The proposed clinical trial shall address whether the combination of pioglitazone and metformin (ACTOplus met XR) has potential utility in the prevention of oral and oropharyngeal cancer. It is a phase IIb window of opportunity trial of the marketed combination of metformin XR 1,000 mg and pioglitazone 30 mg per day given for 14-21 days in patients with stage I-IV oral cavity or oropharyngeal cancer prior to definitive therapy with surgery, radiation, or chemoradiation. The goal is to determine the effects of the drug combination on a variety of tissue biomarkers, both in the tumor and in the surrounding visually normal epithelium. The trial shall be performed at the University of Minnesota, University of Rochester, Johns Hopkins University, and University of Wisconsin under the oversight of the University of Wisconsin.