Comments on Adverse Events Associated with Incretin-Based Therapies: A Narrative Review on Mechanisms, Clinical Management, and Risk Mitigation [Response To Letter]

Dear editor

We thank the authors for their interest in our paper1 and welcome the opportunity to clarify the points raised.

Throughout the review, we intentionally adopted a cautious approach and avoided definitive conclusions where the evidence remains evolving. This is particularly important for incretin-based therapies, for which the evidence base continues to expand and spans heterogeneous study designs. Accordingly, our conclusions reflect the strength, consistency, and limitations of the available evidence, with greater interpretive weight given to higher-level evidence, while pharmacovigilance and mechanistic studies were used primarily to contextualise emerging safety signals.

Our article was explicitly designed as a narrative review, not a systematic review or meta-analysis. The Methods describe the literature search, eligibility criteria, qualitative assessment by two authors, and the principles used to appraise and synthesise evidence according to methodological quality, clinical relevance, study design, and consistency.

Regarding gallbladder and biliary disease, our review explicitly recognised the association with incretin-based therapies, including evidence relating to dose, treatment duration, weight reduction, and baseline susceptibility. It also acknowledged differing meta-analytic findings and their respective limitations. Our review already presents a multifactorial framework involving rapid weight loss, bile supersaturation, impaired gallbladder contractility, and underlying patient risk factors. Thus, the concern raised relates primarily to mechanistic emphasis rather than a substantive difference in the underlying evidence or its interpretation.

Regarding thyroid malignancy, our conclusion was intentionally cautious: available human evidence has not demonstrated an increased risk; however, this does not establish that such a risk is absent. The review specifically acknowledges that longer follow-up is required to characterise potentially long-latency risk and recommends continued pharmacovigilance and long-term surveillance for rare or delayed thyroid outcomes. The additional evidence cited in the Letter does not establish a consistent increase in thyroid malignancy. Thus, the distinction raised between “no demonstrated increase” and “absence of risk” is already reflected in our interpretation and does not alter our conclusion.

Regarding muscle mass, our review does not present the reported lean-mass reduction as a patient-level incidence estimate. It describes lean-mass reduction as a component of overall weight loss and interprets it in the context of physiological adaptation to sustained negative energy balance rather than direct drug-induced myotoxicity. Table 2 specifically describes muscle-mass reduction as a “common component of weight loss,” not as the proportion of treated individuals experiencing a defined adverse event. The Letter itself recognises this distinction.

Regarding pharmacovigilance, we did not use these data to estimate incidence or establish causality. Consistent with our stated methodology, we used pharmacovigilance evidence primarily to contextualise emerging safety signals, while higher-level evidence received greater interpretive weight. Furthermore, the explanatory notes accompanying the safety tables explicitly state that the classifications represent a qualitative synthesis of recurring patterns across the available evidence rather than precise incidence estimates.2 Notably, the Letter itself acknowledges that these limitations were already addressed in our review and characterises its concern as one of presentation rather than omission.

In summary, the points raised in the Letter predominantly seek additional methodological detail or terminological refinement of distinctions already recognised in our review. They do not present substantive evidence that materially changes the synthesis, interpretation, or principal conclusions.

We recognise the important role of Letters to the Editor in scientific discourse. However, their scientific weight should reflect methodological rigour, subject-specific expertise, transparency regarding potential conflicts of interest, and substantive contribution to the literature, particularly where the scholarly record in the specific field under discussion is limited. Ultimately, scientific critique should be judged by whether it materially changes the evidentiary interpretation. In this case, the points raised largely revisit issues already addressed and do not alter our principal conclusions.

Disclosure

The authors declare no conflicts of interest in this communication.