Sodium-glucose Co Transporter 2 (sGLT2) Inhibitor and Endogenous Ketone Production

  • STATUS
    Recruiting
  • End date
    Dec 31, 2022
  • participants needed
    100
  • sponsor
    National Institute on Aging (NIA)
Updated on 26 January 2021

Summary

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.

Description

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.

Details
Condition Ketones, Senility, Physiological Effects of Drugs, antidiabetic agent, Blood Glucose, cognitive, Aging, Empaglifozin, Sodium-Glucose Transporter 2 Inhibitors, Sodium-Glucose Transporter 2 Inhibitors, Sodium-Glucose Transporter 2 Inhibitors, sglt2 inhibitor, sglt2 inhibitors, hypoglycaemic agent, hypoglycaemic, antihyperglycemic, hypoglycemic agents, hypoglycemic drugs, hypoglycemic, hypoglycemic agent
Treatment Jardiance 25 mg
Clinical Study IdentifierNCT03852901
SponsorNational Institute on Aging (NIA)
Last Modified on26 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 55 yrs?
Gender: Male or Female
Do you have any of these conditions: antidiabetic agent or Physiological Effects of Drugs or Senility or Ketones or Aging or Empaglifozin or Sodium-Glucose Transporter 2 Inhibitors or Blo...?
Do you have any of these conditions: Sodium-Glucose Transporter 2 Inhibitors or Physiological Effects of Drugs or hypoglycaemic or Aging or sglt2 inhibitors or Empaglifozin or hypoglycaem...?
Do you have any of these conditions: antihyperglycemic or hypoglycemic agent or Ketones or sglt2 inhibitor or cognitive or Blood Glucose or Aging or hypoglycaemic or hypoglycemic or Sodiu...?
Do you have any of these conditions: hypoglycemic drugs or cognitive or Sodium-Glucose Transporter 2 Inhibitors or antihyperglycemic or Blood Glucose or Physiological Effects of Drugs or ...?
Do you have any of these conditions: hypoglycemic agents or hypoglycemic agent or hypoglycaemic agent or Blood Glucose or cognitive or Empaglifozin or hypoglycemic drugs or sglt2 inhibito...?
Do you have any of these conditions: Aging or hypoglycaemic agent or cognitive or antidiabetic agent or hypoglycemic agents or hypoglycemic drugs or sglt2 inhibitor or Sodium-Glucose Tran...?
Do you have any of these conditions: hypoglycemic agents or antidiabetic agent or Senility or sglt2 inhibitor or hypoglycemic or hypoglycemic agent or Physiological Effects of Drugs or Ke...?
Do you have any of these conditions: antihyperglycemic or Aging or sglt2 inhibitors or Blood Glucose or hypoglycaemic or Empaglifozin or hypoglycemic drugs or antidiabetic agent or hypogl...?
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
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