Use of Empagliflozin to Treat Prediabetes

Study Overview
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Brief Summary
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The overall purpose of this study is to identify how empagliflozin (a drug commonly used to treat type 2 diabetes) impacts skeletal muscle metabolic health among adults with prediabetes. Our aims are to: 1) Test the ability of empagliflozin to improve regulation of glucose metabolism (i.e., blood sugar) among overweight and obese individuals at risk for diabetes, and 2) Identify mechanisms to explain how empagliflozin may improve skeletal muscle glucose metabolism. We hypothesize empagliflozin will improve regulation of glucose metabolism due to changes in whole-body and skeletal muscle metabolism (e.g., increased rates of whole-body fat oxidation, evidence of impaired skeletal muscle mitochondrial respiratory function and increased energetic stress, lower accumulation of skeletal muscle lipids and improved skeletal muscle insulin signaling compared with placebo treatment).

Detailed Description
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The overall study design is a 13-week, double-blind, placebo-controlled intervention trial, testing the ability of empagliflozin to improve glucose metabolism among overweight and obese individuals at risk for diabetes (compared with a multivitamin-placebo). The study involves metabolic testing before and during the intervention to identify changes in outcomes as a function of the intervention and to ensure participant safety. The study involves 9 visits to the Samaritan Athletic Medicine Center on the campus of Oregon State University in Corvallis, Oregon. Full completion of the study is anticipated to take  4 months. The project is being completed in collaboration with physicians at Samaritan Health Services.

Official Title
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Use of Empagliflozin to Treat Prediabetes - a Randomized, Double-blind, Placebo-controlled 13-week Intervention Trial

Conditions
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PreDiabetes, Prediabetic State, Overweight and Obesity

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Multivitamin-Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI 26-45 kg/m2 Weight stable (± 10 lbs in previous 3 months) Fasting blood glucose <126 mg/dL or HbA1c <6.5% (<48mmol/mol) Exclusion Criteria: Regular moderate-vigorous exercise (≥30 min/session on ≥2 days per week) Pregnancy, planning to become pregnant or nursing Lidocaine allergy Current or recent smoking or nicotine use (≤ 1-year abstention) Medications including glucose lowering medications and supplements (SGLT2 inhibitors, GLP1 agonists, sulfonylurea, insulin, TZDs); mono-amine oxidase inhibitors; beta-blockers; diuretics Major metabolic or cardiovascular conditions (e.g., type 1 diabetes, Crohn's disease, untreated hypo- or hyperthyroid, cancer, coronary artery disease, tachycardia, prior bariatric surgery, peripheral vascular disease, liver diseases (e.g., cirrhosis) Diagnosed type 2 diabetes. In absence of diagnosis, two separate samples with test results of fasting blood glucose ≥126 mg/dL or HbA1c ≥6.5% (48 mmol/mol). Contraindications/precautions for empagliflozin (impaired renal function (EGR<60), history of: empagliflozin hypersensitivity, ketoacidosis, hypotension, recurring urinary tract or genital mycotic infections, amputation)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br>Participants will be provided 10-25mg empagliflozin per day for 13 weeks. | Drug: Empagliflozin<br>* Participants will take 10mg empagliflozin per day for 2 weeks. Absent contraindications, dosing will be increased to 25 mg empagliflozin per day for the next 11 weeks.<br>* Other names: Jardiance;|
| Placebo Comparator: Multivitamin-Placebo<br>Participants will be provided 1 multivitamin-placebo per day for 13 weeks. | Drug: Multivitamin-Placebo<br>* Participants will take 1 multivitamin per day for 13 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin-stimulated glucose disposal | The glucose infusion rate to maintain glycemia during insulin clamp, using plasma enrichment of glucose isotope tracer to determine changes in rates of insulin-stimulated glucose disposal | Insulin-stimulated glucose disposal is measured before the start of the intervention (baseline) and during week 13 of the intervention. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral glucose tolerance | The change in blood glucose concentration in response to a 75g glucose beverage | Oral glucose tolerance is measured before the start of the intervention (baseline) and during week 12 of the intervention. | 
| Fasting plasma glucose concentration | The change in fasting plasma glucose concentration | Fasting plasma glucose is measured before the start of the intervention (baseline) and during week 13 of the intervention. | 
| Whole-body fat oxidation | Indirect calorimetry will be used to determine the change in whole-body rate of fat oxidation during basal and insulin-stimulated conditions | Whole-body fat oxidation is measured before the start of the intervention (baseline) and during week 13 of the intervention. | 
| Skeletal muscle insulin signaling | Immunoblotting to determine the change in activation of insulin signaling proteins in skeletal muscle collected at basal and during insulin-stimulated conditions | Skeletal muscle insulin signaling is measured before the start of the intervention (baseline) and during week 13 of the intervention. | 
| Skeletal muscle lipids | Mass spectrometry lipidomic analysis of skeletal muscle to determine changes in muscle lipid content | Skeletal muscle lipids are measured before the start of the intervention (baseline) and during week 13 of the intervention. | 
| Skeletal muscle mitochondrial respiratory function | Changes in skeletal muscle mitochondrial respiratory capacity measured using high-resolution respirometry | Skeletal muscle mitochondrial respiratory function is measured before the start of the intervention (baseline) and during week 13 of the intervention. | 
| Skeletal muscle energetic stress | Immunoblotting to determine changes in activation of AMPK and related signaling proteins pathways | Skeletal muscle energetic stress is measured before the start of the intervention (baseline) and during week 13 of the intervention. |