The Neuroendocrine Effects of Pioglitazone in Patients With Cancer and Cachexia

• Pioglitazone 45 mg (Drug): The dose of pioglitazone will not exceed 45 mg once daily. Pioglitazone dose will titrate progressively over the first three weeks.
• Placebo (Drug): Placebo will have the same appearance as the active drug.

Primary outcomes

• Change in skeletal muscle insulin sensitivity [Baseline, Week 12]: Quantified using hyperinsulinemic-euglycemic clamp

Sex: All, ages: 18 Years to any

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