Effect of Metformin on Frailty in 12 Subjects

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.

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