Effects of Metformin in a Non-Diabetic Patient Population

• ClinicalTrials.gov Identifier: NCT03772964
• Recruitment Status: Completed
• First Posted: December 12, 2018
• Last Update Posted: May 6, 2020
• Sponsor: Brian Zuckerbraun
• Information provided by (Responsible Party): Brian Zuckerbraun, University of Pittsburgh

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 (Clinical Trial)
• 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.
• 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: January 22, 2019
• Actual Primary Completion Date: March 31, 2020
• Actual Study Completion Date: March 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 Name: 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 Name: 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 Name: Metformin ER

Outcome Measures

Primary Outcome Measures :

1. Ex vivo cytokine response of peripheral blood mononucleocytes (PBMC) to inflammatory stimuli compared to baseline, throughout exposure, and following exposure to metformin. [ Time Frame: 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 :

1. Quantify the bacterial population profile of the microbiome via stool samples. [ Time Frame: 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.
2. Measure the rate of clotting of peripheral blood with whole blood aggregometry in response to collagen. [ Time Frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) ]
3. Measure the rate of thrombosis of peripheral blood. [ Time Frame: 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.
4. Changes from baseline in Short Physical Performance Battery (SPPB) during and following exposure to metformin. [ Time Frame: Day 0 (baseline), 90, and 120 (30 days post metformin exposure) ]
5. Changes from baseline in grip strength via a dynamometer during and following exposure to metformin. [ Time Frame: Day 0 (baseline), 90, and 120 (30 days post metformin exposure) ]
6. Mitochondrial respiration in both PBMCs and platelets. [ Time Frame: 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.
7. Mitochondrial content in both PBMCs and platelets. [ Time Frame: 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.
8. Measure biogenesis of PBMCs. [ Time Frame: 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

• Ages Eligible for Study: 55 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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 >45
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 <44 on baseline labs

Contacts and Locations

Locations

United States, Pennsylvania

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States, 15209

Sponsors and Collaborators

Brian Zuckerbraun

Investigators

• Principal Investigator: Brian Zuckerbraun, MD; University of Pittsburgh

More Information

Publications:

Randriamboavonjy V, Mann WA, Elgheznawy A, Popp R, Rogowski P, Dornauf I, Dröse S, Fleming I. Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity. Thromb Haemost. 2015 Aug 31;114(3):569-78. doi: 10.1160/TH14-09-0797. Epub 2015 May 21.

Xin G, Wei Z, Ji C, Zheng H, Gu J, Ma L, Huang W, Morris-Natschke SL, Yeh JL, Zhang R, Qin C, Wen L, Xing Z, Cao Y, Xia Q, Lu Y, Li K, Niu H, Lee KH, Huang W. Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release. Sci Rep. 2016 Nov 2;6:36222. doi: 10.1038/srep36222.

Alazawi W, Pirmadjid N, Lahiri R, Bhattacharya S. Inflammatory and Immune Responses to Surgery and Their Clinical Impact. Ann Surg. 2016 Jul;264(1):73-80. doi: 10.1097/SLA.0000000000001691. Review.

Kato M, Suzuki H, Murakami M, Akama M, Matsukawa S, Hashimoto Y. Elevated plasma levels of interleukin-6, interleukin-8, and granulocyte colony-stimulating factor during and after major abdominal surgery. J Clin Anesth. 1997 Jun;9(4):293-8.

Lin E, Calvano SE, Lowry SF. Inflammatory cytokines and cell response in surgery. Surgery. 2000 Feb;127(2):117-26. Review.

Jansson K, Redler B, Truedsson L, Magnuson A, Matthiessen P, Andersson M, Norgren L. Intraperitoneal cytokine response after major surgery: higher postoperative intraperitoneal versus systemic cytokine levels suggest the gastrointestinal tract as the major source of the postoperative inflammatory reaction. Am J Surg. 2004 Mar;187(3):372-7.

Whelan SP, Zuckerbraun BS. Mitochondrial signaling: forwards, backwards, and in between. Oxid Med Cell Longev. 2013;2013:351613. doi: 10.1155/2013/351613. Epub 2013 May 29. Review.

Waltz P, Carchman EH, Young AC, Rao J, Rosengart MR, Kaczorowski D, Zuckerbraun BS. Lipopolysaccaride induces autophagic signaling in macrophages via a TLR4, heme oxygenase-1 dependent pathway. Autophagy. 2011 Mar;7(3):315-20. doi: 10.4161/auto.7.3.14044.

Keel M, Schregenberger N, Steckholzer U, Ungethüm U, Kenney J, Trentz O, Ertel W. Endotoxin tolerance after severe injury and its regulatory mechanisms. J Trauma. 1996 Sep;41(3):430-7; discussion 437-8.

Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, Modi A, Nagabhyru P, Sumner AE, Liang TJ, Hoofnagle JH. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009 Jan;29(2):172-82. doi: 10.1111/j.1365-2036.2008.03869.x. Epub 2008 Oct 9.

Hou X, Song J, Li XN, Zhang L, Wang X, Chen L, Shen YH. Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun. 2010 May 28;396(2):199-205. doi: 10.1016/j.bbrc.2010.04.017. Epub 2010 Apr 14.

Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5. doi: 10.1038/nature08221. Epub 2009 Jul 8.

Algire C, Moiseeva O, Deschênes-Simard X, Amrein L, Petruccelli L, Birman E, Viollet B, Ferbeyre G, Pollak MN. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila). 2012 Apr;5(4):536-43. doi: 10.1158/1940-6207.CAPR-11-0536. Epub 2012 Jan 18.

Smith DL Jr, Elam CF Jr, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB. Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci. 2010 May;65(5):468-74. doi: 10.1093/gerona/glq033. Epub 2010 Mar 19.

Pernicova I, Korbonits M. Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014 Mar;10(3):143-56. doi: 10.1038/nrendo.2013.256. Epub 2014 Jan 7. Review.

• Responsible Party: Brian Zuckerbraun, Chief, Division of General/Trauma and Acute Care Surgery, Professor of Surgery, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT03772964
• Other Study ID Numbers: PRO17100535
• First Posted: December 12, 2018
• Last Update Posted: May 6, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: There is no current plan to make individual participant data available to other researchers.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Brian Zuckerbraun, University of Pittsburgh:

prefrail; non-diabetic; metformin; thrombosis; microbiome; cellular respiration; short physical performance batter

Additional relevant MeSH terms:

Metformin; Hypoglycemic Agents; Physiological Effects of Drugs