Genomic Outcomes of Metformin

Hypertension Clinical Trial

— GOMET  

Official title:

Genomic Outcomes of Metformin

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02986659
• Other study ID #: IRB00034977
• Status: Completed
• Phase: Phase 4
• Start date: August 3, 2016
• Est. completion date: November 15, 2018

Study information

• Verified date: October 2019
• Source: Wake Forest University Health Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Medical scientists have found that people with diabetes who take the drug Metformin have less age-related disease than those taking other treatments and researchers believe it may prevent numerous diseases and conditions that effect older people. In addition, metformin extends lifespan in some animal models of human disease. The purpose of this study is to see if taking Metformin causes changes in blood cells consistent with improved health and longevity in people who do not have diabetes. In this study Metformin will be compared to placebo. A placebo is a substance, like a sugar pill, that is not thought to have any effect on a participants disease or condition. In this study participants will either receive the active study medication, Metformin or placebo which is not active. Placebos are used in research studies to see if the drug being studied really does have an effect.

Description:

The number of older adults is projected to increase dramatically by 2050. Aging-related diseases and conditions still seriously compromise the quality of life among most older adults. Several pharmaceutical agents, such as metformin, have been tested to extend lifespan and delay aging-related diseases and dysfunctions in mice. Metformin, a biguanide antidiabetic drug, reduces the risk for developing type-2 diabetes in persons at risk by over one-third with few adverse effects (e.g., gastrointestinal irritation). Metformin prevents type-2 diabetes primarily through decreasing hepatic glucose synthesis, as well as enhancing insulin sensitivity and increasing peripheral glucose uptake. The molecular mechanisms remain unclear, although a number of potential mechanism such as activation of AMP-activated protein kinase (AMPK) and inhibition of mitochondrial glycerophosphate dehydrogenase have been proposed. The fact that metformin treatment in persons with type-2 diabetes has been associated with reduced risk of other aging-related diseases and conditions, including cardiovascular disease, cancer and cognitive decline supports the possibility of the beneficial effects of metformin on healthy aging. It is imperative to capitalize on these leads to extend health span among older adults.

To translate animal findings to human intervention trials, appropriate aging biomarkers are needed. Methylomic and transcriptomic profiles in relevant cells may reflect molecular features that mediate effects of both genetic and environmental factors on aging-related functional decline and disease. The roles of monocytes have been implicated in development of many aging-related diseases such as cardiovascular disease, cancer and neurodegenerative disease. In a cross-sectional association study of 1,200 monocyte samples, we identified 1,794 age-associated methylation sites and 2,704 age-associated transcripts, which were over-represented in two networks (autophagy and oxidative phosphorylation) and suggestive of decline in those functions with age. Both autophagy and oxidative phosphorylation are considered as key contributors to the aging process, and their dysfunctions have been linked to aging-related diseases. Changes in these aging-related omic biomarkers may be early indicators of cellular damage or disruption that eventually leads to age-related dysfunctions. Assessment of these aging biomarkers in response to therapeutic intervention may also provide molecular insight for personalizing treatment. The investigators propose a pilot study to examine changes in aging-related omic profiles after 3 months of metformin treatment in 35 monocyte samples from older adults using a randomized, double-blind, placebo-controlled crossover study design.

Our overarching goal of the pilot study is to evaluate the utility of using the aging-related omic biomarkers as an indicator of pharmacologic responses in the anti-aging therapeutic intervention trials through the following specific aims. Although this pilot study does not have sufficient power to definitively test all the aims, it will provide essential preliminary data for developing a full scale research program.

• Aim 1A: To test the effects of the metformin treatment on transcriptomic profiles and related functional changes in human monocytes,

• Aim 1B: To explore the effects of the metformin treatment on methylomic profiles in human monocytes,

• Aim 2: To investigate the longitudinal relationship between transcriptional and functional changes in human monocytes during the metformin treatment and

• Aim 3: To test the effects of the metformin treatment on frailty and other aging-related physical and cognitive measures and investigate the longitudinal relationship between these changes and transcriptional changes.

A randomized, double-blind, placebo-controlled crossover trial in 30 participants using metformin and matching placebo will be used. In the absence of a treatment by sequence interaction effect, this design can increase study power for evaluating treatment effects by allowing each participant to be his/her own control. The period effect may be minimum because the primary outcomes, methylation and transcriptional measures, are relatively stable overtime.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: November 15, 2018
• Est. primary completion date: November 15, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years to 79 Years

Eligibility

Inclusion Criteria:

• Age 65 - 79

Must meet criteria from one or more of the following groups:

Group 1 (Can have 1 or 2 of these, but not all 3)

• History of coronary artery disease (MI/heart attack, stroke, heart failure, or peripheral artery disease)

• Cancer, with no active treatment in the last year

• MCI (MoCA >18<26 -inclusive of 1 point if <12 years of education Group 2

• Decline physical function (walking speed < 1 m/s) Group 3 (Either or both)

• Abdominal obesity (>88cm women, >102cm men) AND hypertension (treated or resting blood pressure >140/90

• Abdominal obesity (>88cm women, >102cm men) AND hyperlipidemia (treated or fasting total cholesterol >240 English literacy Willing to provide informed consent

Exclusion Criteria:

• eGFR <45

• Type 2 diabetes (HbA1c>6.5) or type 1 diabetes

• Any tobacco or nicotine product use in the past year

• Low vitamin B12 Levels (< 300 pg/mL)

• Self-reported severe difficulty or inability to walk 400m or climb 10 steps (from Q 2 and 19 on PAT-D)

• Self-reported difficulty or inability to perform basic ADL functions (from Q 10, 13, 14, 16 on PAT-D)

• Excessive alcohol use (>14 drinks/week)

• Cancer requiring treatment in past year (except skin)

• Dementia - diagnosed and/or MoCA score <18

• Parkinson's or other neurological disease

• Chronic liver disease or cirrhosis

• End stage renal disease or on dialysis

• Rheumatic conditions (Rheumatoid arthritis, lupus, and any other autoimmune disease the -PI deems them to be ineligible for)

• Thyroid problems the PI deems them to be ineligible for

• Gout

• Involved in another interventional study

• Hemoglobin <8 or diagnosed with anemia

• Recent unintentional weight change (+/- 10 lbs. in the last 12 months)

• BMI <18.5

• Likely to not follow the protocol

• PI deems unfit to participate

• Already taking Metformin or any other drug intended to treat diabetes

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Coronary Artery Disease
• Hypertension
• Mild Cognitive Impairment
• Obesity, Abdominal

Intervention

Drug:
• Metformin

• Placebo

Locations

Country	Name	City	State
United States	Wake Forest Health Sciences	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Wake Forest University Health Sciences	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Vital Signs		Baseline through 12 weeks, 12 weeks through 24 weeks
Other	Change in Expanded Short Physical Performance Battery (eSPPB)	Score ranges from 0 (low physical function) to 12 (high physical function).	From baseline through 12 weeks
Other	Change in Expanded Short Physical Performance Battery (eSPPB)	Score ranges from 0 (low physical function) to 12 (high physical function).	From 12 weeks through 24 weeks
Other	Nottingham Power Rig	The Nottingham power rig evaluates mean unilateral leg muscle power	Baseline through 12 weeks, 12 weeks through 24 weeks
Other	Grip Strength	measurement of the amount of static force that the hand can squeeze	Baseline through 12 weeks and 12 weeks through 24 weeks
Other	Change in Montreal Cognitive Assessment (MoCA)	Change in score. Score ranges from 0 (low cognitive function) to 30 (high cognitive function).	Baseline through 12 weeks
Other	Change in Montreal Cognitive Assessment (MoCA)	Change in score. Score ranges from 0 (low cognitive function) to 30 (high cognitive function).	12 weeks through 24 weeks
Other	Blood Lipids--total Cholesterol		Baseline through 12 weeks and 12 weeks through 24 weeks
Other	Blood Lipids--HDL-Cholesterol		Baseline through 12 weeks and 12 weeks through 24 weeks
Other	Blood Lipids--Triglycerides		Baseline through 12 weeks and 12 weeks through 24 weeks
Other	Blood Lipids--calculated LDL Levels		Baseline through 12 weeks and 12 weeks through 24 weeks
Other	Mobility Assessment Tool - Short Form (MAT-sf).	MAT-sf is a tool for assessing self-perception of mobility. The possible range of score is from 30 to 80 with lower score indicating lower perception of mobility.	Baseline through 12 weeks and 12 weeks through 24 weeks
Other	Pepper Assessment Tool for Disability (PAT-D)	The PAT-D is a self-administered questionnaire which consists of 23 items that include a range of activities that assess mobility, activities of daily living (ADL) and instrumental activities of daily living (IADL). Responses are made on a five-point Likert scale ranging from 1 ("usually did with no difficulty") to 5 ("unable to do") or a box can be checked that reads "usually did not do for other reasons".	Baseline through 12 weeks and 12 weeks through 24 weeks
Other	Medication Adherence	Amount of medication expected to be taken vs. amount participant actually takes.	Baseline through 12 weeks and 12 weeks through 24 weeks
Primary	Change in Eigengene Scores	Part of blood sample analysis will give results for Individual methylation sites and transcripts, especially the eigengenes of autophage, oxidative phosphorylation and protein synthesis networks Methylomic and transcriptomic profiles in monocytes. All of the results for these measures will be aggregated into an eigengene score. The eigengene score is a summary measure of a group of correlated genes. This score may indicate status of a biological function. In this analysis, the observed range of values were from -0.48 to 0.66. A lower score means downregulation of the gene group, while a higher score upregulation. No theoretical minimum or maximum value exist for this assay.	baseline through 12 weeks
Primary	Change in Eigengene Scores	Part of blood sample analysis will give results for Individual methylation sites and transcripts, especially the eigengenes of autophage, oxidative phosphorylation and protein synthesis networks Methylomic and transcriptomic profiles in monocytes. All of the results for these measures will be aggregated into an eigengene score. The eigengene score is a summary measure of a group of correlated genes. This score may indicate status of a biological function. In this analysis, the observed range of values were from -0.48 to 0.66. A lower score means downregulation of the gene group, while a higher score upregulation. No theoretical minimum or maximum value exist for this assay.	baseline through 24 weeks
Secondary	Functional Measures--macroautophagy	Macroautophagy is a process of wrapping cellular components inside autophagosomes and delivering them to lysosomes for degradation.	baseline through 12 weeks, 12 weeks through 24 weeks
Secondary	Functional Measures--microautophagy		Baseline through 12 weeks, 12 weeks through 24 weeks
Secondary	Functional Measures--chaperone-mediated Autophagy		Baseline through 12 weeks, 12 weeks through 24 weeks
Secondary	Mitochondria Function: Respiratory Control Ratio (RCR)		Baseline through 12 weeks, 12 weeks through 24 weeks
Secondary	Mitochondria Function: State 3 (Maximal Oxygen Consumption Rate)		Baseline through 12 weeks, 12 weeks through 24 weeks
Secondary	Mitochondria Function: State 4 (Oxygen Consumption Upon Inhibition of ATP Synthase)		Baseline through 12 weeks, 12 weeks through 24 weeks