- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04659915
Counteracting Deleterious Metabolic Glucocorticoid Effects With Metformin (Gluco-Met)
Counteracting Deleterious Metabolic Glucocorticoid Effects With Metformin - A Double-blind, Randomized, Placebo-controlled, Cross-over Study
Supraphysiological doses of glucocorticoids (GCs) are widely prescribed as immunosuppressants and metabolic side effects such as obesity and diabetes are extremely common. Efforts to investigate and prevent these side effects are lacking. The antidiabetic drug metformin was shown in previous studies to prevent deterioration of glucose homeostasis during GC therapy in patients. However, mechanisms of metformin counteracting GC-induced side effects remain poorly understood.
In a randomized, placebo-controlled, cross-over study, 18 healthy volunteers will receive a 7-day course of prednisone with metformin or placebo. Established methods will be used to assess systemic changes in energy homeostasis and novel techniques such as metabolomics will identify underlying pathways. This will advance the understanding of energy homeostasis during GC excess, may prevent thousands of patients from GC-induced side effects and also offers a model for targeting disrupted endogenous GCs secretion.
Study Overview
Status
Conditions
Detailed Description
Obesity is one of the most serious health problems in the 21st century (1). Currently, more than 700 million people world-wide are obese and face an increased risk of morbidity and a reduced life-expectancy of up to 10 years (1, 2). High energy food and a sedentary lifestyle are driving the current obesity pandemic (3). Sleep deprivation and psychological stress also have been identified as contributing factors (4). Many of these factors activate the hypothalamic-pituitary-adrenal (HPA) axis, the key regulatory pathway of energy homeostasis. Activation of the HPA-axis leads to secretion of glucocorticoids (GCs) from the adrenal glands. GCs control energy homeostasis by mobilizing and redistributing energy substrates (5). In an evolutionary context, GCs are particularly important during periods of stress, especially when food is scarce. In today's environment, where food is abundantly available, GCs potentially can become deleterious by severely disrupting energy homeostasis. Therefore, the GC pathway has gained interest as a potential treatment target for the metabolic syndrome.
Next to their essential role in energy homeostasis, glucocorticoids are the most commonly prescribed immunosuppressant drugs. GCs are used for acute as well as chronic conditions in virtually all medical disciplines (6). It is well known that patients on GC treatment are at high risk for developing numerous side effects. Next to dyslipidaemia, arterial hypertension and cardiovascular disease, up to 80% of patients experience weight gain, while around 40% develop diabetes (7). Currently, no therapies exist to prevent any of these side effects. The only available strategy to prevent GC-induced side effects is to restrain GC use.
The objective of this project is to test in a clinical study in humans whether metformin can counteract the deleterious metabolic effects developed after a short-term glucocorticoid treatment. The primary objective is to test how metformin counteracts metabolic side effects of GCs compared to placebo. Secondary objectives are to detect underlying pathways in blood (metabolomics), adipose tissue (gene expression analysis) and mitochondria (Cytosensor) with metformin in combination with prednisone compared to placebo and prednisone.
This is a double-blind, randomized, placebo-controlled cross-over study. After screening, subjects will be randomized to two crossover 7-day study periods with a washout period of 28 days:
A) Participants will receive prednisone 30 mg/d p.o. and metformin (starting with a dose of 500 mg/d and increasing the dose by 500 mg every other day until 2000 mg/d are achieved).
B) Participants will receive prednisone 30 mg/d p.o. and placebo p.o. (starting with a dose of 500 mg/d and increasing the dose by 500 mg every other day until 2000 mg/d are achieved).
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
Basel-Stadt
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Basel, Basel-Stadt, Switzerland, 4031
- University Hospital Basel
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- BMI 18.5 - 25 kg/m2
Exclusion Criteria:
- Any current significant disease,
- Any medication
- Glucocorticoids and/ or metformin for up to four weeks before study inclusion
- Regular alcohol intake (>30g/d),
- Regular physical activity (>4hrs per week),
- Known allergy to metformin,
- Inability or unwillingness to provide informed consent.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Metformin + Prednison
During one of the study periods, subjects receive Metformin 500 mg tablets p.o. for seven days (starting with a dose of 500 mg /d, then the dose will be increased by 500 mg the next days until 2000 mg /d is achieved). Subjects also receive Prednisone 20 mg 1.5x/d tablets p.o. for seven days. |
During one phase of the study: Metformin 500mg Day 1 1-0-0 Day 2 1-0-0 Day 3 1-0-1 Day 4 1-0-1 Day 5 2-0-1 Day 6 2-0-1 Day 7 4-0-0 In combination with prednisone 20mg: day 1 to day 7 1.5-0-0. |
Placebo Comparator: Placebo + Prednison
During the other study period, subjects receive the same dose of placebo tablets p.o instead of metformin.
Subjects also receive Prednisone 20 mg 1.5x/d tablets p.o. for seven days.
|
During another phase of the study: identical looking placebo pills starting day 1 500mg 1-0-0, day 2 500mg 1-0-0, day 3 500mg 1-0-1, day 4 500mg 1-0-1, day 5 500mg 2-0-1.
day 6 2-0-1, day 7 4-0-0.
In combination with prednisone 20mg: day 1 to day 7 1.5-0-0.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Insulin sensitivity
Time Frame: Two 1-week intervention periods
|
Change in insulin sensitivity (HOMA-Index) assessed with a mixed meal tolerance test.
|
Two 1-week intervention periods
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Lipids (mmol/l)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
Cortisol (nmol/l)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
GLP-1 (nmol/l)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
GIP (nmol/l)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
PYY (pg/ml)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
C-peptide (pmol/l)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
T3 (nmol/l)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
T4 (nmol/l)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
TSH (mIU/l)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
HGH (mIU/l)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
Sympathetic nervous system activity
Time Frame: Two 1-week intervention periods
|
Heart rate variability analysis
|
Two 1-week intervention periods
|
Blood pressure
Time Frame: Two 1-week intervention periods
|
Assessment of blood pressure with a standard blood pressure monitor.
|
Two 1-week intervention periods
|
Weight
Time Frame: Two 1-week intervention periods
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Measurement of weight with a standard scale
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Two 1-week intervention periods
|
Energy expenditure
Time Frame: Two 1-week intervention periods
|
Basal metabolic rate measured with indirect calorimetry
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Two 1-week intervention periods
|
Substrate utilisation
Time Frame: Two 1-week intervention periods
|
Respiratory quotient assessed with indirect calorimetry
|
Two 1-week intervention periods
|
GDF-15 (pg/mL)
Time Frame: Two 1-week intervention periods
|
Blood sample
|
Two 1-week intervention periods
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Metabolomics
Time Frame: Two 1-week intervention periods
|
Metabolomics will be performed in blood plasma
|
Two 1-week intervention periods
|
Gene expression analysis
Time Frame: Two 1-week intervention periods
|
Adipose tissue biobsy
|
Two 1-week intervention periods
|
Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Arnlov J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Furst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang YH, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin MJ, Shiri R, Shiue I, Roba HS, Silva DAS, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabares-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017 Jul 6;377(1):13-27. doi: 10.1056/NEJMoa1614362. Epub 2017 Jun 12.
- Prospective Studies Collaboration, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009 Mar 28;373(9669):1083-96. doi: 10.1016/S0140-6736(09)60318-4. Epub 2009 Mar 18.
- van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015 Mar 26;161(1):119-132. doi: 10.1016/j.cell.2015.03.008.
- Vgontzas AN, Lin HM, Papaliaga M, Calhoun S, Vela-Bueno A, Chrousos GP, Bixler EO. Short sleep duration and obesity: the role of emotional stress and sleep disturbances. Int J Obes (Lond). 2008 May;32(5):801-9. doi: 10.1038/ijo.2008.4. Epub 2008 Feb 5.
- de Guia RM, Rose AJ, Herzig S. Glucocorticoid hormones and energy homeostasis. Horm Mol Biol Clin Investig. 2014 Aug;19(2):117-28. doi: 10.1515/hmbci-2014-0021.
- Laugesen K, Jorgensen JOL, Sorensen HT, Petersen I. Systemic glucocorticoid use in Denmark: a population-based prevalence study. BMJ Open. 2017 May 29;7(5):e015237. doi: 10.1136/bmjopen-2016-015237.
- McDonough AK, Curtis JR, Saag KG. The epidemiology of glucocorticoid-associated adverse events. Curr Opin Rheumatol. 2008 Mar;20(2):131-7. doi: 10.1097/BOR.0b013e3282f51031.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- EKNZ 2020-01233
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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