Abstract
Introduction
Cancer cachexia affects approximately 50% to 80% of patients with advanced cancer and contributes to an estimated 20% to 30% of cancer-related deaths. Cachexia develops when catabolic muscle-protein degradation exceeds anabolic protein synthesis, resulting in progressive skeletal muscle loss. Angiotensin II (Ang II) is elevated in patients with cancer and has been implicated in muscle wasting associated with cardiac cachexia. Ang II-driven oxidative and inflammatory signaling may activate nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3), increase the muscle-specific ubiquitin ligases MuRF1 and atrogin-1, and suppress anabolic IGF-1/Akt/mTOR signaling. We evaluated the association between angiotensin receptor blocker use and coded cachexia in patients with cancer and tested telmisartan, tempol, and YK-4-250, a telmisartan-tempol conjugate designed to simultaneously target AT1 receptor signaling, reactive oxygen species, and PPARγ activity as a potential triple-action strategy against cachexia-associated muscle wasting.
Methods
A retrospective cohort study was conducted using the TriNetX Global Collaborative Network, including approximately 180 healthcare organizations. Adults with neoplasms receiving angiotensin receptor blockers were compared with patients receiving calcium channel blockers as an active comparator. Cohorts were balanced using 1:1 propensity-score matching, and coded cachexia was evaluated over 5 years. A secondary head-to-head analysis compared telmisartan with losartan. For the preliminary in vitro study, differentiated C2C12 myotubes were assigned to untreated control, Ang II-only, or intervention groups. All Ang II-exposed wells, including intervention wells, received Ang II at 500 nM. Intervention wells additionally received pretreatment with YK-4-250 at 1 or 10 µM, telmisartan at 1 µM, or Tempol at 100 µM. Myotube diameter was measured from brightfield images, with 36 myotubes evaluated per condition in a single experimental well.
Results
After matching, 1,140,036 angiotensin receptor blocker users and 1,136,253 calcium channel blocker users were analyzed. At 5 years, coded cachexia occurred in 0.6% and 1.1% of patients, respectively (OR, 0.533; 95% CI, 0.517 to 0.549; log-rank P 0.001). Telmisartan was associated with 28.5% lower odds of coded cachexia than losartan (OR, 0.715; 95% CI, 0.527 to 0.970; log-rank P = 0.037). In C2C12 myotubes, Ang II reduced mean diameter from 27.28 µm in untreated cells to 18.33 µm in Ang II-only cells. Mean diameters were 25.31 and 26.13 µm after YK-4-250 at 1 and 10 µM, respectively, compared with 26.99 µm after telmisartan and 26.85 µm after tempol. Telmisartan and YK-4-250 restored Ang II-reduced myotube diameter toward untreated values, with YK-4-250 producing comparable rescue at lower tested concentrations than tempol.
Conclusion
Angiotensin receptor blocker use was associated with 46.7% lower odds of coded cachexia, while telmisartan was associated with 28.5% lower odds than losartan. Telmisartan and YK-4-250 attenuated Ang II-induced myotube narrowing, and YK-4-250 demonstrated a promising efficacy-to-dose profile relative to Tempol. These findings support a potential triple-target strategy combining AT1 receptor blockade, PPARγ modulation, and ROS scavenging. Such complementary mechanisms may reduce muscle catabolism and could contribute to improved clinical outcomes, including survival. Replicated studies will evaluate MuRF1, atrogin-1, NF-κB, STAT3, IGF-1/Akt/mTOR signaling, and oxidative-stress endpoints.