Effects of Sodium-glucose Co-transporter-2( SGLT-2 ) Inhibition on Sympathetic Nervous System Activity in Humans

Study Overview
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Brief Summary
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This study is designed to investigate whether the sodium-glucose co-transporter-2 (SGLT-2) inhibitor Empagliflozin reduces sympathetic nervous system (SNS) activity in humans.

Detailed Description
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This is a randomised, double-blind, placebo controlled, cross-over study. Participants will be randomly assigned to receive either Empagliflozin 10mg/daily or Placebo and will later receive the alternate treatment. Comprehensive testing will occur after each 4 week treatment phase and will include assessment of muscle sympathetic nerve activity, cardiac and renal noradrenaline spillover to assess organ specific SNS activity.

Official Title
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Effects of SGLT-2 Inhibition on Sympathetic Nervous System Activity in Humans

Conditions
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Metabolic Syndrome, Type 2 Diabetes Mellitus, Obesity

Intervention / Treatment
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* Drug: Empagliflozin Oral Tablet [Jardiance]
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 25 -65 years (Body Mass Index) BMI≥30kg/m2 Currently weight stable (+/- 3% in previous 6-12 months and not on any specific exercise or dietary program) Metabolic syndrome (defined as having: obesity (BMI ≥30kg/m2 ) plus any two of the following four factors: Elevated triglycerides (Triglyceride≥ 1.7mmol/L), Reduced HDL (High - density lipoprotein) cholesterol (<1.0mmol/L in males, <1.3mmol/L in females), Elevated clinic systolic (Blood Pressure) BP ≥130 or diastolic BP ≥85mmHg, Fasting glucose ≥5.6mmol/L or type 2 diabetes. office BP for screening purposes ≤160/90mmHg drug naïve for at least 6 weeks prior to baseline assessment Exclusion Criteria: Grade 2-3 hypertension (systolic office BP >160, diastolic office BP >100 mmHg) Secondary causes of hypertension CKD (Chronic kidney disease) stage 4-5 {(estimated glomerular filtration) eGFR<30ml/min} Heart failure NYHA (New York Heart Association) class II-IV Recent CV (cardiovascular) event (acute myocardial infarction, acute coronary syndrome, stroke or transient ischaemic attack within the previous six months) unstable psychiatric condition medication such as corticosteroids, several antidepressants and antipsychotics Female participants of childbearing potential must have a negative pregnancy test prior to treatment

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Phase 1<br>Empagliflozin 10mg daily or placebo | Drug: Empagliflozin Oral Tablet [Jardiance]<br>* Participants will be randomly assigned to receive either Empagliflozin 10mg/daily or Placebo and will later receive the alternate treatment. As the study is double blind neither the participant nor the study personnel will be aware of which treatment is currently being tested to avoid any effect this may have on the results. The two 4-week treatment phases will be separated by a 4-week wash out (drug-free) period. The study will consist of a total of 5 visits conducted over approximately 18 weeks; one screening visit, one baseline visit, 1 short visit at the start of the second treatment phase and 2 comprehensive testing visits, each at the end of the two treatment phases<br>Drug: Placebo Oral Tablet<br>* Participants will be randomly assigned to receive either Empagliflozin 10mg/daily or Placebo and will later receive the alternate treatment. As the study is double blind neither the participant nor the study personnel will be aware of which treatment is currently being tested to avoid any effect this may have on the results. The two 4-week treatment phases will be separated by a 4-week wash out (drug-free) period. The study will consist of a total of 5 visits conducted over approximately 18 weeks; one screening visit, one baseline visit, 1 short visit at the start of the second treatment phase and 2 comprehensive testing visits, each at the end of the two treatment phases<br>|
| Placebo Comparator: Phase2<br>Empagliflozin 10mg daily or placebo | Drug: Empagliflozin Oral Tablet [Jardiance]<br>* Participants will be randomly assigned to receive either Empagliflozin 10mg/daily or Placebo and will later receive the alternate treatment. As the study is double blind neither the participant nor the study personnel will be aware of which treatment is currently being tested to avoid any effect this may have on the results. The two 4-week treatment phases will be separated by a 4-week wash out (drug-free) period. The study will consist of a total of 5 visits conducted over approximately 18 weeks; one screening visit, one baseline visit, 1 short visit at the start of the second treatment phase and 2 comprehensive testing visits, each at the end of the two treatment phases<br>Drug: Placebo Oral Tablet<br>* Participants will be randomly assigned to receive either Empagliflozin 10mg/daily or Placebo and will later receive the alternate treatment. As the study is double blind neither the participant nor the study personnel will be aware of which treatment is currently being tested to avoid any effect this may have on the results. The two 4-week treatment phases will be separated by a 4-week wash out (drug-free) period. The study will consist of a total of 5 visits conducted over approximately 18 weeks; one screening visit, one baseline visit, 1 short visit at the start of the second treatment phase and 2 comprehensive testing visits, each at the end of the two treatment phases<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in cardiac sympathetic nerve activity | Cardiac sympathetic nerve activity assessed by cardiac noradrenaline spillover | 18 weeks | 
| Reduction in renal sympathetic nerve activity | Renal sympathetic nerve activity assessed by renal noradrenaline spillover | 18 weeks | 
| Reduction in muscle sympathetic nerve activity | Muscle sympathetic nerve activity assessed by microneurography | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in ambulatory BP (blood pressure) | Blood Pressure assessed by ambulatory blood pressure monitoring | 18 weeks | 
| Reduction in central Blood Pressure | central Blood Pressure assessed by Sphygmocor XCEL | 18 weeks | 
| Change in urinary sodium excretion | Urinary sodium excretion assessed in a 24 hour urine sample | 18 weeks | 
| Change in glycemic control | Glycemic control as assessed by an oral glucose tolerance test | 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolic Syndrome, Central sympathetic nervous system, Sodium-glucose co-transporter-2 (SGLT2), Blood Pressure