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Background <p>Patients with type 2 diabetes mellitus (T2DM) have an elevated risk of colorectal cancer. SGLT-2 inhibitors and GLP-1 receptor agonists have demonstrated potential anticancer properties through distinct mechanisms. However, the association of combination therapy with colon cancer risk remains unknown.</p> Methods <p>We conducted a target trial emulation using the TriNetX Global Collaborative Network (2017–2025). Adults with T2DM and a history of polypectomy receiving dual therapy (SGLT-2 inhibitor plus GLP-1 receptor agonist) were compared with SGLT-2 inhibitor monotherapy using 1:1 propensity score matching without replacement. A new-user design and 180-day landmark analysis were employed to address immortal time bias. The primary outcome was incident colon cancer. Secondary outcomes included colectomy, other gastrointestinal cancers, cardiovascular events, renal outcomes, and all-cause mortality. Bonferroni correction was applied for multiple secondary comparisons (α = 0.05/11 = 0.0045).</p> Results <p>After propensity score matching, 28,934 patients were included in each group. Dual therapy was associated with a lower risk of colon cancer compared with SGLT-2 inhibitor alone (HR&#xa0;0.786, 95%&#xa0;CI&#xa0;0.671–0.919;&#xa0;P = 0.003), representing a 21% relative risk reduction (NNT = 490 over 5&#xa0;years). Significant reductions were also observed in colectomy (HR&#xa0;0.456), other gastrointestinal cancers (HR&#xa0;0.690), end-stage renal disease (HR&#xa0;0.808), major adverse kidney events (HR&#xa0;0.710), and all-cause mortality (HR&#xa0;0.658). Negative control outcomes showed no meaningful differences, supporting study validity.</p> Conclusions <p>In post-polypectomy T2DM patients, dual therapy was associated with a 21% lower risk of colon cancer versus SGLT-2 inhibitor monotherapy. Co-primary analysis demonstrated this association also persisted when comparing dual therapy against GLP-1 receptor agonist monotherapy alone (HR&#xa0;0.871;&#xa0;P = 0.041), indicating additive chemopreventive effects of the combination warranting prospective investigation.</p>

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Association of dual SGLT-2 inhibitor and GLP-1 receptor agonist therapy with colon cancer risk in post-polypectomy patients with diabetes: a target trial emulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月29日

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  • Chih-Hsuan Wang,
  • Wei-Cheng Chang,
  • Hsin-Yu Chen,
  • Po-Huang Chen,
  • Ming Hsun Lin,
  • Cho-Hao Lee

摘要

Background

Patients with type 2 diabetes mellitus (T2DM) have an elevated risk of colorectal cancer. SGLT-2 inhibitors and GLP-1 receptor agonists have demonstrated potential anticancer properties through distinct mechanisms. However, the association of combination therapy with colon cancer risk remains unknown.

Methods

We conducted a target trial emulation using the TriNetX Global Collaborative Network (2017–2025). Adults with T2DM and a history of polypectomy receiving dual therapy (SGLT-2 inhibitor plus GLP-1 receptor agonist) were compared with SGLT-2 inhibitor monotherapy using 1:1 propensity score matching without replacement. A new-user design and 180-day landmark analysis were employed to address immortal time bias. The primary outcome was incident colon cancer. Secondary outcomes included colectomy, other gastrointestinal cancers, cardiovascular events, renal outcomes, and all-cause mortality. Bonferroni correction was applied for multiple secondary comparisons (α = 0.05/11 = 0.0045).

Results

After propensity score matching, 28,934 patients were included in each group. Dual therapy was associated with a lower risk of colon cancer compared with SGLT-2 inhibitor alone (HR 0.786, 95% CI 0.671–0.919; P = 0.003), representing a 21% relative risk reduction (NNT = 490 over 5 years). Significant reductions were also observed in colectomy (HR 0.456), other gastrointestinal cancers (HR 0.690), end-stage renal disease (HR 0.808), major adverse kidney events (HR 0.710), and all-cause mortality (HR 0.658). Negative control outcomes showed no meaningful differences, supporting study validity.

Conclusions

In post-polypectomy T2DM patients, dual therapy was associated with a 21% lower risk of colon cancer versus SGLT-2 inhibitor monotherapy. Co-primary analysis demonstrated this association also persisted when comparing dual therapy against GLP-1 receptor agonist monotherapy alone (HR 0.871; P = 0.041), indicating additive chemopreventive effects of the combination warranting prospective investigation.