The goal of this clinical trial is evaluate the effect of pioglitazone compared with placebo on skeletal muscle insulin sensitivity in subjects with cancer and cachexia.

Inclusion Criteria:

• Age ≥18 years
• Documented histologic or cytologic diagnosis of non-small-cell lung cancer or gastrointestinal cancer that is locally advanced and inoperable or metastatic (e.g., spread to distant organs)
• Cachexia defined by Fearon criteria
• Insulin resistance syndrome, defined with the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
• Ability to provide written informed consent, willing and able to comply with all scheduled visits, treatment plans, laboratory tests, and other study procedures
• Provide written approval by a qualified healthcare professional
• Allow the collection and storage of biospecimens and data for future use

Exclusion Criteria:

• Prior diagnosis of type 2 diabetes
• Prior or current thiazolidinedione (TZD) therapy
• Known hypersensitivity to TZD
• New York Heart Association (NYHA) class I-IV heart failure
• History of or actively treated bladder cancer
• Current use of CYP2C inhibitor (e.g., gemfibrozil) or CYP2C inducer (e.g., rifampin)
• Inadequate hepatic function
• Currently pregnant, breastfeeding, or planning to become pregnant within the next 16 weeks
• Contraindications to magnetic resonance imaging (e.g., implanted cardiac device, cochlear implant)
• Any other condition that, in the investigator's opinion, would preclude participation or successful compliance with the protocol