Counteracting Deleterious Metabolic Glucocorticoid Effects With Metformin

Glucocorticoid Effect Clinical Trial

— Gluco-Met  

Official title:

Counteracting Deleterious Metabolic Glucocorticoid Effects With Metformin - A Double-blind, Randomized, Placebo-controlled, Cross-over Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04659915
• Other study ID #: EKNZ 2020-01233
• Status: Completed
• Phase: Phase 4
• Start date: February 25, 2021
• Est. completion date: August 18, 2021

Study information

• Verified date: September 2021
• Source: University Hospital, Basel, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: August 18, 2021
• Est. primary completion date: August 18, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

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.

Related Conditions & MeSH terms

• Glucocorticoid Effect

Intervention

Drug:
• Metformin 500 mg Oral Tablets + Prednisone 20mg Tablets
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 500 mg Tablets + Prednisone 20mg Tablets
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.

Locations

Country	Name	City	State
Switzerland	University Hospital Basel	Basel	Basel-Stadt

Sponsors (1)

Lead Sponsor	Collaborator
Eleonora Seelig

Country where clinical trial is conducted

Switzerland, 

References & Publications (7)

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. Review. — View Citation

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 — View Citation

Laugesen K, Jørgensen JOL, Sørensen 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. — View Citation

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. Review. — View Citation

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. Lanc — View Citation

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. Review. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Metabolomics	Metabolomics will be performed in blood plasma	Two 1-week intervention periods
Other	Gene expression analysis	Adipose tissue biobsy	Two 1-week intervention periods
Primary	Insulin sensitivity	Change in insulin sensitivity (HOMA-Index) assessed with a mixed meal tolerance test.	Two 1-week intervention periods
Secondary	Lipids (mmol/l)	Blood sample	Two 1-week intervention periods
Secondary	Cortisol (nmol/l)	Blood sample	Two 1-week intervention periods
Secondary	GLP-1 (nmol/l)	Blood sample	Two 1-week intervention periods
Secondary	GIP (nmol/l)	Blood sample	Two 1-week intervention periods
Secondary	PYY (pg/ml)	Blood sample	Two 1-week intervention periods
Secondary	C-peptide (pmol/l)	Blood sample	Two 1-week intervention periods
Secondary	T3 (nmol/l)	Blood sample	Two 1-week intervention periods
Secondary	T4 (nmol/l)	Blood sample	Two 1-week intervention periods
Secondary	TSH (mIU/l)	Blood sample	Two 1-week intervention periods
Secondary	HGH (mIU/l)	Blood sample	Two 1-week intervention periods
Secondary	Sympathetic nervous system activity	Heart rate variability analysis	Two 1-week intervention periods
Secondary	Blood pressure	Assessment of blood pressure with a standard blood pressure monitor.	Two 1-week intervention periods
Secondary	Weight	Measurement of weight with a standard scale	Two 1-week intervention periods
Secondary	Energy expenditure	Basal metabolic rate measured with indirect calorimetry	Two 1-week intervention periods
Secondary	Substrate utilisation	Respiratory quotient assessed with indirect calorimetry	Two 1-week intervention periods
Secondary	GDF-15 (pg/mL)	Blood sample	Two 1-week intervention periods