Sodium-glucose Co Transporter 2 (sGLT2) Inhibitor and Endogenous Ketone Production
Condition: Empaglifozin; Physiological Effects of Drugs; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors
Intervention: empagliflozin (Jardiance) 25 mg
Intervention description: Oral empagliflozin 25 mg/day x 14 days
Intervention MeSH terms: Empagliflozin
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 55 Years
Healthy volunteers: No
Keywords: Ketones; Metabolism; Hormones; Alzheimer's Disease

Summary:

      Background:

      The drug empagliflozin treats diabetes. It lowers blood sugar by increasing glucose the
      kidneys excrete. This increases levels of ketones formed in the blood. The body makes ketones
      when it does not have enough glucose for fuel. The brains of many people with age-related
      diseases like Alzheimer's do not use glucose well. Brain use of ketones might improve mental
      ability. We investigated how empagliflozin affects ketone levels, which could lead to ways to
      improve brain health as people age.

      Objectives:

      To study how taking empagliflozin affects systemic and brain metabolism including ketone
      levels in people without diabetes.

      Eligibility:

      Adults at least 55 years old without diabetes

      Design:

      After a screening Visit, eligible participants were admitted to the NIA Clinical Unit during
      Visits 1 (baseline), 2 (first dose) and 3 (last/14th dose). On each Visit, blood draws were
      performed and circulating metabolites and hormones were repeatedly measured over 34-hour
      periods. Using plasma from fasting state only, we isolated total and neuronal-origin
      extracellular vesicles to measure proteins of the IGF-1 and insulin signaling cascades.
      Furthermore, on each Visit, we performed magnetic resonance spectroscopy (MRS) to measure
      concentrations of a plethora of metabolites in the brain. Between Visits 2 and 3,
      participants were taking the drug at home. A continuous glucose monitoring device was placed
      to detect potential glucose fluctuations while at home. The study was concluded for
      participants after the end of Visit 3.
    

Eligibility criteria:

        INCLUSION CRITERIA:

          -  Age 55 years and older.

          -  Healthy (see exclusion criteria below).

          -  Able to understand the study risks and procedures, and consent to participate in the
             study.

          -  Able to read and speak English.

        EXCLUSION CRITERIA:

          -  History of diabetes (requiring any medical treatment other than diet and exercise) or
             fasting plasma glucose > 126 mg/dl or HbA1c> 6.5 %.

          -  History of hypoglycemia.

          -  BMI > 35 kg/m(2).

          -  Creatinine clearance less than 60 ml/min as measured by GFR.

          -  Glucosuria

          -  History of anemia within the past 6 months or Hgb <11.0 mg/dL for women and Hgb <12.5
             mg/dL for men.

          -  Current steroid use or steroid use within 90 days of screening, excluding eye drops.

          -  Currently taking loop diuretics (Lasix, for example).

          -  Participant presently following a calorie restriction diet, low carb/high fat diet.

          -  HIV virus infection

          -  Hepatitis B infection, as evidenced by a positive HBsAG at screen visit.

          -  Hepatitis C infection that has not been treated. (The screen blood work must show HCV
             RNA quantitative is not detectable).

          -  Active infection/fever that may cause changes in glucose metabolism.

          -  Known allergy to sGLT2 inhibitors in the past.

          -  Thyroid dysfunction that is not controlled or treated. This will be determined by Free
             T3, T4, Free T4 or TSH not within MedStar Harbor Hospital laboratory normal ranges for
             this pilot study.

          -  Adrenal dysfunction as determined by a cortisol level not within the normal range for
             MedStar Harbor Hospital Laboratory for this pilot study.

          -  Kidney or liver disease, (GFR < 60 mL/min/1.73 m(2) and/or liver enzymes not within
             normal ranges for MedStar Harbor Hospital Laboratory for this pilot study.

          -  Severe gastrointestinal diseases such as Crohn s disease or ulcerative colitis
             requiring continuous treatment.

          -  History of severe pulmonary disease such as chronic obstructive pulmonary disease
             (COPD) or asthma requiring continuous medication use.

          -  Patients with known, or evidence of, peripheral vascular disease.

          -  History of chronic urinary tract infections.

          -  History of recurrent or recent dehydration in the past year.

          -  History of recurrent or recent vaginal yeast infection.

          -  Alcohol intake greater than 30 grams (drink more than 2 beers OR equivalent per day).

          -  History of severe psychiatric conditions associated with behavioral problems or
             requiring chronic medical treatment.

          -  Poor venous access.

          -  Inability to walk 2,000 steps

          -  Donation or loss of 400 mL or more of blood within 56 days prior to and subsequent to
             screening.

          -  Participation in another study in the past 30 days, in which a study drug was
             administered.

          -  Currently participating in another study unless the investigator feels it would not
             interfere with the study.

          -  History of a medical condition or any other reason that, in the opinion of the
             investigator, will make participation in this study unsafe.

          -  Blood work or urine tests that are not considered by the study physician to be in an
             acceptable range for the study.

          -  Metal implants and devices incompatible with 3T Magnetic Resonance Imaging (MRI), or
             another contraindication to MRI.