WEIGHT-LOSS–ASSOCIATED THERAPIES AND OBESITY ASSOCIATED CANCERS IN PEOPLE WITH TYPE 2 DIABETES: REAL-WORLD OBSERVATIONAL STUDY
IPAYE T. 1,2,3, GOLDNEY J. 1,2, WILKINSON T. 1,2, ZACCARDI . 1,2, YATES T. 1,2, KHUNTI K. 1,2, AKALESTOU E. 5,6, DAVIES M. 1,2, BROWN K. 1,3, PAPAMARGARITIS D. 1,2
1 NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom; 2 Leicester Diabetes Centre, Leicester General Hospital, University of Leicester, Leicester, United Kingdom; 3 Leicester Cancer Research Centre, University of Leicester, Leicester, United Kingdom; 4 Leicester Real World Evidence Unit, Leicester, United Kingdom; 5 Division of Cardiovascular Sciences, College of Life Sciences, University of Leicester, Leicester, United Kingdom; 6 Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, Leicester, United Kingdom
Background
Obesity is a major modifiable risk factor for several cancers, particularly among individuals with type 2 diabetes (T2D). Therapeutic interventions for T2D differ in their metabolic effects, including their typical impact on body weight and related biological pathways, which may influence obesity-associated cancer (OAC) risk. Comparative real-world evidence on cancer outcomes across contemporary glucose-lowering therapies and bariatric surgery remains limited.
Objectives
To evaluate associations between initiation of semaglutide, tirzepatide, bariatric surgery, or sodium–glucose co-transporter-2 inhibitors (SGLT-2i) and OAC risk in people with obesity, with each intervention compared separately to dipeptidyl peptidase-4 inhibitors (DPP-4i).
Methods
Using the TriNetX, US collaborative network, we conducted retrospective cohort analyses of adults with T2D and overweight or obesity initiating semaglutide, tirzepatide, bariatric surgery, or SGLT-2i between June 2005 (weight-lowering interventions) and January 2026 (SGLT2i). Individuals with prior cancer or cancer diagnosis within six months of treatment initiation were excluded. Each cohort was propensity score–matched 1:1 to DPP-4i initiators. Individuals with prior cancer or cancer diagnosis within six months of initiation were excluded. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for composite OAC and site-specific cancers, including colorectal, liver, pancreatic, ovarian, uterine, oesophageal, and gastric cardia cancers.
Results
Among 64,178 matched pairs (mean follow-up 911 days), semaglutide initiation was associated with lower composite OAC risk (HR 0.88; 95% CI 0.82–0.95) and reduced colorectal (0.80; 0.67–0.97), liver (0.75; 0.60–0.95), and pancreatic (0.76; 0.60–0.96) cancer rates compared with DPP-4i. Tirzepatide (19,682 matched pairs; mean follow-up 435 days) showed a non-significant reduction in composite OAC (0.84; 0.69–1.01) and a lower ovarian (0.31; 0.10–0.95) cancer rate. Bariatric surgery (9,642 matched pairs; mean follow-up 1,746 days) was associated with reduced composite OAC (0.85; 0.74–0.98), liver (0.56; 0.32–0.97), and uterine (0.59; 0.38–0.90) cancer risk, but higher rates of oesophageal (4.78; 1.04-21.87) and gastric cardia (10.54; 1.35-82.38) cancers. Rates of other outcomes were not significantly different across exposures. SGLT-2i initiation was not associated with composite OAC risk (0.99; 0.93-1.05), with largely neutral findings overall.
Conclusions / Implications
In separate comparisons with DPP-4 inhibitors, semaglutide and bariatric surgery were associated with lower rates of obesity-associated cancers in individuals with T2D, whereas SGLT-2 inhibitors showed neutral associations. Tirzepatide demonstrated directionally similar but non-significant findings, likely reflecting limited follow-up. Although individual-level weight data were unavailable, these results support a potential role for metabolic pathways linked to weight reduction in obesity-associated cancer risk and highlight the need for longer-term mechanistic studies.