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

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

Ketones, Metabolism, Hormones, Alzheimer's Disease

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.

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.

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