Metformin for Preventing Frailty in High-risk Older Adults

Physical frailty is a geriatric syndrome that leads to poor health outcomes such as falls,
disability, institutionalization, and death. The prevalence of frailty is estimated to be
7-15% among community-dwelling older U.S. adults. The associated costs of frailty were
estimated to be more than $18 billion in 2000 and these will continue to increase over the
next two decades. Thus, an increasingly frail older population will have major implications
for the demand for health care services, including hospital usage, home care, and long-term
care.

Data from several studies have suggested strong roles for diabetes and insulin resistance,
which are associated with increased inflammation, in the physiological basis of frailty. The
investigators' recent epidemiological research with a community-based population of older
adults showed that diabetes was the most significant predictor of frailty onset and worsening
over time. While the importance of frailty and its impact on an aging U.S. society have been
widely recognized, to date there are no effective interventions to prevent or treat frailty.
Therefore, the major goal of this study is to test a drug with insulin-sensitizing and
anti-inflammatory properties, such as metformin, as a novel intervention for frailty
prevention.

The investigators hypothesize that metformin will lead to reduced inflammation and insulin
resistance present in older glucose-intolerant subjects and that these changes will
consequently prevent the onset and/or progression of frailty in this sub-population of older
adults. Subjects with impaired glucose intolerance will be enrolled in this study because
this group encompasses approximately 1/3rd of the older population, this group is at
increased risk for developing diabetes and frailty, and is the most likely to benefit from a
potential anti-inflammatory and insulin-sensitizing intervention.

Inclusion Criteria:

- Men and women

- All ethnic groups

- Age 65 and older

- Community-dwelling

- Pre-diabetic based on oral glucose tolerance test with 2 hour values of 140 - 199
mg/dL after an oral glucose load, and no diagnosis of diabetes in the past 12 months

- Subjects must have the following laboratory values: Hematocrit ≥ 33%, aspartate
aminotransferase < 2 X upper limit of normal, alanine aminotransferase < 2 X upper
limit of normal, alkaline phosphatase < 2 X upper limit of normal, normal urinalysis,
normal electrolytes, normal platelets, prothrombin time and partial thromboplastin
time, and normal renal function for the subject's age (defined by a serum creatinine
<1.5 mg/dL in males or <1.4 mg/dL in females and creatinine clearance ≥ 60 mL/min).

Exclusion Criteria:

- Characterized as frail, defined as the presence of 3 or more of: 1) weak hand grip
strength, 2) slow walking speed, 3) low physical activity, 4) unintentional weight
loss of ≥ 10 pounds over the past year, 5) self-reported exhaustion

- Resident of nursing home or long-term care facility

- Subjects with diabetes based on American Diabetes Association criteria or currently
taking glucose lowering medications

- Subjects taking drugs known to affect glucose homeostasis

- Untreated depression or Geriatric Depression Scale score on 15-item scale >7

- Diagnosis of any disabling neurologic disease Parkinson's Disease, Amyotrophic Lateral
Sclerosis, multiple sclerosis, cerebrovascular accident with residual deficits (muscle
weakness or gait disorder), diagnosis of dementia or Mini-mental State Exam score <18

- History of moderate-severe heart disease (New York Heart Classification greater than
grade II) or pulmonary disease (dyspnea on exertion upon climbing one flight of stairs
or less; abnormal breath sounds on auscultation)

- Poorly controlled hypertension (systolic >170 mmHg, diastolic >105 mmHg)

- Subjects who have taken systemic steroids, anabolic steroids, growth hormone or
immunosuppressants within 6 months

- Chronic inflammatory condition, autoimmune disease, or infectious processes (e.g.,
active tuberculosis, Human Immunodeficiency Virus, rheumatoid arthritis, systemic
lupus erythematosus, hepatitis B or C)

- Active tobacco use (within 6 months)

- Active malignancy, non-skin

- Disease or condition likely to cause death within 5 years

- Hypersensitivity to metformin or pioglitazone

- Donated blood within the last 2 months