Effects of Metformin in a Non-Diabetic Patient Population

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Pilot Study: Metformin as an Inflammatory Modulating Therapy in Older Adults Without Diabetes

Conditions
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Inflammatory Response

Intervention / Treatment
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* Drug: MetFORMIN Hydrochloride ER
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥55 and ≤85 years of age Non-diabetic Adjusted risk analysis index (RAI) 20-42 Estimated glomerular filtration rate >45 No evidence of hepatic dysfunction on comprehensive metabolic panel No clinical evidence of cardiac failure Existing University of Pittsburgh Medical Center Patients Exclusion Criteria: Hypersensitivity to metformin or any component of the formulation Acute or chronic metabolic acidosis with or without coma Pregnant or breastfeeding females Evidence or history of hepatic, renal, or cardiopulmonary failure Excessive acute or chronic ethanol use Planned or known hospital admission, exposure to anesthesia, or surgical intervention 30 days prior to study or scheduled 30 days after the trial initiation Laboratory analysis showing HbgA1c >6.1 or eGFR <44 on baseline labs

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 500mg exposure<br>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. | Drug: MetFORMIN Hydrochloride ER<br>* 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.<br>* Other names: Metformin ER;|
| Experimental: 1000mg exposure<br>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days. | Drug: MetFORMIN Hydrochloride ER<br>* 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.<br>* Other names: Metformin ER;|
| Experimental: 1500mg exposure<br>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. | Drug: MetFORMIN Hydrochloride ER<br>* 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.<br>* Other names: Metformin ER;|
| Placebo Comparator: Placebo<br>Subjects will be exposed to placebo for up to 90 days. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ex Vivo Cytokine Response of Peripheral Blood Mononucleocytes (PBMC) to Inflammatory Stimuli Compared to Baseline, Throughout Exposure, and Following Exposure to Metformin. | Venous blood samples will be gathered throughout the study in order to quantify the changes in cytokine expression (FN-γ, IL-10, IL12p40, IL-12p70, IL-1α, IL1β, IL-2, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, TNF-α) following ex vivo PBMC exposure to endotoxin. | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantify the Bacterial Population Profile of the Microbiome Via Stool Samples. | Bacterial communities using 16S rRNA sequencing in relationship to metformin dosing over time. Species richness or diversity in the sample is measured by Choa1 metric. Chao1 is an estimate of how many species are present in an ecosystem. In general, having more species is considered to be healthier and these values typically range from 100-200 for fecal samples. The Chao1 index over numerous samples across time are explored to understand treatment effects. | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) | 
| Measure the Rate of Clotting of Peripheral Blood With Whole Blood Aggregometry in Response to Collagen. | Aggregometry area under the curve with the Y-axis being % aggregometry and the X-axis time in minutes. | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) | 
| Measure the Rate of Thrombosis of Peripheral Blood. | The endpoints for isolated platelets include platelet activation as measured by FACS for CD62p. | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) | 
| Changes From Baseline in Short Physical Performance Battery (SPPB) During and Following Exposure to Metformin. | The SPPB is a group of measures that combines the results of the gait speed, chair stand and balance tests. The minimum is zero (worse performance) and the maximum is 12 (best performance). | Day 0 (baseline), 90, and 120 (30 days post metformin exposure) | 
| Changes From Baseline in Grip Strength Via a Dynamometer During and Following Exposure to Metformin. | Grip strength over time. | Day 0 (baseline), 90, and 120 (30 days post metformin exposure) | 
| Mitochondrial Respiration in Both PBMCs and Platelets. | Oxidative phosphorylation, respiration, and complex activity will be tested using an Oroboros respirometer. | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) | 
| Mitochondrial Content in Both PBMCs and Platelets. | Mitochondrial content will be measured by staining for mitotracker, and mitochondrial DNA oxidation will be determined by co-localizing staining for 8-hydroxydeoxyguanosine (8-OHdG). Markers of autophagy will be determined by measuring LC-3 flux, p62, beclin-1, and ATG7 protein levels. | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) | 
| Measure Biogenesis of PBMCs. | Biogenesis will be determined by measuring RNA for PGC1a, NRF-1, and Tfam. | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prefrail, non-diabetic, metformin, thrombosis, microbiome, cellular respiration, short physical performance batter