Prevention of Metabolic Complications of Glucocorticoid Excess

Prevention of Metabolic Complications of Glucocorticoid Excess - a Randomised, Doubleblind,Placebo Controlled Study

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.

Study Overview

• Status: Completed
• Conditions: Iatrogenic Cushing Disease
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Barts and The London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• patients diagnosed with an inflammatory condition and not started yet on GC treatment or • patients with an inflammatory condition treated with GC >20mg/d of prednisolone (or its cumulative equivalent) for at least 4wks
• minimal duration of prospective therapy 12w
• dose of prednisolone ≥10mg/d (or equivalent GC)
• ambulatory patients
• patients >18 years old
• ability to understand verbal and written instructions and informed consent

Exclusion Criteria:

• prior therapy with metformin during the last 6 months
• known pre-existing diabetes
• pregnancy
• breastfeeding
• liver impairment: ALT and/or AST ≥2.5 x UNL
• renal impairment: serum creatinine levels ≥135.0 µmol/L in males and ≥110.0 µmol/L in females
• current malignancy
• patients unable to give written informed consent
• or patients not understanding English

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Metformin; Metformin 850mg TDS (12 weeks)	Drug: Metformin; Metformin 850mg TDS (12 weeks); Other Names: metformin tablet containing 850mg metformin
PLACEBO_COMPARATOR: Placebo; Placebo 850mg TDS (12 weeks)	Drug: Placebo; Placebo 850mg TDS (12 weeks); Other Names: Placebo tablet matching the active drug tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CT Abdomen	change in visceral/subcutaneous fat	3 months minus baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HOMA2-IR	The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and beta (β)-cell function. HOMA2-IR is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin resistance which is the reciprocal of insulin sensitivity (%S)(100/%S) as a percentage of a normal reference population (normal young adults). HOMA2-IR is calculated using the HOMA model: www.dtu.ox.ac.uk/homacalculator/	3 months minus baseline

Collaborators and Investigators

• Sponsor: Barts & The London NHS Trust
• Collaborators: Barts and the London School of Medicine and Dentistry
• Investigators: Principal Investigator: Marta Korbonits, MD, PhD, Barts and The London

Publications and helpful links

General Publications

• Pernicova I, Kelly S, Ajodha S, Sahdev A, Bestwick JP, Gabrovska P, Akanle O, Ajjan R, Kola B, Stadler M, Fraser W, Christ-Crain M, Grossman AB, Pitzalis C, Korbonits M. Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial. Lancet Diabetes Endocrinol. 2020 Apr;8(4):278-291. doi: 10.1016/S2213-8587(20)30021-8. Epub 2020 Feb 25.

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (ACTUAL): August 1, 2014
• Study Completion (ACTUAL): January 1, 2015

Study Registration Dates

• First Submitted: February 21, 2011
• First Submitted That Met QC Criteria: March 21, 2011
• First Posted (ESTIMATE): March 22, 2011

Study Record Updates

• Last Update Posted (ACTUAL): April 12, 2019
• Last Update Submitted That Met QC Criteria: January 14, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: glucocorticoid
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Hypothalamic Diseases; Hyperpituitarism; Pituitary Diseases; Adenoma; Pituitary Neoplasms; ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 09/H1102/82

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO