Sodium-glucose Co Transporter 2 (sGLT2) Inhibitor and Endogenous Ketone Production
| Status: | Recruiting |
|---|---|
| Conditions: | Healthy Studies |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 55 - 100 |
| Updated: | 4/6/2019 |
| Start Date: | April 10, 2019 |
| End Date: | December 31, 2021 |
| Contact: | Denise L Melvin, R.N. |
| Email: | dm381j@nih.gov |
| Phone: | (410) 350-3924 |
Sodium-Glucose CoTransporter 2 (sGLT2) Inhibitor and Endogenous Ketone Production
Background:
The drug Jardiance 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.
Researchers want to see how Jardiance affects ketone levels, which could lead to ways to
improve brain health as people age.
Objectives:
To study how taking Jardiance affects ketone levels in people without diabetes.
Eligibility:
Adults at least 55 years old without diabetes
Design:
Participants will fast before all visits and sometimes during visits. Snacks or meals will be
provided.
Participants will be screened with medical history, physical exam, and blood tests.
At 3 study visits over about 4 weeks, participants will:
Have a thin plastic tube inserted in an arm vein for frequent blood samples
Have their urine collected throughout the visit
Write what they eat and when in a diary
Answer questions about symptoms
Have an MRI/MRS scan. A strong magnetic field and radio waves will take pictures of the brain
and measure its blood flow and function. Participants will lie on a table that slides into
the scanner. They will wear a plastic device on their head and earplugs.
Participants will take the study drug once a day for 2 weeks.
Participants will get an activity monitor and walk about 2,000 steps most evenings.
A small sensor will be inserted in participants upper arm for 4 weeks to measure blood
glucose.
Participants will have a follow-up phone call.
The drug Jardiance 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.
Researchers want to see how Jardiance affects ketone levels, which could lead to ways to
improve brain health as people age.
Objectives:
To study how taking Jardiance affects ketone levels in people without diabetes.
Eligibility:
Adults at least 55 years old without diabetes
Design:
Participants will fast before all visits and sometimes during visits. Snacks or meals will be
provided.
Participants will be screened with medical history, physical exam, and blood tests.
At 3 study visits over about 4 weeks, participants will:
Have a thin plastic tube inserted in an arm vein for frequent blood samples
Have their urine collected throughout the visit
Write what they eat and when in a diary
Answer questions about symptoms
Have an MRI/MRS scan. A strong magnetic field and radio waves will take pictures of the brain
and measure its blood flow and function. Participants will lie on a table that slides into
the scanner. They will wear a plastic device on their head and earplugs.
Participants will take the study drug once a day for 2 weeks.
Participants will get an activity monitor and walk about 2,000 steps most evenings.
A small sensor will be inserted in participants upper arm for 4 weeks to measure blood
glucose.
Participants will have a follow-up phone call.
Objective and Specific Aims: The objective of this proof-of-concept study is to demonstrate
in non-diabetic men and women age > 55 years that a sGLT2 inhibitor will increase ketone
bodies and metabolites used for gluconeogenesis. We also hypothesize that sGLT2 inhibitor
(empagliflozin) will increase circulating glucagon and fatty acids, decrease circulating
amino acids, increase expression of receptors and mediators of ketone metabolism in plasma
exosomes and change Magnetic Resonance Spectroscopy (MRS) brain metabolism measures.
Experimental Design and Methods: 10 men and 10 women will be recruited for this pilot study.
Each eligible participant will have a screen visit (Visit 0) and three additional 2-day study
visits (Visit 1-3). On Visits 1, 2 and 3, frequent blood sampling for Beta-hydroxybutyrate
butyrate (Beta-OHB), acetoacetate, fatty and amino acids, glucagon, insulin and glucose
levels will be carried out; these visits will also include blood work for exosome markers and
brain MRS. In addition, placement of a continuous glucose monitor (CGM) along with a 34-hour
urine collection will be carried out. On Visits 1 and 2 the participants will wear the CGM
until they return for their next visit. On Visit 3 the CGM will be removed at the end of the
study visit. On Visit 1, no empagliflozin will be administered. Participants will return in
13 +/- 2 days for Visit 2. Visit 2 is the same as Visit 1 except empagliflozin 25 mg will be
administered both mornings, at least 30 minutes before eating breakfast and participants will
continue empagliflozin 25 mg once every morning, at least 30 minutes before eating breakfast,
at home until they return in 13 +/- 2 days for Visit 3. At the end of Visit 3, empagliflozin
will be stopped.
Medical Relevance and Expected Outcome: Elevating ketone bodies may bolster neuronal health
and delay onset and progression of cognitive impairment. The expected outcome of this study
is that we will see an increase in circulating levels of ketones, glucagon and fatty acids,
an increased expression of receptors and mediators of ketone metabolism in plasma exosomes
and a change in Magnetic Resonance Spectroscopy (MRS) brain metabolism measures, in subjects
taking a sGLT2 inhibitor. We expect circulating amino acid levels will decrease, especially
during the overnight hours. This study will aid in deciding whether this class of compound
may be used in a larger study to improve cognitive function in patients with diagnosis
consistent with declining cognitive function. We require that empagliflozin be taken for up
to 2 weeks before returning for Visit 3, because we need to fully understand the homeostatic
adaptations that may occur in the metabolite response to empagliflozin due to prolonged (up
to 2 weeks) sGLT2 inhibition. It is our goal in the future to use the information gathered in
this pilot study to design a long-term study in people who actually suffer from mild
cognitive impairment/AD and therefore a Visit 2 (34-hour acute study) only, as outlined
above, would not give us the full picture of the metabolic changes that might occur with
prolonged use, especially in a non-diabetic population.
in non-diabetic men and women age > 55 years that a sGLT2 inhibitor will increase ketone
bodies and metabolites used for gluconeogenesis. We also hypothesize that sGLT2 inhibitor
(empagliflozin) will increase circulating glucagon and fatty acids, decrease circulating
amino acids, increase expression of receptors and mediators of ketone metabolism in plasma
exosomes and change Magnetic Resonance Spectroscopy (MRS) brain metabolism measures.
Experimental Design and Methods: 10 men and 10 women will be recruited for this pilot study.
Each eligible participant will have a screen visit (Visit 0) and three additional 2-day study
visits (Visit 1-3). On Visits 1, 2 and 3, frequent blood sampling for Beta-hydroxybutyrate
butyrate (Beta-OHB), acetoacetate, fatty and amino acids, glucagon, insulin and glucose
levels will be carried out; these visits will also include blood work for exosome markers and
brain MRS. In addition, placement of a continuous glucose monitor (CGM) along with a 34-hour
urine collection will be carried out. On Visits 1 and 2 the participants will wear the CGM
until they return for their next visit. On Visit 3 the CGM will be removed at the end of the
study visit. On Visit 1, no empagliflozin will be administered. Participants will return in
13 +/- 2 days for Visit 2. Visit 2 is the same as Visit 1 except empagliflozin 25 mg will be
administered both mornings, at least 30 minutes before eating breakfast and participants will
continue empagliflozin 25 mg once every morning, at least 30 minutes before eating breakfast,
at home until they return in 13 +/- 2 days for Visit 3. At the end of Visit 3, empagliflozin
will be stopped.
Medical Relevance and Expected Outcome: Elevating ketone bodies may bolster neuronal health
and delay onset and progression of cognitive impairment. The expected outcome of this study
is that we will see an increase in circulating levels of ketones, glucagon and fatty acids,
an increased expression of receptors and mediators of ketone metabolism in plasma exosomes
and a change in Magnetic Resonance Spectroscopy (MRS) brain metabolism measures, in subjects
taking a sGLT2 inhibitor. We expect circulating amino acid levels will decrease, especially
during the overnight hours. This study will aid in deciding whether this class of compound
may be used in a larger study to improve cognitive function in patients with diagnosis
consistent with declining cognitive function. We require that empagliflozin be taken for up
to 2 weeks before returning for Visit 3, because we need to fully understand the homeostatic
adaptations that may occur in the metabolite response to empagliflozin due to prolonged (up
to 2 weeks) sGLT2 inhibition. It is our goal in the future to use the information gathered in
this pilot study to design a long-term study in people who actually suffer from mild
cognitive impairment/AD and therefore a Visit 2 (34-hour acute study) only, as outlined
above, would not give us the full picture of the metabolic changes that might occur with
prolonged use, especially in a non-diabetic population.
- 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 (SCREENING VISIT):
- 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.
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