Metformin and Reduced Risk of Cancer in the Hong Kong Diabetes Registry: Real Effect or Immortal Time Bias?

Whether metformin reduces cancer risk has been hotly debated. One common opinion is that the observed beneficial effects of metformin are the consequence of immortal time bias. To examine whether the observed beneficial effects of metformin on cancer risk are the consequence of immortal time bias. Retrospective cohort study. A cohort of 3485 patients who started metformin before or at enrollment, 1226 patients who initiated metformin after enrollment, and an unexposed group of 1392 patients who never used metformin. Metformin users were categorized into 11 groups in terms of length of time between metformin initiation and enrollment. The percent changes in immortal person-time were calculated for each group. As the groups of current metformin users (n = 3485) were added sequentially to the metformin group with potential immortal time bias (n = 1226), the proportion of immortal person-time decreased gradually by 74%. As the immortal time decreased, the association between metformin and cancer risk remained statistically significant (uncorrected hazard ratio 0.54, 95% confidence interval 0.42–0.69, P < 0.0001). The change in the association between metformin and cancer is small compared with the changes in the proportion of immortal time, suggesting that immortal time bias does not account for the observed beneficial effect of metformin on cancer risk. Further studies are warranted to confirm this finding in other cohort studies.