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

Obesity Clinical Trial

— EMPA-SNS  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03912909
• Other study ID #: REG 16-157
• Status: Recruiting
• Phase: Phase 4
• Start date: August 1, 2018
• Est. completion date: December 30, 2024

Study information

• Verified date: September 2022
• Source: Royal Perth Hospital
• Contact: Anu Joyson, MSN
• Phone: +61 8 92240390
• Email: anu.joyson[@]uwa.edu.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 30, 2024
• Est. primary completion date: March 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Metabolic Syndrome
• Obesity
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Empagliflozin Oral Tablet [Jardiance]
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
• Placebo Oral Tablet
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

Locations

Country	Name	City	State
Australia	Royal Perth Hospital	Perth	Western Australia

Sponsors (1)

Lead Sponsor	Collaborator
Royal Perth Hospital

Country where clinical trial is conducted

Australia, 

References & Publications (9)

Esler M, Straznicky N, Eikelis N, Masuo K, Lambert G, Lambert E. Mechanisms of sympathetic activation in obesity-related hypertension. Hypertension. 2006 Nov;48(5):787-96. Epub 2006 Sep 25. Review. — View Citation

Hall JE, Jones DW, Kuo JJ, da Silva A, Tallam LS, Liu J. Impact of the obesity epidemic on hypertension and renal disease. Curr Hypertens Rep. 2003 Oct;5(5):386-92. Review. — View Citation

Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, Hoppe UC, Vonend O, Rump LC, Sobotka PA, Krum H, Esler M, Böhm M. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation. 2011 May 10;123(18):1940-6. doi: 10.1161/CIRCULATIONAHA.110.991869. Epub 2011 Apr 25. — View Citation

Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation. 2003 Aug 5;108(5):560-5. Epub 2003 Jul 7. — View Citation

Straznicky NE, Grima MT, Sari CI, Karapanagiotidis S, Wong C, Eikelis N, Richards KL, Lee G, Nestel PJ, Dixon JB, Lambert GW, Schlaich MP, Lambert EA. The relation of glucose metabolism to left ventricular mass and function and sympathetic nervous system activity in obese subjects with metabolic syndrome. J Clin Endocrinol Metab. 2013 Feb;98(2):E227-37. doi: 10.1210/jc.2012-3277. Epub 2012 Dec 27. — View Citation

Straznicky NE, Lambert EA, Grima MT, Eikelis N, Richards K, Nestel PJ, Dawood T, Masuo K, Sari CI, Dixon JB, Esler MD, Paul E, Schlaich MP, Lambert GW. The effects of dietary weight loss on indices of norepinephrine turnover: modulatory influence of hyperinsulinemia. Obesity (Silver Spring). 2014 Mar;22(3):652-62. doi: 10.1002/oby.20614. Epub 2013 Dec 6. — View Citation

Sverrisdóttir YB, Jansson LM, Hägg U, Gan LM. Muscle sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy individuals. PLoS One. 2010 Feb 17;5(2):e9257. doi: 10.1371/journal.pone.0009257. — View Citation

Ziegler D, Weise F, Langen KJ, Piolot R, Boy C, Hübinger A, Müller-Gärtner HW, Gries FA. Effect of glycaemic control on myocardial sympathetic innervation assessed by [123I]metaiodobenzylguanidine scintigraphy: a 4-year prospective study in IDDM patients. Diabetologia. 1998 Apr;41(4):443-51. — View Citation

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Reduction in cardiac sympathetic nerve activity	Cardiac sympathetic nerve activity assessed by cardiac noradrenaline spillover	18 weeks
Primary	Reduction in renal sympathetic nerve activity	Renal sympathetic nerve activity assessed by renal noradrenaline spillover	18 weeks
Primary	Reduction in muscle sympathetic nerve activity	Muscle sympathetic nerve activity assessed by microneurography	18 weeks
Secondary	Reduction in ambulatory BP (blood pressure)	Blood Pressure assessed by ambulatory blood pressure monitoring	18 weeks
Secondary	Reduction in central Blood Pressure	central Blood Pressure assessed by Sphygmocor XCEL	18 weeks
Secondary	Change in urinary sodium excretion	Urinary sodium excretion assessed in a 24 hour urine sample	18 weeks
Secondary	Change in glycemic control	Glycemic control as assessed by an oral glucose tolerance test	18 weeks