Metformin for the Prevention of Oral Cancer in Patients With Oral Leukoplakia or Erythroplakia

Inclusion Criteria:

* Participants with oral leukoplakia or erythroplakia with mild, moderate, or severe histologic dysplasia or hyperplasia at the high risk sites (e.g., floor of mouth, tongue). Lesions arising from the radiation field are excluded as study lesions.
* Measurable disease - minimum lesion size of 8x3 mm before initial biopsy
* Age \>= 21 years. Adults 18-20 are not included as Canadian law prohibits purchase of cigarettes under the age of 21; investigators wish to keep criteria consistent among all trial sites. Also, smokers aged \< 20 years would most likely not have oral leukoplakia
* Current and former smokers (\>= 5 packs in the lifetime)
* Karnofsky performance scale \>= 70%
* Leukocytes \>= 3,000/microliter
* Absolute neutrophil count \>= 1,000/microliter
* Platelets \>= 100,000/microliter
* Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 1.5 x institutional ULN
* Estimation glomerular filtration rate (eGFR) \> 45 mL/min (eGFR calculated using the equation Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] creatinine)
* Willing to use adequate contraception (barrier method, abstinence, subject or partner has had a vasectomy or partner is using effective birth control or is postmenopausal) for the duration of study participation because the effects of metformin on the developing human fetus are unknown even though it is not teratogenic in rats and rabbits at 2-6 times the maximum recommended human daily dose. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and 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.
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
* Ability to take oral medication
* Ability to understand and the willingness to sign a written informed consent document in English or Spanish

Exclusion Criteria:

* Patients with diabetes who are being treated with insulin or an anti-diabetic medication
* History of diabetic ketoacidosis
* Participants may not be receiving any other investigational agents within past 3 months at screening
* History of allergic reactions attributed to compounds of similar chemical composition to metformin or prior use of metformin within the last year
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, human immunodeficiency virus (HIV) positive, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Oral carcinoma in situ from the baseline biopsy
* History of chronic alcohol use or abuse defined as any one of the following: a) average consumption of 3 or more alcohol containing beverages daily in the past 12 months; b) consumption of 7 or more alcoholic beverages within a 24 hour (hr) period in the past 12 months
* Hemoglobin A1c (HbA1c) \> 8%
* Pregnancy or nursing women. Pregnant women are excluded from this study because the effects of metformin on the developing human fetus are unknown even though it is not teratogenic in rats and rabbits at 2-6 times the maximum recommended human daily dose. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with metformin, breastfeeding should be discontinued
* Acute or chronic liver disease, evidence of hepatitis (infectious or autoimmune), cirrhosis or portal hypertension
* History of renal disease
* Have received hormone therapy, chemotherapy, immunotherapy and/or radiation for any malignancy (excluding non-melanoma skin cancer and cancers confined to organs with removal as only treatment) within the past 18 months. History of prior curatively treated cancer, including oral cancer, is allowed as long as all primary and adjuvant treatment is completed \>= 18 months prior to enrollment. Ongoing adjuvant hormonal treatment (e.g., for breast cancer) is allowed.
* Current use of carbonic anhydrase inhibitors (e.g. topiramate, zonisamide, acetazolamide, or dichlorphenamide) or ranolazine