Effect of Fluvastatin on Brown Fat Activity

Insulin Resistance Clinical Trial

— FluvaBAT  

Official title:

Short Term Effect of Fluvastatin on Brown Adipose Tissue Thermogenesis and Activity in Humans

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03189511
• Other study ID #: FluvaBAT
• Status: Completed
• Phase: Phase 4
• Start date: May 31, 2017
• Est. completion date: February 19, 2018

Study information

• Verified date: May 2018
• Source: University of Zurich
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to elucidate the effects of Fluvastatin on brown adipose tissue activity in humans.

Description:

Statins, inhibitors of cholesterol biosynthesis, act by inhibiting the enzyme of the mevalonate pathway. Although the clinical benefits of statins are undisputable, they have been shown to increase insulin resistance and incidence of type 2 diabetes mellitus, the mechanism of which is currently not clear.

The main function of brown adipose tissue (BAT) is non-shivering thermogenesis (i.e. heat production through energy dissipation) in brown adipocytes. There has been a growing interest in BAT as a novel therapeutic approach to increase energy expenditure in order to facilitate weight-loss and increase insulin sensitivity.

BAT activity will be assessed using calorimetric test and [18F]-Fluorodeoxyglucose (FDG) positron emission tomography (PET).

We speculate that statins inhibit BAT function and that this mechanism may contribute to the above mentioned increase in insulin resistance.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: February 19, 2018
• Est. primary completion date: January 23, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

• Male volunteers (18-40 y)

• body mass index 19 to 27 kg/m²

• Fluent in German or English

Exclusion Criteria:

• Regular physical exercise of more than >150 min of exercise per week.

• Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product,

• Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, cardiovascular disease, etc.),

• Clinically indicated intake of the following medications: Corticosteroids, CYP3A4-Inhibitors (Itraconazol, Voriconazol, Fluconazol, Clarithromycin, Erythromycin, Indinavir, Nelfinavir, Ritonavir, Grapefruit juice), Beta-Blocker, Neuroleptics, Tricyclic Antidepressants,

• Known or suspected non-compliance, drug or alcohol abuse,

• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant,

• Participation in another study with investigational drug within the 30 days preceding and during the present study,

• Participation in another study involving ionizing radiation in the same year,

• Previous enrolment into the current study,

• Enrolment of the investigator, his/her family members, employees and other dependent persons,

• MRI contraindications: Not MRI-compatible metal in the body, cardiac pacemaker, History of surgery with possible metal clips/parts still in the body, claustrophobia.

• Resting pulse rate > 70 bpm

• Known arterial hypertension or resting blood pressure > 130/80 mmHg.

• frequence corrected QT-time (QTc) >430 ms

• Serum creatinine > 1.5x upper limit of norm (ULN), i.e.> 145 µmol/L

• creatine kinase > 1.5x ULN, i.e. > 300 U/L

• aspartate transaminase (ASAT) > 1.5x ULN, i.e. > 51 U/L

• alanine aminotransferase (ALAT) > 1.5x ULN, i.e. > 88 U/L

• Hypothyroidism

• Vitamin D deficiency, Vitamin D3 < 25 nmol/L

• Intake of anticoagulants or inhibitors of platelet aggregation (e.g. Aspirin, clopidogrel).

• Known tendency to form keloids (hypertrophic scar tissue)

Related Conditions & MeSH terms

• Adipose Tissue, Brown
• Clinical Trial
• Insulin Resistance

Intervention

Drug:
• Fluvastatin
Fluvastatin 40 mg twice daily per mouth for 14 days.

Locations

Country	Name	City	State
Switzerland	University Hospital of Basel	Basel
Switzerland	University Hospital of Zurich, PET/MR Center	Schlieren	Zurich

Sponsors (2)

Lead Sponsor	Collaborator
University of Zurich	University of Basel

Country where clinical trial is conducted

Switzerland, 

References & Publications (5)

Chapple CR, Dvorak V, Radziszewski P, Van Kerrebroeck P, Wyndaele JJ, Bosman B, Boerrigter P, Drogendijk T, Ridder A, Van Der Putten-Slob I, Yamaguchi O; Dragon Investigator Group. A phase II dose-ranging study of mirabegron in patients with overactive bladder. Int Urogynecol J. 2013 Sep;24(9):1447-58. doi: 10.1007/s00192-013-2042-x. Epub 2013 Mar 8. — View Citation

Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elía E, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM. Activation of human brown adipose tissue by a ß3-adrenergic receptor agonist. Cell Metab. 2015 Jan 6;21(1):33-8. doi: 10.1016/j.cmet.2014.12.009. — View Citation

Duvnjak L, Blaslov K. Statin treatment is associated with insulin sensitivity decrease in type 1 diabetes mellitus: A prospective, observational 56-month follow-up study. J Clin Lipidol. 2016 Jul-Aug;10(4):1004-1010. doi: 10.1016/j.jacl.2016.04.012. Epub 2016 May 10. — View Citation

Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, Ray KK. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011 Jun 22;305(24):2556-64. doi: 10.1001/jama.2011.860. — View Citation

Puurunen J, Piltonen T, Puukka K, Ruokonen A, Savolainen MJ, Bloigu R, Morin-Papunen L, Tapanainen JS. Statin therapy worsens insulin sensitivity in women with polycystic ovary syndrome (PCOS): a prospective, randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2013 Dec;98(12):4798-807. doi: 10.1210/jc.2013-2674. Epub 2013 Oct 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	(18)F-FDG uptake in the supraclavicular brown adipose tissue measured by PET by the maximum standardized uptake value (SUVmax)	Cold and Mirabegron induced 18F-FDG uptake into the supra-clavicular brown adipose tissue (scBAT) as determined by 18F-FDG PET/MR standardized uptake value (SUVmax) after two weeks of treatment with Fluvastatin.	14 days
Secondary	The mean standardized uptake value for 18F-FDG uptake (SUVmean) in the supraclavicular adipose tissue depot	SUVmean in the supraclavicular adipose tissue depot (analog. SUVmax)	14 days
Secondary	Volume of supraclavicular BAT	Volume of supraclavicular BAT as determined on Magnetic Resonance Imaging (MRI)	14 days
Secondary	fat fraction with T2 relaxation time of the BAT depot	fat fraction with T2 relaxation time of the scBAT depot as determined by MRI	14 days
Secondary	Cold induced thermogenesis	Cold induced thermogenesis: Increase in energy expenditure above resting metabolic rate in response to a mild cold stimulus and pharmacologic stimulation with Mirabegron.	14 days
Secondary	Supraclavicular skin temperature in response to mild cold stimulus	Supraclavicular skin temperature in response to mild cold stimulus measured by local probe	14 days