Counteracting Deleterious Metabolic Glucocorticoid Effects With Metformin

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Glucocorticoid Effect

Intervention / Treatment
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* Drug: Metformin 500 mg Oral Tablets + Prednisone 20mg Tablets
* Drug: Placebo 500 mg Tablets + Prednisone 20mg Tablets


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Double-blind, randomized, placebo-controlled cross-over study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin + Prednison<br>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<br>* 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.<br>|
| Placebo Comparator: Placebo + Prednison<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity | 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) | Blood sample | Two 1-week intervention periods | 
| Cortisol (nmol/l) | Blood sample | Two 1-week intervention periods | 
| GLP-1 (nmol/l) | Blood sample | Two 1-week intervention periods | 
| GIP (nmol/l) | Blood sample | Two 1-week intervention periods | 
| PYY (pg/ml) | Blood sample | Two 1-week intervention periods | 
| C-peptide (pmol/l) | Blood sample | Two 1-week intervention periods | 
| T3 (nmol/l) | Blood sample | Two 1-week intervention periods | 
| T4 (nmol/l) | Blood sample | Two 1-week intervention periods | 
| TSH (mIU/l) | Blood sample | Two 1-week intervention periods | 
| HGH (mIU/l) | Blood sample | Two 1-week intervention periods | 
| Sympathetic nervous system activity | Heart rate variability analysis | Two 1-week intervention periods | 
| Blood pressure | Assessment of blood pressure with a standard blood pressure monitor. | Two 1-week intervention periods | 
| Weight | Measurement of weight with a standard scale | Two 1-week intervention periods | 
| Energy expenditure | Basal metabolic rate measured with indirect calorimetry | Two 1-week intervention periods | 
| Substrate utilisation | Respiratory quotient assessed with indirect calorimetry | Two 1-week intervention periods | 
| GDF-15 (pg/mL) | Blood sample | Two 1-week intervention periods |