertheless, these findings are constrained by residual confounding and substantial heterogeneity. In contrast, a comprehensive meta‐analysis of 90 RCTs (124 791 participants, mean follow‐up 3.1 years) with high certainty of evidence and low risk of bias found no significant association between GLP‐1 RA therapy and colorectal cancer incidence. 17 However, cancer was captured as an adverse event rather than a prespecified outcome. Moreover, large real‐world cohort studies suggest that GLP‐1‐based therapies may be associated with a reduced risk of obesity‐related cancers, including colorectal cancer, compared with other glucose‐lowering agents, with the apparent benefit being more pronounced in individuals with higher BMI. 18 Accordingly, dedicated RCTs with colorectal cancer as a prespecified outcome are needed to determine whether GLP‐1 RAs can truly modify colorectal carcinogenesis and reduce cancer incidence, particularly in individuals with obesity. Given the strong link between early‐life obesity and colorectal cancer, such trials may be especially informative in younger high‐risk cohorts, where observational data suggesting reduced colorectal cancer risk with GLP‐1 RA use provide a compelling rationale for long‐term prevention studies.
Turning from solid tumours to hematological malignancies, a similarly compelling case can be made for targeting individuals with MGUS, an obesity‐associated premalignant state that carries a lifelong risk of progression to multiple myeloma. 4 , 19 In a retrospective cohort study with 30 034 propensity score‐matched patients, GLP‐1 RA use was associated with improved progression‐free survival [hazard ratio 95% confidence intervals (CI): 0.63 (0.58–0.68)] and overall survival [HR (95% CI): 0.61 (0.56–0.66)], as well as a reduced risk of progression to symptomatic multiple myeloma [HR (95% CI): 0.82 (0.69–0.98)]. 20 A RCT is now needed to evaluate the efficacy of GLP‐1 medicines in individuals with MGUS, particularly those with coexisting DM or obesity, to determine whether these agents can modify the natural history of the disease, including progression to MM and related mortality.
Beyond premalignant and high‐risk clinical states such as MASLD/MASH, colorectal neoplasia, and MGUS, another pragmatic avenue for trial design lies in individuals with inherited predisposition to obesity‐associated cancers. Carriers of high‐risk germline variants, such as BRCA1/2 mutation carriers, who have an increased risk of breast and ovarian cancer, or individuals with Lynch syndrome, who have a markedly elevated risk of colorectal and endometrial cancer, represent an ideal target population for prevention‐focused studies. 21 These groups have a substantially higher baseline incidence of malignancy and a clearly defined genetic risk profile. As a result, trials in these populations could be smaller, more efficient, and require shorter follow‐up to achieve adequate statistical power. In hereditary cancer syndromes, obesity‐related hormonal and insulin‐signalling pathways may further accelerate tumorigenesis. In this context, GLP‐1 RAs offer a means of modifying the underlying metabolic milieu‐the “soil” in which genetically driven malignancies arise. Testing whether such agents can delay or prevent cancer development in carriers of high‐risk germline mutations represents an important and largely unexplored frontier in preventive oncology.
In parallel, trials are also needed in individuals with cancer to determine whether pharmacologic weight loss and metabolic modulation with GLP‐1‐based medicines, added to standard oncologic care, can enhance treatment tolerance, slow disease progression, or improve survival. Such studies should incorporate established oncology endpoints, including progression‐free survival, overall survival, and treatment response rates. In this direction, the FITWISE trial is evaluating tirzepatide as a weight‐loss intervention in patients receiving adjuvant therapy for early‐stage hormone receptor‐positive, HER2‐negative breast cancer, with a primary endpoint of achieving ≥5% weight loss while establishing safety, tolerability, and feasibility. 22 Secondary outcomes include 3‐year invasive disease‐free and distant relapse‐free survival, changes in BMI and body fat distribution, metabolic markers, and circulating tumour DNA. Similarly, the TRIM‐EBC trial is testing whether tirzepatide‐induced weight loss in patients with HR+, HER2−, node‐positive, high‐risk early breast cancer and overweight/obesity can favourably alter metabolic and hormonal pathways. 23 Its primary focus is on cancer‐related outcomes, specifically clearance of minimal residual disease as detected by tumour‐informed circulating tumour DNA and reduction in subsequent metastatic disease.
The obesity paradox, however, cannot be overlooked in this context. Several studies have reported a paradoxical association between higher BMI and improved survival in certain cancers. 24 This apparent advantage is thought to reflect limitations of BMI as a crude measure, illness‐related unintentional weight loss, and heterogeneity in obesity phenotypes and cardiorespiratory fitness, rather than a genuinely protective effect of excess adiposity. 24 At the same time, GLP‐1 medicines can lead to loss of lean mass. A meta‐analysis of 22 RCTs (2258 participants) showed a significant reduction in lean mass (mean difference −0.86 kg), with approximately one quarter of total weight loss attributable to lean tissue. 25 In people living with cancer, where preservation of skeletal muscle is critical, this potential to exacerbate or precipitate sarcopenia is particularly concerning and underscores the need for careful monitoring of muscle mass when GLP‐1‐based medicines are used alongside oncologic therapies. Trials of GLP‐1 medicines or other weight‐modulating therapies in this setting should therefore move beyond BMI and incorporate body composition analysis, particularly serial assessment of skeletal muscle and adipose tissue, as a key safety endpoint to ensure that “metabolic modulation” does not come at the expense of lean mass and functional capacity.
Moreover, the potential adverse effects of GLP‐1‐based medicines must be carefully considered in individuals with malignancy. The most common side effects are gastrointestinal, mainly nausea, vomiting, diarrhoea, and constipation, which are typically dose‐dependent, most pronounced during dose escalation, and often lessen with continued therapy. In patients receiving chemotherapy regimens that already induce similar symptoms, GLP‐1‐related nausea and vomiting could be particularly problematic and may further compromise nutritional status, treatment tolerance, and quality of life. For these reasons, GLP‐1‐based medicines should be used with particular caution in this population, with close monitoring of symptoms, nutritional status, and body composition.
With tens of millions of adults worldwide now eligible for obesity therapy, even modest effects on cancer incidence or risk of progression could carry profound population‐level consequences. If these agents ultimately reduce cancer risk, they could redefine the landscape of preventive oncology in much the same way that statins transformed cardiovascular prevention. Such a paradigm would also reshape preventive medicine more broadly: premalignant conditions that currently lack disease‐modifying therapy, such as MGUS, might warrant systematic screening, with pharmacologic obesity treatment considered for those living with obesity. If their effect proves neutral, these therapies would remain valuable and safe options for weight management and cardiometabolic risk reduction. Conversely, if an increased risk of cancer emerges with longer exposure, this would necessitate urgent re‐evaluation of their risk–benefit profile, and implementation of robust pharmacovigilance and regulatory measures.
Beyond individual patient care, these questions call for closer integration of metabolic and cancer research programs, engaging diabetologists, obesity medicine specialists, oncologists, and epidemiologists in the joint design and evaluation of clinical outcomes. Understanding these effects will shape not only clinical decisions but also the regulatory, reimbursement, and ethical frameworks that guide long‐term obesity treatment.
As the therapeutic paradigm for obesity rapidly evolves, the boundary between metabolic and oncologic disease prevention is becoming increasingly indistinct. Whether treating obesity with GLP‐1‐based medicines can modify cancer risk or outcomes remains one of the most important unanswered questions in modern medicine. The convergence of obesity biology now calls for collaborative research that extends beyond cardiovascular endpoints. Clarifying these effects will determine not only the reach of obesity therapeutics but also their potential to reshape chronic disease prevention for decades to come, a task that will ultimately require dedicated RCTs.
CONFLICT OF INTEREST STATEMENT
The authors report no conflicts of interest.
ACKNOWLEDGMENT
The publication of this article in OA mode was financially supported by HEAL‐Link.
Tentolouris A, Ntanasis‐Stathopoulos I. If treating obesity with GLP‐1‐based therapies protects the heart, could it also prevent cancer or improve cancer outcomes? The case for randomized trials. Diabetes Obes Metab. 2026;28(3):1599‐1602. doi: 10.1111/dom.70394
DATA AVAILABILITY STATEMENT
Not applicable as no new data generated.
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Associated Data
Data Availability Statement
Not applicable as no new data generated.