Comparison of cardiovascular and metabolic profiles in lorlatinib vs. other ALK inhibitors in global network

Background/Introduction Lorlatinib has been reported to be associated with hyperlipidaemia, and emerging evidence suggests a potential link between lorlatinib exposure and cancer therapy–related cardiovascular disease. As hyperlipidaemia represents a major modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD), clarification of its cardiovascular safety profile is clinically important. Purpose This study aimed to evaluate whether lorlatinib use is associated with an increased risk of major adverse cardiovascular events (MACE) and ASCVD compared with other anaplastic lymphoma kinase (ALK) inhibitors. Methods A retrospective cohort study was conducted using the TriNetX global research network. Two cohorts were identified: patients receiving lorlatinib and those treated with other ALK inhibitors. Propensity score matching was performed to minimise baseline differences and emulate treatment randomisation. Patients were followed for at least 1,400 days after treatment initiation. Kaplan–Meier survival analysis and Cox proportional hazards regression were used to estimate outcome risks. Results Lorlatinib use was associated with a significantly increased risk of hyperlipidaemia (HR 3.38, 95% CI 2.35–4.86), with a markedly earlier median onset compared with the comparator group (85 days vs 787 days). Despite this, no significant differences were observed in MACE (HR 0.994, 95% CI 0.605–1.634) or secondary outcomes, including stroke and myocardial infarction (MI). Lorlatinib exposure was associated with a significant increase in low-density lipoprotein (LDL) levels, whereas high-density lipoprotein (HDL) levels remained unchanged. Notably, approximately 96% of patients received lipid-lowering therapy during follow-up. No increase in mortality risk was identified. Discussion The absence of an increased ASCVD risk may be attributable to several factors. First, proactive lipid monitoring and widespread use of lipid-lowering therapy among lorlatinib recipients may have mitigated cardiovascular risk. Second, the follow-up duration may have been insufficient to capture long-term ASCVD outcomes. Furthermore, the TriNetX database provides limited lipid-related parameters (total cholesterol, LDL, HDL, and triglycerides), and potential effects of lorlatinib on other cardiometabolic pathways could not be fully evaluated. Conclusion(s) Longer-term studies incorporating comprehensive cardiovascular risk assessment are warranted to further clarify the cardiovascular safety of lorlatinib. Although no significant increase in MACE, mortality or ASCVD events was observed, routine cardiovascular monitoring and lipid management remain essential in patients receiving lorlatinib.HyperlipidemiaMACE