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Dear Editor, The systematic review and meta-analysis by Gong et al.1 addresses an important safety question regarding tirzepatide. However, several methodological limitations weaken the conclusions, especially the interpretation of the apparent biliary risk associated with the 5 mg dose. The biliary outcomes examined—particularly cholelithiasis—are rare across the included randomized trials. The authors employed standard random-effects models with continuity corrections in RevMan, an approach known to generate biased or unstable estimates when event counts are low. Sweeting et al. demonstrated that traditional continuity corrections can significantly distort risk ratios in rare-event meta-analyses, especially when zero-event studies are involved2. More robust analytical frameworks (e.g., Peto OR, GLMM, or beta-binomial models) are recommended in such scenarios but were not utilized. Although the reported I2 values are low, the included trials vary considerably in population characteristics, comparator agents, and duration of exposure. These factors are clinically significant because background risk differs across populations, and GLP-1 receptor agonists used as comparators may themselves affect biliary physiology. Furthermore, treatment durations ranging from 12 to 72 weeks restrict the ability to observe the temporal progression of biliary complications. Consequently, pooled estimates cannot be confidently ascribed to tirzepatide itself, independent of trial design or comparator context. The main limitation is the absence of adjustment for the magnitude and timing of weight loss, a well-known risk factor for gallstone formation. Rapid weight loss raises biliary cholesterol saturation and hinders gallbladder emptying, increasing the risk of cholelithiasis, as shown in mechanistic and epidemiological studies3, 4. Since tirzepatide causes significant and early weight loss—more than most comparators—the risk observed at the 5 mg dose is more likely due to a temporary, weight-loss–related effect rather than a specific pharmacological toxicity related to the dose. Participants generally receive lower doses (5 mg) during the initial titration phase, which corresponds to the period of most rapid weight loss. In contrast, exposure to 10 mg and 15 mg usually occurs later, when the rate of weight loss levels off and the risk linked to acute metabolic shifts decreases. Therefore, the isolated association at 5 mg likely reflects early-phase weight changes rather than a true dose–response pattern. This interpretation aligns with physiological models of gallstone formation during rapid weight change3, 4. We recognize that in certain SURPASS trials, the 5 mg dose was also administered as a maintenance regimen in specific study groups. However, exposure during the maintenance phase is less likely to overlap with the period of maximum and fastest weight loss, which is probably the main factor driving gallstone formation. Therefore, future analyses should differentiate between titration-phase and maintenance-phase exposure and include weight-loss adjustments to better determine whether the observed signal is due to timing or truly dose-related adverse effects. In conclusion, the current evidence indicates that the biliary risk is primarily a timing-dependent, weight-loss–related phenomenon rather than a dose-specific adverse effect of tirzepatide. Future analyses should include weight-loss adjustments and utilize appropriate statistical methods for rare events to clarify this relationship better. The author declares no conflict of interest. Approval of the research protocol: N/A. Informed consent: N/A. Registry and the registration no. of the study/trial: N/A. Animal studies: N/A. The data that support the findings of this study are available from the corresponding author upon reasonable request.