Effects of Metformin in a Non-Diabetic Patient Population

Sponsor

Brian Zuckerbraun (Other)

Overall Status

Completed

CT.gov ID

NCT03772964

Collaborator

(none)

Enrollment

Location

Arms

14.3

Actual Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Inflammatory Response	Drug: MetFORMIN Hydrochloride ER	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

32 participants

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.Subjects will act as their own controls: data will be collect on each subject at baseline, throughout exposure and following, exposure to metformin.

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Jan 22, 2019

Actual Primary Completion Date :

Mar 31, 2020

Actual Study Completion Date :

Mar 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 500mg exposure Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.	Drug: MetFORMIN Hydrochloride ER 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. Other Names: Metformin ER
Experimental: 1000mg exposure Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.	Drug: MetFORMIN Hydrochloride ER 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. Other Names: Metformin ER
Experimental: 1500mg exposure Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.	Drug: MetFORMIN Hydrochloride ER 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. Other Names: Metformin ER

Arm

Intervention/Treatment

Experimental: 500mg exposure

Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.

Drug: MetFORMIN Hydrochloride ER

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.

Other Names:

Metformin ER

Experimental: 1000mg exposure

Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.

Drug: MetFORMIN Hydrochloride ER

Other Names:

Metformin ER

Experimental: 1500mg exposure

Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.

Drug: MetFORMIN Hydrochloride ER

Other Names:

Metformin ER

Outcome Measures

Primary Outcome Measures

Ex vivo cytokine response of peripheral blood mononucleocytes (PBMC) to inflammatory stimuli compared to baseline, throughout exposure, and following exposure to metformin. [Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)]
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.

Secondary Outcome Measures

Quantify the bacterial population profile of the microbiome via stool samples. [Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)]
Changes in the bacterial communities using 16S rRNA sequencing in relationship to metformin dosing overtime.
Measure the rate of clotting of peripheral blood with whole blood aggregometry in response to collagen. [Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)]
Measure the rate of thrombosis of peripheral blood. [Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)]
The endpoints for isolated platelets include platelet activation as measured by FACS for CD62p.
Changes from baseline in Short Physical Performance Battery (SPPB) during and following exposure to metformin. [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. [Day 0 (baseline), 90, and 120 (30 days post metformin exposure)]
Mitochondrial respiration in both PBMCs and platelets. [Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)]
Oxidative phosphorylation, respiration, and complex activity will be tested using an Oroboros respirometer.
Mitochondrial content in both PBMCs and platelets. [Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)]
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.
Measure biogenesis of PBMCs. [Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)]
Biogenesis will be determined by measuring RNA for PGC1a, NRF-1, and Tfam.

Eligibility Criteria

Criteria

Ages Eligible for Study:

55 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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