Iatrogenic Cushing Disease
Conditions
Keywords
glucocorticoid
Brief 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.
Interventions
DRUGMetformin
Metformin 850mg TDS (12 weeks)
DRUGPlacebo
Placebo 850mg TDS (12 weeks)
Sponsors
Barts and the London School of Medicine and Dentistry
Barts & The London NHS Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CT Abdomen | 3 months minus baseline | change in visceral/subcutaneous fat |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HOMA2-IR | 3 months minus baseline | 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/ |
Countries
United Kingdom
Participant flow
Pre-assignment details
Patients were recruited into Prevention and Treatment algorithms initially. However, only the Treatment algorithm proved feasible for logistic reasons. Below are the results relating to patients randomized into the Treatment algorithm.
Participants by arm
| Arm | Count |
|---|---|
| Metformin Metformin 850mg TDS | 26 |
| Placebo Placebo 850mg TDS | 27 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 7 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | Metformin |
|---|---|---|---|
| Age, Continuous | 45 years STANDARD_DEVIATION 15 | 46 years STANDARD_DEVIATION 15 | 47 years STANDARD_DEVIATION 15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 53 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HOMA2-IR | 4.2 HOMA score | 4.4 HOMA score | 4.7 HOMA score |
| Sex: Female, Male Female | 15 Participants | 29 Participants | 14 Participants |
| Sex: Female, Male Male | 12 Participants | 24 Participants | 12 Participants |
| visceral to subcutanous fat ratio | 0.58 ratio | 0.50 ratio | 0.44 ratio |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 26 | 22 / 27 |
| serious Total, serious adverse events | 1 / 26 | 9 / 27 |
Outcome results
Primary
CT Abdomen
change in visceral/subcutaneous fat
Time frame: 3 months minus baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | CT Abdomen | 0.08 ratio | Standard Deviation 0.19 |
| Placebo | CT Abdomen | -0.03 ratio | Standard Deviation 0.22 |
Secondary
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/
Time frame: 3 months minus baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | HOMA2-IR | 0.22 HOMA score | Standard Deviation 3.26 |
| Placebo | HOMA2-IR | 2.35 HOMA score | Standard Deviation 3.23 |