Pioglitazone for Oral Premalignant Lesions

Inclusion Criteria:

* STAGE I:
* Males or females with a suspected or histologically confirmed oral premalignant lesion(s) (up to three target lesions may be followed for the purpose of the study) that has a length (longest diameter) of 8 mm or greater and width (diameter perpendicular to greatest length) of 3 mm or greater in size

  * If a participant has had a biopsy of the target oral premalignant lesions (OPL) lesion(s) within 6 weeks prior to the screening visit and archival tissue is available and the participant agrees to have archival tissue used for histologic confirmation and biomarker analysis, then NO additional biopsies (of the OPL) need to be performed at the screening visit; the pre-screening biopsy must undergo centralized pathology review before the second stage of registration can be performed; if archival tissue is not available, a waiting period of 6 weeks from the time of the last biopsy must be observed before re-biopsy for study purposes
  * If a participant has not had a biopsy of the suspected OPL at the time of the screening visit, then a biopsy of the lesion must be performed during the screening visit; the screening biopsy must undergo centralized pathology review before the second stage of registration can be performed
* The participant's life expectancy is \> 6 months
* The participant has discontinued any other oral cancer chemopreventive therapy at least 12 weeks prior to the baseline visit and all toxicities have been fully resolved; daily aspirin is permitted
* The participant is willing and able to fully participate for the duration of the study
* Women must not be pregnant or lactating; women of child-bearing potential (women are considered not of childbearing potential if they are at least two years postmenopausal and/or surgically sterile) must have used adequate contraception (abstinence; barrier methods such as IUD, diaphragm with spermicidal gel, condom, or others; and hormonal methods such as birth control pills or others) since her last menses prior to study entry; women of child-bearing potential and men must agree to use adequate contraception for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
* Ability to understand and the willingness to sign a written informed consent document
* STAGE II:
* The participant has one or more target lesions histologically confirmed by a biopsy obtained no more than 9 weeks prior to randomization, that is either:

  * An EARLY premalignant lesion defined to be at high risk:

    * Mild dysplasia of any site
    * Hyperplastic leukoplakia of a high-risk site

      * Dorsal, lateral or ventral tongue
      * Floor of mouth
  * An ADVANCED premalignant lesion defined as the presence of at least one of the following:

    * Moderate dysplasia
    * Severe dysplasia (excluding carcinoma in situ)
    * Erythroplakia (due to the high risk for progression associated with erythroplakia, erythroplakia of any histology will be defined as an ADVANCED oral premalignant lesion)
* Hemoglobin levels equal to or above the lower limit of normal
* White blood cells \>= 3,000/uL
* Platelets \>= 125,000/uL
* Total bilirubin =\< 1.5 \* upper limit of normal (ULN)
* BUN and serum creatinine =\< 1.5 \* ULN
* Glucose, serum \< 200 mg/dL
* The participant's Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1
* If the participant is female and of childbearing potential and not lactating she has a documented negative serum pregnancy test within 14 days prior to randomization
* The participant has a baseline EKG that does not show signs of acute cardiac ischemia or cardiac dysrhythmia (except for 1st degree AV block or chronic atrial fibrillation); EKG can be an earlier report within 12 weeks prior to registration
* Participants using the drugs listed below may not be randomized unless they are willing to stop the medications (and possibly change to alternative non-excluded medications to treat the same conditions) no less than 3 days prior to starting pioglitazone or placebo on this study; the use of the following drugs or drug classes is prohibited during pioglitazone/placebo treatment: participants taking inhibitors of CYP2C8 (gemfibrozil, ketoconazole, quercetin, trimethoprim), enzyme inducers of CYP2C8 (cortisol, dexamethasone, phenobarbital, rifampin), and CYP3A4 substrate

Exclusion Criteria:

* The participant has active cancer or carcinoma in situ of the head and neck
* The participant has a contraindication to biopsy
* The participant has presence of congestive heart failure (New York Heart Association (NYHA) class II-IV), uncontrolled hypertension (systolic \> 150 or diastolic \> 100), or unstable angina
* The participant has any history of congestive heart failure or history of myocardial infarction within the past 6 months
* The participant exhibits clinical evidence of active liver disease or history of chronic liver disease
* The participant has \> Common Terminology Criteria for Adverse Events (CTCAE) grade 1 edema
* The participant has known diabetes and is on insulin or oral agents; the participant is receiving medical therapy for dysregulated blood sugar
* The participant who currently receives an enzyme inhibitor of CYP2C8 (gemfibrozil, ketoconazole, quercetin, trimethoprim), or enzyme inducer of CYP2C8 (cortisol, dexamethasone, phenobarbital, rifampin), or CYP3A4 substrate will not be eligible for randomization after assessing eligibility in stage two unless he/she will not be eligible for randomization after assessing eligibility in stage two unless he/she is willing to stop these drugs and possibly replace them with alternative therapies
* The participant currently receives pregabalin or thioridazine
* The participant has experienced jaundice with Rezulin (troglitazone)
* The participant has a history of colorectal cancer, familial adenomatous polyposis (FAP) or hereditary non-polyposis colorectal cancer (HNPCC)
* The participant has a history of bladder cancer or in situ bladder cancer
* The participant has a history of invasive cancer within the past 18 months (excluding non-melanoma skin cancer and in situ cervical cancer); participants (excluding those with a history of colorectal cancer, FAP, HNPCC, bladder cancer or in situ bladder cancer) who received curative treatment and have shown no evidence of recurrence for 18 months will be eligible