Effects of Metformin in a Non-Diabetic Patient Population

Metformin is considered first-line therapy for patients with type two diabetes with
hyperglycemia that cannot be controlled with lifestyle alone. Unlike other oral medications,
metformin is favored for its insulin-sensitizing effects resulting in improved glycemic
control, weight loss, and overall improvement of metabolic syndrome. Over the past fifteen
years, metformin has received significant attention for its other potential therapeutic uses.
Metformin has been found to decrease the rate of age-related illness progression improving
longevity, especially in the setting of cancer. Recent clinical trials across multiple
disease states have shown metformin to decrease all-cause mortality in diabetic and
non-diabetic patients. Additionally, in both animal models and human trails, metformin has
been shown to decrease the risk of arterial and venous thrombosis without affecting bleeding
time through its interaction with platelet mitochondria. Although the mechanisms by which
metformin effects longevity is an active area of both basic science and clinical research, it
clearly has anti-inflammatory properties which are both independent and dependent of glycemic
control. Recently, surgical outcomes have focused on optimizing older, deconditioned patients
prior to the operation with varying protocols referred to as prehabilitation. These programs
work to improve the body's response to the surgical stress resulting in improved wound
healing, decreased postoperative complications, and decreased hospital length of stay. The
affect of metformin, like increasing physical activity, has widespread affects on physiology.
The investigators, therefore, hypothesize that metformin administration to non-diabetic
adults will improve clinical outcomes to physiologic stress by improving underlying immune
and inflammatory responses, that can be deleterious.

Subjects will have venous samples collected to better understand the cellular response to
inflammation, thrombosis, and cellular respiration at baseline, at 4 time points throughout
the 90 day exposure to metformin, and 30 days following the completion of exposure to
metformin. At the same time points, subjects will have stool samples collected in order to
assess changes in their microbiome. Finally, subjects will undergo cognitive testing through
the NIH toolbox as well as physiologic testing including (six-minute walk test, grip strength
as measured by a dynamometer, and a short physical performance battery) at baseline, after 90
days of exposure, and again 30 days after the completion of exposure.

Inclusion Criteria:

1. Age ≥55 and ≤85 years of age

2. Non-diabetic

3. Adjusted risk analysis index (RAI) 20-42

4. Estimated glomerular filtration rate >60

5. No evidence of hepatic dysfunction on comprehensive metabolic panel

6. No clinical evidence of cardiac failure

7. Existing University of Pittsburgh Medical Center Patients

Exclusion Criteria:

1. Hypersensitivity to metformin or any component of the formulation

2. Acute or chronic metabolic acidosis with or without coma

3. Pregnant or breastfeeding females

4. Evidence or history of hepatic, renal, or cardiopulmonary failure

5. Excessive acute or chronic ethanol use

6. Planned or known hospital admission, exposure to anesthesia, or surgical intervention
30 days prior to study or scheduled 30 days after the trial initiation

7. Laboratory analysis showing HbgA1c >6.1 or eGFR <59 on baseline labs