Metformin in Longevity Study (MILES). (MILES)

• ClinicalTrials.gov Identifier: NCT02432287
• Recruitment Status: Completed
• First Posted: May 4, 2015
• Results First Posted: May 31, 2018
• Last Update Posted: May 21, 2021
• Sponsor: Albert Einstein College of Medicine
• Information provided by (Responsible Party): Albert Einstein College of Medicine

Tracking Information

• First Submitted Date: February 24, 2015
• First Posted Date: May 4, 2015
• Results First Submitted Date: December 20, 2017
• Results First Posted Date: May 31, 2018
• Last Update Posted Date: May 21, 2021
• Actual Study Start Date: October 2014
• Actual Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 1, 2018)

Increase in Number of Expressed Genes in Muscle and Adipose Tissue Using RNA Sequencing (RNA-Seq) [ Time Frame: 6 weeks ]

The investigators hypothesize that treatment with metformin will result in changes in the transcriptome. The investigators will test this by identifying increases in gene expression in muscle and adipose tissue with RNA Sequencing (RNA-Seq) in metformin and in placebo.

Original Primary Outcome Measures (submitted: May 1, 2015)

Gene expression. (changes in gene expression in muscle and adipose tissue with RNA Sequencing (RNA-Seq) [ Time Frame: 12 weeks treatment ]

The investigators hypothesize that treatment with metformin will result in changes in the transcriptome, reverting the expression profile of older adults with IGT to a younger level. The investigators will test this by identifying changes in gene expression in muscle and adipose tissue with RNA Sequencing (RNA-Seq). The investigators will also study expression of specific target genes (using RT-PCR), mitochondrial number and morphology and adipose macrophage content and activation.

Current Secondary Outcome Measures (submitted: May 1, 2018)

Mixed Meal Tolerance. Assessment of Insulin Sensitivity and Insulin Secretion (Using a Modification of the Matsuda Index) [ Time Frame: 6 weeks ]

Assessment of insulin sensitivity and insulin secretion. Insulin sensitivity will be estimated from insulin and glucose levels obtained following the standard meal challenge, using a modification of the Matsuda index, which has been widely used for non-invasive assessment of insulin sensitivity and shows good correlation (r=0.73) with results obtained from euglycemic hyperinsulinemic clamp studies. A higher Matsuda index indicates better insulin sensitivity. The insulin sensitivity index (ISI (comp) was calculated using the following equation (where g denotes glucose at various time points and i denotes insulin at various time points): ISI (comp)= 10000/ ((g0*i0* ((g0*15+ g30*30+ g60*30+ g90*30+ g120*30+ g180*30+ g240*15)/240))* ((i0*15+ i30*30+ i60*30+ i90*30*+ i120*30+ i180*30+ i240*15)/240))^0.5

Original Secondary Outcome Measures (submitted: May 1, 2015)

Mixed meal tolerance. Assessment of insulin sensitivity and insulin secretion (using a modification of the Matsuda index) [ Time Frame: 12 weeks treatment ]

Assessment of insulin sensitivity and insulin secretion. Insulin sensitivity will be estimated from insulin and glucose levels obtained following the standard meal challenge, using a modification of the Matsuda index, which has been widely used for non-invasive assessment of insulin sensitivity and shows good correlation (r=0.73) with results obtained from euglycemic hyperinsulinemic clamp studies

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Metformin in Longevity Study (MILES).
• Official Title: Metformin in Longevity Study (MILES).
• Brief Summary: Metformin, an FDA approved first-line drug for the treatment of type 2 diabetes, has known beneficial effects on glucose metabolism. Evidence from animal models and in vitro studies suggest that in addition to its effects on glucose metabolism, metformin may influence metabolic and cellular processes associated with the development of age-related conditions, such as inflammation, oxidative damage, diminished autophagy, cell senescence and apoptosis. As such, metformin is of particular interest in clinical translational research in aging since it may influence fundamental aging factors that underlie multiple age-related conditions. The investigators therefore propose a pilot study to examine the effect of metformin treatment on the biology of aging in humans. Namely, whether treatment with metformin will restore the gene expression profile of older adults with impaired glucose tolerance (IGT) to that of young healthy subjects.

Detailed Description

Aging in humans is a well-established primary risk factor for many disabling diseases and conditions, among them diabetes, cardiovascular disease, Alzheimer's disease and cancer. In fact, the risk of death from these causes is dramatically accelerated (100-1000 fold) between the ages of 35 and 85 years. For this reason, there is a need for the development of new interventions to improve and maintain health into old age - to improve "healthspan".

Several mechanisms have been shown to delay the aging process, resulting in improved healthspan in animal models, including mammals. These include caloric restriction, alteration in GH/IGF1 pathways, as well as use of several drugs such as resveratrol (SIRT1 activator) and rapamycin (mTOR inhibitor). At Einstein, the investigators have been working to discover pathways associated with exceptional longevity. The investigators propose the study of drugs already in common clinical use (and FDA approved) for a possible alternative purpose -healthy aging. The investigators goal is to identify additional mechanisms involved in aging, the delay of aging and the prevention of age-related diseases. In this proposal, the investigators explore the possibility of a commonly used drug, metformin, to reverse relevant aspects of the physiology and biology of aging.

Metformin is an FDA approved drug in common use in the US since the 1990s. It is the first-line drug of choice for prevention and treatment of type 2 diabetes (T2DM). The effect of metformin on aging has been extensively studied, and has been associated with longevity in many rodent models. Metformin also extends the lifespan of nematodes, suggesting an evolutionarily conserved mechanism. A recent high impact study demonstrated that metformin reduces oxidative stress and inflammation and extends both lifespan and health span in a mouse model .

If indeed metformin is an "anti-aging" drug, its administration should be associated with less age-related disease in general, rather than the decreased incidence of a single age-related disease. This notion led investigators to further study whether anti-aging effects can be demonstrated in the type 2 diabetes population. Notably, in the United Kingdom Prospective Diabetes Study (UKPDS) metformin, compared with other anti-diabetes drugs, demonstrated a decreased risk of cardiovascular disease. This has been suggested in other studies and meta-analyses and remains an active area of research.

In addition, numerous epidemiologic studies have shown an association of metformin use with a decreased risk of cancer, as well as decreased cancer mortality. There is also evidence from studies performed both in-vitro and in-vivo of metformin's role in attenuating tumorigenesis. The mechanisms proposed relate to its effects on reducing insulin levels, improved insulin action, decreased IGF-1 signaling (central to mammalian longevity), as well as activation of AMP-kinase. In fact, metformin's potential protective effect against cancer has been gaining much attention, with over 100 ongoing studies registered on the Clinical Trials.gov website.

To characterize pathways associated with increased lifespan and healthspan, the investigators plan to compile a repository of muscle and adipose biopsy samples obtained from young healthy subjects and older adults before and after treatment with potential anti-aging drugs. RNA-Seq analysis will be used to identify a unique biological "fingerprint" for aging in these tissues by comparing changes in gene expression in older adults post-drug therapy to the profiles of young healthy subjects. This overall approach is supported by a grant from the Glenn Foundation for the Study of the Biology of Human Aging.

The investigators believe that if metformin changes the biology of aging in tissues to a younger profile, it supports the notion that this drug may have more widespread use - as an "anti-aging" drug.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
• Condition: Aging

Intervention

• Drug: Metformin
  To determine if treatment with metformin (1700 mg/day) will restore the gene expression profile of older, glucose intolerant adults to that of young healthy subjects.
  Other Name: Glucophage
• Drug: Placebo
  there is no other name we used for the placebo
  Other Name: no others

Study Arms

• Experimental: Metformin
  Metformin, an FDA approved first-line drug for the treatment of type 2 diabetes, has known beneficial effects on glucose metabolism.
  Intervention: Drug: Metformin
• Experimental: Placebo
  Placebo
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 1, 2018): 16
• Original Estimated Enrollment (submitted: May 1, 2015): 15
• Actual Study Completion Date: December 2017
• Actual Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Men and women;
2. age >60 years with IGT based on 75g OGTT (fasting plasma glucose < 126 mg/dl, 2-hr glucose between 140 - 199 mg/dl);
3. this definition of IGT will include individuals with combined impaired fasting glucose (IFG) and IGT.

The investigators chose these inclusion criteria in order to study subjects who have evidence of impaired glucose regulation, but are not yet diabetic.

Exclusion Criteria:

1. Serious chronic or acute illness: cancer, clinically significant congestive heart failure, COPD, inflammatory conditions, serum creatinine > 1.4 mg/dl (female) or > 1.5 mg/dl (male), active liver disease, history of metabolic acidosis, poorly controlled hypertension, epilepsy, recent (within 3 months) CVD event (MI, PTCA, CABG, stroke); history of bariatric or other gastric surgery, cigarette smoking, binge alcohol use (>7 drinks in 24 hrs).
2. Treatment with drugs known to influence glucose metabolism (other diabetes medications, systemic glucocorticoids, pharmacologic doses of niacin)
3. Hypersensitivity to metformin or any component of the formulation

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02432287
• Other Study ID Numbers: 2014-3444
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Albert Einstein College of Medicine
• Original Responsible Party: Same as current
• Current Study Sponsor: Albert Einstein College of Medicine
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jill Crandall, MD; Einstein College of Medicine

• PRS Account: Albert Einstein College of Medicine
• Verification Date: May 2021