Effects of Metformin in a Non-Diabetic Patient Population
Condition: Inflammatory Response
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Metformin has a well-established safety profile and it has become clear that metformin has
      additional salutary effects, including anti-inflammatory, anti-aging, and anti-thrombotic
      properties. In this study, subjects will provide both venous blood samples and stool samples
      in addition to completing cognitive and physiologic testing at baseline, throughout a 90 day
      exposure to metformin, and 30 days following exposure to metformin in order to evaluate their
      immune, microbiome, cellular respiration, thrombotic, and inflammatory responses.
    

Detailed description: 
      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.
    

Intervention name(s): MetFORMIN Hydrochloride ER; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Subjects will be exposed to 500mg, 1000mg, or 1500mg of daily ER Metformin, by mouth, for up to 90 days. Subjects will have their venous blood sampled and baseline, throughout the trial, and following completion of their metformin exposure.; Subjects will be exposed to placebo, by mouth, for up to 90 days. Subjects will have their venous blood sampled and baseline, throughout the trial, and following completion of their metformin exposure.
Other intervention name(s): Metformin ER
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will act as their own controls: data will be collect on each subject at baseline, throughout exposure and following, exposure to metformin.
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: prefrail; non-diabetic; metformin; thrombosis; microbiome; cellular respiration; short physical performance batter