Counteracting Deleterious Metabolic Glucocorticoid Effects With Metformin
Condition: Glucocorticoid Effect
Study type: Interventional
Phase: Phase 4

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.
    

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).
    

Intervention name(s): Metformin 500 mg Oral Tablets + Prednisone 20mg Tablets; Placebo 500 mg Tablets + Prednisone 20mg Tablets
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Intervention MeSH terms: Metformin; Prednisone
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Double-blind, randomized, placebo-controlled cross-over study
Masking: Double (Participant, Investigator)
Primary purpose: Prevention