Effect of Metformin on Frailty in 12 Subjects

(MATE) Metformin and Aging Trial in the Elderly: A Pilot and Feasibility Study

This study will test whether chronic metformin administration will improve longevity of the cell, improves its machinery by reducing aging-related biochemical parameters and thereby improving physical performance, as measured by short physical performance battery test.

Study Overview

• Status: Terminated
• Conditions: Inflammation; Frailty; Aging
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

Detailed Description

Heart disease is the number one cause of death in the United States and disproportionately affects older adults, underscoring the need to examine determinants of survivorship. Recognizing this gap, current guidelines lay emphasis to assess frailty, a key construct prevalent in elderly and known to impact their prognosis.Older persons are commonly frail, manifest hyperglycemia and their health span is truncated by illnesses during which physiological declines together with accumulation of additional deficits results in multimorbidity and functional dependence. High incidence of functional decline and stress hyperglycemia in patients with coronary artery disease (CAD) makes pharmacologic manipulation, an attractive strategy to improve frailty and reduce adverse cardiovascular outcomes. Metformin exerts its effect on health span as a calorie restriction-mimetic through inhibition of mitochondrial complex 1 and activation of activated protein kinase (AMP).This drug is safe and has been shown to prolong life in mammals. Metformin by reducing effects of cellular senescence and improving glycemic control may improve the functioning of older adults.

In CAD, cellular senescence and inflammation affect organ dysfunction through interference with tissue homeostasis and regeneration. The deleterious effect of senescence includes pro-inflammatory senescence-associated secretory phenotype (SASP). Normal biological function through alteration in cellular homeostasis and restoration of glycemic control may be achieved by metformin. The phenotypic manifestations of these changes are incompletely characterized as it is yet unknown whether cell-intrinsic regenerative mechanisms can be translated into clinical improvement in physical performance and whether it's chronic administration is safe in older adults. These major gaps in knowledge hinder utilization of metformin as an agent to promote cellular regeneration and to reduce the impact of cellular senescence.

Targeting frail individuals with high levels of inflammation and SASP factors would necessitate identification of predictors of improvement with metformin in tissue inflammation and function. A clinomics approach implementing simultaneous assessment of clinical impact coupled with serological profiling would provide enhanced understanding of the local and systemic impact mediated by metformin. Through correlation of molecular profiles with phenotypic expression changes, as proposed herein, investigators will enhance understanding of the regenerative impact of metformin and the basis for clinical improvement in the setting of senescence.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 60 years
• Stable CAD

• Prediabetes (one of the following criteria should be met)

  • Fasting plasma glucose: 100-126 mg/dL
  • HbA1C: 5.7-6.4
• Frailty (Short Physical Performance Battery: Score <9)
• Able to return for follow-up
• Written informed consent

Exclusion criteria:

• Pre-existing or new-onset diabetes
• Any active malignancy, hematological disorder, post organ transplant, immunocompromised
• Cancer requiring treatment in the past 3 years (other than non-melanoma skin cancer)
• Dementia [mini mental state examination (MMSE <20)]
• Disability (need for assistance in >2 of any six activities on Katz activities of daily living (ADL)46
• Prior stroke with disability
• Acute coronary syndrome <3months or participating in cardiac rehabilitation
• Severe Parkinson's
• Hepatic insufficiency and/or chronic liver disease (cirrhosis)
• Chronic kidney disease (GFR < 45 mL/min)
• Taking metformin for any indication
• Acute alcohol intoxication
• Known hypersensitivity to metformin hydrochloride
• Acute/chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; Metformin 500mg tablet by mouth, every 6 to 8 hours for one year	Drug: Metformin; Oral metformin (up to 2gm) will be given in divided doses
Active Comparator: Placebo; Placebo by mouth every 6 to 8 hours for one year	Drug: Placebo; Oral Placebo will be given in divided doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Frailty	Frailty will be measured by the Short Physical Performance Battery (SPPB). The short physical performance battery (SPPB) is a group of measures that combines the results of the gait speed, chair stand and balance tests. It has been used as a predictive tool for possible disability and can aid in the monitoring of function in older people. The scores range from 0 (worst performance) to 12 (best performance). Frailty is defined as a score of <9.	Baseline, 12 months
Change in Balance Score Standing With Feet Close Together	This measure is part of the SPPB. The scores range from 0 (not attempted), to 2 (held for 10 seconds). Ability to stand longer in this position indicates greater balance.	Baseline, 12 months
Change in Balance Score Standing in Semi Tandem Position	This measure is part of the SPPB. The semi tandem position is the heel of one foot place by the big toe of the other foot. The scores range from 0 (not attempted), to 2 (held for 10 seconds). Ability to stand longer in this position indicates greater balance.	Baseline, 12 months
Change in Balance Score Standing in Full Tandem Position	This measure is part of the SPPB. The full tandem position is with the feet directly in front of each other. The scores range from 0 (not attempted), to 2 (held for 10 seconds). Ability to stand longer in this position indicates greater balance.	Baseline, 12 months
Change in Gait Speed	This measure is part of the SPPB. Subjects will be asked to walk 8 feet or 2.44 meters at their usual pace. They will be allowed to use a cane or other walking aid if it is their custom. Scores range from 0 = could not do to 4 =<3.1 seconds.	Baseline, 12 months
Change in Score, Standing Test From Chair	This measure is part of the SPPB. Subjects will be asked to try to stand up from a chair 5 times with arms folded across their chest, and will be timed. Scores range from 0 to 4, with 0 = unable to stand without using arms, and 4 = completing 5 stands in <11.1 seconds.	Baseline,12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Interleukin 6 (pg/ml)	Serum will be collected to measure the effect of metformin on senescent markers.	Baseline, 12 months
Change in Matrix Metalloproteinase (ng/ml)	Serum will be collected to measure the effect of metformin on senescent markers.	Baseline, 12 months
Change in Plasminogen Activator Inhibitor	Serum will be collected to measure the effect of metformin on senescent markers.	Baseline, 12 months
Change in Monocyte Chemotactic Protein-1	Serum will be collected to measure the effect of metformin on senescent markers.	Baseline, 12 months
Change in Activin	Serum will be collected to measure the effect of metformin on senescent markers.	Baseline, 12 months

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Mandeep Singh, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2018
• Primary Completion (Actual): December 16, 2021
• Study Completion (Actual): December 16, 2021

Study Registration Dates

• First Submitted: January 30, 2018
• First Submitted That Met QC Criteria: February 23, 2018
• First Posted (Actual): March 1, 2018

Study Record Updates

• Last Update Posted (Actual): November 17, 2022
• Last Update Submitted That Met QC Criteria: October 24, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Frailty; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 17-003088

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No plan to do that

Drug and device information, study documents

• 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