Prevention of Metabolic Complications of Glucocorticoid Excess
Condition: Iatrogenic Cushing Disease
MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      According to current estimates, nearly 1% of the general population is treated with long-term
      glucocorticoids. Chronic hypercortisolism leads to a phenotype that resembles the metabolic
      syndrome. The investigators have shown that inhibition of adenosine-monophosphate-activated
      protein kinase (AMPK) activity in adipose tissue plays a role in corticosteroid-mediated
      insulin resistance. Metformin, one of the mainstay therapies for type 2 diabetes, is a known
      activator of AMPK, which mediates its beneficial effects on glucose and lipid metabolism. The
      investigators have shown in an animal model that metformin - via altering AMPK activity -
      prevents the development of the metabolic complications of glucocorticoid excess, and the
      investigators wish to confirm this in a human study. The aim of this prospective, randomised,
      double-blind, placebo-controlled study is to investigate the effect of metformin treatment on
      metabolic parameters in patients on long-term high-dose glucocorticoids. The study is part of
      the investigators translational project and could rapidly lead to immediate patient benefit,
      improving quality of life and reducing health care costs for the NHS.
    

Detailed description: 
      2 Study Aims and Objectives To investigate the effect of metformin treatment on metabolic
      parameters in patients with long-term high dose GCs.

      3 Study Design 3.1 General Design We will recruit patients (18-75y) requiring glucocorticoid
      treatment for various inflammatory conditions (e.g. rheumatoid arthritis, giant cell
      arteritis/polymyalgia rheumatic, asthma, sarcoidosis) into a pilot, randomised, double-blind,
      placebo-controlled trial. These patients will be treated with metformin to prevent or reverse
      their metabolic complications. Prevention algorithm: Patients who are about to start GC
      treatment predictably for ≥12w at a ≥10mg/d prednisolone (or equivalent) dose who consent to
      participate in this study will be randomly assigned to receive either placebo (20
      patients/group, see power calculations) or metformin at the maximum tolerated dose with a
      minimum of 850 mg bd for 12w. Treatment algorithm: Consenting patients already on long-term
      GC treatment (≥4w, ≥20mg/d prednisolone or equivalent) who are expected to continue for at
      least 12w at ≥10mg/d prednisolone will be randomly assigned to receive either placebo or
      metformin for 12w. In both algorithms, metformin treatment will be started gradually (as
      standard practice) to avoid gastrointestinal side effects and the full dose will be reached
      by day 10. Patients will have a full clinical assessment before the start of the metformin
      treatment and at the end of the 12w treatment period. Anthropometric and biochemical
      parameters and questionnaires will be repeated at 4 and 8 weeks.
    

Intervention name(s): Metformin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Metformin 850mg TDS (12 weeks); Placebo 850mg TDS (12 weeks)
Other intervention name(s): metformin tablet containing 850mg metformin; Placebo tablet matching the active drug tablet
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: glucocorticoid