Gluco-Met: Counteracting Deleterious Metabolic Glucocorticoid Effects With Metformin
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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:
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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).
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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 Design
Arms and Interventions
| 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. |
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 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. |
Drug: 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.
|
Outcome Measures
Primary Outcome Measures
- Insulin sensitivity [Two 1-week intervention periods]
Change in insulin sensitivity (HOMA-Index) assessed with a mixed meal tolerance test.
Secondary Outcome Measures
- Lipids (mmol/l) [Two 1-week intervention periods]
Blood sample
- Cortisol (nmol/l) [Two 1-week intervention periods]
Blood sample
- GLP-1 (nmol/l) [Two 1-week intervention periods]
Blood sample
- GIP (nmol/l) [Two 1-week intervention periods]
Blood sample
- PYY (pg/ml) [Two 1-week intervention periods]
Blood sample
- C-peptide (pmol/l) [Two 1-week intervention periods]
Blood sample
- T3 (nmol/l) [Two 1-week intervention periods]
Blood sample
- T4 (nmol/l) [Two 1-week intervention periods]
Blood sample
- TSH (mIU/l) [Two 1-week intervention periods]
Blood sample
- HGH (mIU/l) [Two 1-week intervention periods]
Blood sample
- Sympathetic nervous system activity [Two 1-week intervention periods]
Heart rate variability analysis
- Blood pressure [Two 1-week intervention periods]
Assessment of blood pressure with a standard blood pressure monitor.
- Weight [Two 1-week intervention periods]
Measurement of weight with a standard scale
- Energy expenditure [Two 1-week intervention periods]
Basal metabolic rate measured with indirect calorimetry
- Substrate utilisation [Two 1-week intervention periods]
Respiratory quotient assessed with indirect calorimetry
- GDF-15 (pg/mL) [Two 1-week intervention periods]
Blood sample
Other Outcome Measures
- Metabolomics [Two 1-week intervention periods]
Metabolomics will be performed in blood plasma
- Gene expression analysis [Two 1-week intervention periods]
Adipose tissue biobsy
Eligibility Criteria
Criteria
Inclusion Criteria:
- BMI 18.5 - 25 kg/m2
Exclusion Criteria:
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Any current significant disease,
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Any medication
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Glucocorticoids and/ or metformin for up to four weeks before study inclusion
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Regular alcohol intake (>30g/d),
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Regular physical activity (>4hrs per week),
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Known allergy to metformin,
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Inability or unwillingness to provide informed consent.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Hospital Basel | Basel | Basel-Stadt | Switzerland | 4031 |
Sponsors and Collaborators
- Eleonora Seelig
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- EKNZ 2020-01233