Phase 1 N=21 Basic Science

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

Empaglifozin · Physiological Effects of Drugs · Hypoglycemic Agents · Sodium-Glucose Transporter 2 Inhibitors

Bottom Line

View on ClinicalTrials.gov: NCT03852901 ↗

Enrolled (actual)

Serious AEs

0.0%

Results posted

Aug 2022

Primary outcome: Primary: Change in Serum β-hydroxybutyrate (BHB) — 40.717 µM — p=<0.001

Study Design & Population

Study type: Interventional
Phase: Phase 1
Interventions: empagliflozin (Jardiance) 25 mg (Drug)
Age: Adult, Older Adult · 55+ yrs
Sex: All
Sponsor: National Institute on Aging (NIA)
Primary completion: Nov 2020

Outcome Measures

Outcome	Result	p-value
PRIMARY Change in Serum β-hydroxybutyrate (BHB)	40.717	<0.001 sig
SECONDARY Change in Plasma Glucose	-.637	0.545
SECONDARY Change in Serum Non-esterified Fatty Acids (NEFAs)	.027	0.003 sig
SECONDARY Change in Plasma Insulin	-2.647	0.047 sig
SECONDARY Change in Serum Acetoacetate (AcAc)	-5.573	0.003 sig
SECONDARY Change in 1H MRS BHB	0.04	0.5849
SECONDARY Change in 1H MRS Glutamate (Glu)	-0.23	0.0142 sig
SECONDARY Change in 1H MRS Glutamine (Gln)	-0.27	0.024 sig

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.

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Data sourced from ClinicalTrials.gov (NCT03852901). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.