ACTOplus Met XR in Treating Patients With Stage I-IV Oral Cavity or Oropharynx Cancer Undergoing Definitive Treatment

Inclusion Criteria:

* Participant has a newly diagnosed, histologically confirmed, stage I-IV squamous cell carcinoma or squamous cell carcinoma in situ of the oral cavity or oropharynx and will be undergoing definitive surgical, radiotherapy, or chemoradiation treatment; patients who are NOT candidates for localized treatment (surgery, radiation or chemoradiation) with curative intent (i.e.patients with distant metastasis or contra-indication to localized treatment) are not eligible OR
* Participant has a lesion in the oral cavity or oropharynx that is not yet biopsied but is highly suspicious for cancer; (randomization will be placed on hold until the presence of cancer is histologically confirmed, and a treatment plan is established; if the presence of cancer is not confirmed, the participant will be considered a screen failure)
* The participant's primary tumor is accessible for the collection of 4 mm samples of tumor and adjacent visually normal appearing tissue for biomarker analysis and the participant is willing to have these samples collected at baseline and at the end of study visit. (The protocol requires the collection of fresh tissue for biomarker analysis)

  * Patients who have not yet had a diagnostic biopsy:

    * The tissue samples for biomarker analysis may be collected in conjunction with the patient's standard of care diagnostic biopsy but not until after the patient has signed informed consent and it has been determined that they meet all of the eligibility criteria for this protocol with the exception of normal organ and marrow function as defined by the clinical laboratory test results listed for that criterion. In this situation, because the patient would be having a biopsy regardless of whether or not they were participating in this study, it is not required to obtain these results prior to conducting the biopsy. It is however, required to confirm normal organ and marrow function prior to randomization.
    * Patients who are scheduled for a direct operative laryngoscopy with biopsy (DL biopsy) for diagnostic purposes may be candidates for this study provided the following criteria are met:

      * The lesion to be biopsied is within the anatomic confines of the oropharynx (i.e. above the epiglottis).
      * Tissue samples for biomarker analysis of the required 4 mm size are able to be obtained from both the lesion and an area of visually normal appearing tissue adjacent to but 1 cm distant from the lesion.

In this situation, randomization will be placed on hold until the following criteria are met:

* Normal organ and marrow function is confirmed.
* There is histologic confirmation of squamous cell carcinoma.
* It has been determined that surgical excision will be the first line standard of care treatment and the end of study tissue samples will be obtained in conjunction with that surgery.

Because these patient's lesions are not accessible to end of study tissue sample collection in the outpatient clinic setting, the only way to obtain those samples is in conjunction with standard of care surgical excision of the lesion. If the first line of treatment will be non-surgical, the patient will be considered a screen failure. Under no circumstances will DL biopsy be used for the sole purpose of collecting tissue samples for biomarker analysis.

* Patients who have already had a diagnostic biopsy:

  * The baseline tissue samples for biomarker analysis will be collected in the outpatient clinic setting as a "for research purposes only" procedure. The samples may not be collected until it has been determined that the participant meets all eligibility criteria for this protocol.
* End of study tissue sample collection:

  * If surgical excision will be the patient's first line treatment, the end of study tissue samples for biomarker analysis will be collected in conjunction with that surgery. If, for any reason, the patient's surgery is delayed beyond Day 26, the end of study tissue samples may be collected in the outpatient clinic setting.
  * If the patient's first line of treatment will not be surgical excision, the end of study tissue samples for biomarker analysis will be collected in the outpatient clinic setting prior to initiation of the non-surgical treatment.

    * Participant is able to complete a minimum of 10 days of study agent dosing prior to initiation of definitive treatment for their cancer
    * Participant is scheduled for an end of study biopsy within 22 days of starting study agent and within 52 days of their study screening visit; (if the participant is scheduled for surgical excision of the tumor and the surgery is delayed for any reason after the participant has started taking the study agent, study agent dosing may be extended up to a maximum of 25 days without compromising the evaluability of the end of study biomarkers)
    * Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1
    * Life expectancy is \> 6 months
    * Body mass index (BMI) is \>= 18.5
    * Hemoglobin \>= 10 g/dl
    * White blood cells \>= 3,000/microliter
    * Platelets \>= 100,000/microliter
    * Total bilirubin =\< 1.2 x institutional upper limit of normal
* With the exception of candidates with a diagnosis of Gilbert's disease in which case the total bilirubin may extend up to 1.5 x institutional upper limit of normal

  * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 1.2 x institutional upper limit of normal
  * Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 1.2 x institutional upper limit of normal
  * Glucose, serum \< 200 mg/dL
  * Estimated glomerular filtration rate (eGFR) \> 45 mL/min (if eGFR is not included on the clinical lab report, the chronic kidney disease epidemiology \[CKD-EPI\] creatinine calculator may be used)
  * Participant is able to swallow a tablet whole
  * Participant is willing and able to participate for the duration of the study
  * Participant of childbearing potential agrees to use adequate contraception (a hormonal method that has been in continual use for a minimum of 3 months prior to the study screening visit, a barrier method, or abstinence) for the duration of their study participation. (Therapy with pioglitazone may result in ovulation in some premenopausal anovulatory women. In addition, the effects of ACTOplus Met XR on the developing human fetus at the recommended therapeutic dose are unknown. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.)
* Note: Due to the risks associated with hormonal methods of birth control, participants should not start hormonal therapy for the purpose of meeting the eligibility criteria for this protocol.

  * Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Participant has received or will receive some form of treatment for their cancer prior to completing a minimum of 10 days of study agent dosing; (a biopsy is not considered a form of treatment)
* Participant has a concurrent diagnosis of type I or type II diabetes that is being treated with insulin or an oral antidiabetic agent; (participants whose type II diabetes is controlled with diet and/or exercise alone are eligible provided they meet all other eligibility criteria)
* Participant has taken any of the following medications within the past 3 months:

  * A thiazolidinedione (e.g. pioglitazone \[Actos\] or rosiglitazone \[Avandia\]),
  * A biguanide (e.g. metformin \[Glucophage, Glumetza, Fortamet, Riomet\] or proguanil \[Paludrine\])
  * A combination drug containing one of the agents above (brand names include: ACTOplus Met, Avandamet, Avandaryl, Duetact, Glucovance, Invokamet, Janumet, Jentadueto, Komboglyze, Metaglip, PrandiMet, Synjardy, Xigudo)
* Participant is currently taking a strong CYP2C8 inhibitor (e.g. gemfibrozil \[Lopid\])
* Participant is currently taking an enzyme inducer of CYP2C8 (carbamazepine \[Carbatrol, Epitol, Equetro, Tegretol\] cortisol \[Hydrocortisone\]; dexamethasone \[Decadron\]; phenobarbital \[Luminal Sodium\]; phenytoin \[Dilantin, Phenytek, Novaplus Phenytoin Sodium\]; primidone \[Mysoline\]; rifampin \[Rifadin, Rimactane\]; rifapentine \[Priftin\]; secobarbital \[Seconal\])
* Participant is currently taking topiramate (Topamax) commonly used in epilepsy or to prevent migraines or other carbonic anhydrase inhibitors (e.g. zonisamide \[Zonegran\]; acetazolamide \[Diamox Sequels\]; or dichlorphenamide \[Keveyis, Daranide\])
* Participant is currently taking a cationic drug or multidrug and toxin extrusion \[MATE\] inhibitor (e.g. amiloride \[Midamor\]; cimetidine \[Tagamet\]; digoxin \[Lanoxin, Digitek, Digox\]; dolutegravir \[Tivicay\]; morphine \[Roxanol, Duramorph, Kadian, MS Contin\]; procainamide \[Pronestyl, Procanbid\]; quinidine \[Quinidex, Cardioquin, Quin-G, Quinora\]; quinine \[Qualaquin, Quinamm, Quiphile\]; ranitidine \[Zantac, Deprizine, Gabitidine\]; ranolazine \[Ranexa\]; triamterene \[Dyrenium)\] trimethoprim \[Proloprim, Trimpex, Primsol\]; vancomycin \[Vancocin, Vancoled\]; or vandetanib \[Calpresa\])
* Participants is taking another investigational agent
* Participant has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ACTOplus Met XR
* Participant has a contraindication to biopsy
* Participants with a history of congestive heart failure or New York Heart Association (NYHA) class III or IV functional status are excluded
* Participant has a history of liver disease
* Participant has \> Common Terminology Criteria for Adverse Events (CTCAE) grade 1 limb edema (5 - 10% inter-limb discrepancy in volume or circumference at point of greatest visible difference; swelling or obscuration of anatomic architecture on close inspection)
* Participant has a history of hypoglycemia
* Participant is an active alcoholic or consumes excessive amounts of alcohol per the following definitions:

  * Female: More than 3 drinks on any day or a total of more than seven drinks in a week
  * Male: More than 4 drinks on any day or a total of more than 14 drinks in a week

    * 1 drink =

      * Beer: 12 oz. (1 standard size can or bottle)
      * Wine: 5 oz. (one standard glass)
      * Spirits: 6 oz. (one mixed drink or one 1.5 fluid oz. shot)
* Participant has a history of macular edema
* Participant has a history of bladder cancer (including in situ bladder cancer)
* Participant has a history of invasive cancer (other than non-melanoma skin cancer or cervical cancer in situ) active within 18 months prior to the baseline study visit; (participants who have a history of cancer that was curatively treated without evidence of recurrence in the 18 months prior to the baseline study visit are considered eligible)
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Participant is pregnant, breast feeding or planning to become pregnant; (all participants of childbearing potential regardless of method of birth control must have a negative pregnancy test at baseline; a woman is considered not to be of childbearing potential if she has had a hysterectomy, bilateral oophorectomy, or if she is \> 55 years of age with \>= 2 years of amenorrhea)

  * Breastfeeding should be discontinued if the mother is treated with ACTOplus met XR