Treatment with trimetazidine dihydrochloride and lung cancer survival: Implications on metabolic re-programming

Background: Metabolic re-wiring with preferential fatty acid oxidation has been observed in lung cancer cells. Whether the use of trimetazidine, an anti-anginal agent that inhibits fatty acid oxidation, alters clinical outcomes in ischemic heart disease (IHD) patients with lung cancers is unknown. Methods: We carried out this territory-wide, retrospective cohort study of 279,894 IHD patients prescribed with trimetazidine or long-acting oral nitrates in Hong Kong (population coverage of 7.5 millions, January 1999 − December 2020). A total of 6561 patients with pre-existing or de novo lung cancers were identified. Clinical outcomes of all-cause mortality were longitudinally compared between lung cancer patients who received trimetazidine (n = 547) versus non-users (control, n = 6014). Results: Over 902.9 ± 1410.6 days, lower incidence of deaths occurred in the trimetazidine group (79.0 %, n = 432/547) compared to controls (90.5 %, n = 5442/6014, P < 0.001). Kaplan-Meier analyses showed that trimetazidine use was associated with significantly higher survival from all-cause mortality in IHD patients (trimetazidine: mean survival = 1840.6 [95 %CI 1596.0–2085.3], versus control: 1056.7 [95 %CI 1011.3–1102.0] days, Log Rank = 69.4, P < 0.001). Cox regression showed that trimetazidine use was significantly associated with reduced risk of all-cause mortality in crude (HR = 0.60 [95 %CI: 0.53 to 0.68], P < 0.001) and multivariable models (HR = 0.65 [95 % CI: 0.57 to 0.74], P < 0.001). Pre-specified analyses amongst patients with pre-existing lung cancers yielded similar findings (HR = 0.49 [95 %CI: 0.35 to 0.67], P < 0.001). Survival benefits related to trimetazidine use was predominantly restricted to non-cardiovascular mortality (P < 0.001). Conclusions: Trimetazidine use is associated with higher overall survival in IHD patients with lung cancers, particularly from non-cardiovascular death. These findings need to be confirmed by randomized controlled trials.