EmpaglifozinPhase 1NCT03852901
Sodium-glucose Co Transporter 2 (sGLT2) Inhibitor and Endogenous Ketone Production
A Phase 1 study testing empagliflozin (Jardiance) 25 mg in people with Empaglifozin and Physiological Effects of Drugs, run by National Institute on Aging (NIA) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 55 years and older
- Conditions the study is for
- Empaglifozin, Physiological Effects of Drugs, Hypoglycemic Agents
- What is being tested?
- empagliflozin (Jardiance) 25 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteUnited States
- Study dates
- 28 Mar 2019to 13 Dec 2021
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 33Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institute on Aging, Clinical Research Unit
Baltimore, Maryland, 21224
About this study
Official title: Sodium-Glucose CoTransporter 2 (sGLT2) Inhibitor and Endogenous Ketone Production
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.
Read more
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.
Read the detailed description
Objective and Specific Aims: The objective of this proof-of-concept study was to demonstrate in non-diabetic men and women age > 55 years that a sGLT2 inhibitor (empagliflozin) can increase ketone bodies and metabolites used for gluconeogenesis. We also hypothesized that empagliflozin would increase circulating glucagon and fatty acids, decrease circulating amino acids, upregulate IGF-1 and insulin cascades in plasma extracellular vesicles, and change MRS brain metabolism measures.
Experimental Design and Methods: men and women (total n=21) were recruited for this pilot study. Each eligible participant had 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 (BHB), acetoacetate (AcAc), fatty and amino acids, glucagon, insulin and glucose levels will be carried out; these visits also included blood work for extracellular vesicle biomarkers and brain MRS. In addition, placement of a continuous glucose monitor (CGM) along with a 34-hour urine collection was carried out. On Visit 2 the participants wore the CGM until they returned for their next Visit. On Visit 3 the CGM was removed at the end of the study Visit. On Visit 1, no empagliflozin was administered. Participants returned in 13 +/- 2 days for Visit 2. Visit 2 was the same as Visit 1 except empagliflozin 25 mg was administered both mornings, at least 30 minutes before eating breakfast and participants continueed empagliflozin 25 mg once every morning, at least 30 minutes before eating breakfast, at home until they returned in 13 +/- 2 days for Visit 3. At the end of Visit 3, empagliflozin was 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 was an increase in circulating levels of ketones, glucagon and fatty acids, an increased expression of receptors and mediators of ketone metabolism in plasma exosomes, an upregulation of IGF-1/insulin cascades in exosomes, and a change in Magnetic Resonance Spectroscopy (MRS) brain metabolism measures, in subjects taking a sGLT2 inhibitor. We expected circulating amino acid levels to 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 required that empagliflozin was taken for up to 2 weeks before returning for Visit 3, because we needed 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/Alzheimer's disease 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.
- Conditions
- Empaglifozin, Physiological Effects of Drugs, Hypoglycemic Agents, Sodium-Glucose Transporter 2 Inhibitors
- Being tested
- empagliflozin (Jardiance) 25 mg
- Keywords
- Ketones, Metabolism, Hormones, Alzheimer's Disease
- Medical subject headings
- Ketosis, Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
empagliflozin (Jardiance) 25 mgDrug
Oral empagliflozin 25 mg/day x 14 days
| Study group | Role | What they receive |
|---|---|---|
| Single Arm | Experimental | Single group Receives: Drug: empagliflozin (Jardiance) 25 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Serum β-hydroxybutyrate (BHB)
Change in serum β-hydroxybutyrate (BHB) after 14 days on empagliflozin, compared with baseline.
Measured: 14 days
Secondary outcomes (7)
Change in Plasma Glucose
Change in plasma glucose after 14 days on empagliflozin, compared with baseline.
Measured: 14 days
Change in Serum Non-esterified Fatty Acids (NEFAs)
Change in serum non-esterified fatty acids (NEFAs) after 14 days on empagliflozin, compared with baseline.
Measured: 14 days
Change in Plasma Insulin
Change in plasma insulin after 14 days on empagliflozin, compared with baseline.
Measured: 14 days
Change in Serum Acetoacetate (AcAc)
Change in serum Acetoacetate (AcAc) after 14 days on empagliflozin, compared with baseline.
Measured: 14 days
Change in 1H MRS BHB
Change in 1H MRS β-hydroxybutyrate (BHB) after 14 days on empagliflozin, compared with baseline.
Measured: 14 days
Change in 1H MRS Glutamate (Glu)
Change in 1H MRS glutamate (Glu) after 14 days on empagliflozin, compared with baseline.
Measured: 14 days
Change in 1H MRS Glutamine (Gln)
Change in 1H MRS glutamine (Gln) after 14 days on empagliflozin, compared with baseline.
Measured: 14 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Feb 2019
- Study start28 Mar 2019
- Primary completion12 Nov 2020
- Study completion13 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for EmpaglifozinStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute on Aging (NIA)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Josephine M Egan, M.D., Principal investigator, National Institute on Aging (NIA)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03852901
- Sponsor's protocol ID
- 190060
- Other IDs
- 19-AG-0060
- Status last verified
- 13 Dec 2021
- First submitted
- 22 Feb 2019
- Last updated
- 2 Aug 2022
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Sodium-Glucose CoTransporter 2 (sGLT2) Inhibitor and Endogenous Ketone Production
- ClinicalTrials.gov ID
- NCT03852901
- Acronym / sponsor ID
- 190060
- Conditions
- Empaglifozin, Physiological Effects of Drugs, Hypoglycemic Agents, Sodium-Glucose Transporter 2 Inhibitors
- Keywords
- Ketones, Metabolism, Hormones, Alzheimer's Disease
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- National Institute on Aging (NIA)US National Institutes of Health
- Study start
- 28 Mar 2019 (actual)
- Primary completion
- 12 Nov 2020 (actual)
- Study completion
- 13 Dec 2021 (actual)
- First posted
- 25 Feb 2019 (actual)
- Results
- Posted 2 Aug 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Objective and Specific Aims: The objective of this proof-of-concept study was to demonstrate in non-diabetic men and women age > 55 years that a sGLT2 inhibitor (empagliflozin) can increase ketone bodies and metabolites used for gluconeogenesis. We also hypothesized that empagliflozin would increase circulating glucagon and fatty acids, decrease circulating amino acids, upregulate IGF-1 and insulin cascades in plasma extracellular vesicles, and change MRS brain metabolism measures.
Experimental Design and Methods: men and women (total n=21) were recruited for this pilot study. Each eligible participant had 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 (BHB), acetoacetate (AcAc), fatty and amino acids, glucagon, insulin and glucose levels will be carried out; these visits also included blood work for extracellular vesicle biomarkers and brain MRS. In addition, placement of a continuous glucose monitor (CGM) along with a 34-hour urine collection was carried out. On Visit 2 the participants wore the CGM until they returned for their next Visit. On Visit 3 the CGM was removed at the end of the study Visit. On Visit 1, no empagliflozin was administered. Participants returned in 13 +/- 2 days for Visit 2. Visit 2 was the same as Visit 1 except empagliflozin 25 mg was administered both mornings, at least 30 minutes before eating breakfast and participants continueed empagliflozin 25 mg once every morning, at least 30 minutes before eating breakfast, at home until they returned in 13 +/- 2 days for Visit 3. At the end of Visit 3, empagliflozin was 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 was an increase in circulating levels of ketones, glucagon and fatty acids, an increased expression of receptors and mediators of ketone metabolism in plasma exosomes, an upregulation of IGF-1/insulin cascades in exosomes, and a change in Magnetic Resonance Spectroscopy (MRS) brain metabolism measures, in subjects taking a sGLT2 inhibitor. We expected circulating amino acid levels to 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 required that empagliflozin was taken for up to 2 weeks before returning for Visit 3, because we needed 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/Alzheimer's disease 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.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single Arm | Experimental | Drug: empagliflozin (Jardiance) 25 mgSingle group |
Who may qualify
- Ages
- 55 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (33 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| empagliflozin (Jardiance) 25 mgOral empagliflozin 25 mg/day x 14 days | Drug | Single Arm |
Primary outcome
Change in Serum β-hydroxybutyrate (BHB)
Time frame: 14 days
Change in serum β-hydroxybutyrate (BHB) after 14 days on empagliflozin, compared with baseline.
7 secondary outcomes
Change in Plasma Glucose
Time frame: 14 days
Change in Serum Non-esterified Fatty Acids (NEFAs)
Time frame: 14 days
Change in Plasma Insulin
Time frame: 14 days
Change in Serum Acetoacetate (AcAc)
Time frame: 14 days
Change in 1H MRS BHB
Time frame: 14 days
Change in 1H MRS Glutamate (Glu)
Time frame: 14 days
Change in 1H MRS Glutamine (Gln)
Time frame: 14 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Aug 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Josephine M Egan, M.D. principal investigator
National Institute on Aging (NIA)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing empagliflozin (Jardiance) 25 mg in people with Empaglifozin and Physiological Effects of Drugs, run by National Institute on Aging (NIA) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Aug 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Serum β-hydroxybutyrate (BHB) (time frame: 14 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Aug 2022.