EP692 - Beyond Exercise: Is Metformin the Missing Piece in Colorectal Cancer Surgery Prehabilitation?

Purpose/Background: Prehabilitation has become an established component of Enhanced Recovery After Surgery (ERAS) protocols, with multimodal programs cutting severe complications by nearly half—47%—in colorectal cancer surgery. Most efforts center on exercise, nutrition, psychological support, and smoking cessation. Emerging data point to metformin as a potential add-on, acting through AMPK activation, dampening inflammation, improving mitochondrial function, and tuning metabolism. That possibility prompts a simple question: could a medication—specifically metformin—complete the prehabilitation puzzle?

Methods/Interventions: We reviewed the current evidence on metformin’s perioperative effects across surgical populations, drawing on large retrospective cohorts, recent randomized trials, mechanistic studies, and real-world implementation in both diabetic and non-diabetic patients. Outcomes of interest included mortality, complications, functional recovery, inflammatory markers, and tolerability.

Results/Outcomes: Large-scale retrospective studies demonstrate compelling benefits. Metformin use is associated with a 28% drop in 90-day mortality (HR 0.72, 95% CI 0.55–0.95) and a 40% lower chance of ICU admission (OR 0.60, 95% CI 0.59–0.62), alongside fewer cases of postoperative sepsis, renal failure, and readmissions. Mechanistic studies echo these benefits, showing anti-inflammatory effects, including a reduction in neutrophil-to-leukocyte ratios from 5.0 to 4.5 (p < 0.001) and markers of greater cellular resilience. However, randomized data are mixed. The SPRY trial (n=302) and MET-PREVENT (n=72) did not meet their primary endpoints, and 30–40% of participants stopped treatment due to gastrointestinal side effects. By contrast, more targeted work in prefrail older adults showed functional gains—a walk-speed increase of +0.13 m/s—that exceed minimal clinically important thresholds.

Conclusion/Discussion: Metformin has a strong biological rationale and encouraging retrospective support, but current randomized evidence does not justify routine use in prehabilitation. High discontinuation rates and uneven benefits argue for more precise selection criteria, finer dosing strategies, and thoughtful integration with existing programs. As a first step toward pharmacological prehabilitation, metformin is promising, but colorectal cancer–specific trials using biomarker-guided enrollment are the following essential move. Broadening prehabilitation from exercise, nutrition, and psychology to tailored metabolic optimization may be the field’s natural evolution.