Steroid-Induced Diabetes, Steroid Induced Hyperglycemia
Conditions
Brief summary
TITLE: How GLP-1 Analogues prevent steroid-induced diabetes (The GAPSID Study) DESIGN: A double-blind study evaluating how GLP-1 analogues, compared with metformin, prevent hyperglycaemia in response to a 7-day course of dexamethasone (DEX) 6 mg once daily. This is a mechanistic experimental medicine study. AIMS: To evaluate the mechanisms by which GLP-1 analogues reduce steroid-induced hyperglycaemia compared to metformin. OUTCOME MEASURES: * Primary: Glucose tolerance in response to standardised mixed meal test (MMT) lasting for 240 minutes, measured in all participants at baseline and on day 7 DEX. * Secondary: Indices of insulin resistance (M-value), beta-cell function (acute insulin response to glucose) and disposition, as measured by a combined IV glucose tolerance test and hyperinsulinaemic-euglycaemic clamp, performed at baseline and on day 7 DEX. * Exploratory: Tissue specific changes in adipose AMPK determined from adipose and muscle biopsies, taken from a subset of approximately 8 individuals in each group. ELIGIBILITY: People living with pre-diabetes or lifestyle controlled diabetes STUDY DURATION: This study will take place over 3 weeks for each partcipant. Study procedures include 10 days of baseline continuous glucose monitoring (CGM) followed by 7 days of dexamethasone with GLP-1, metformin or placebo. Participants will attend a follow-up visit 3-5 days after completing the 7-day course of study drug. The study will run over a period of 3 years. ANTICIPATED IMPACT: Mechanistic evidence for the use of GLP-1 analogues, compared with metformin, in the treatment of steroid-induced diabetes.
Interventions
DRUGSemaglutide Oral Product
Oral semaglutide 3mg once uptitrated to twice daily
Metformin modified release tablets 500mg once daily uptitrated to twice daily).
DRUGPlacebo
Placebo tablets
Sponsors
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Adults ≥ 18 years; * Male or female; * Pre-diabetes (HbA1c ≥42 and \<47 mmol/mol, or lifestyle-controlled diabetes (HbA1c ≥48 and ≤52 mmol/mol); measurements within range on two separate occasions ≥90 days apart) * Body mass index ≥22.5 kg/m2
Exclusion criteria
* Prior treatment with any diabetes medication within 90 days; * Current or planned pregnancy, or current breastfeeding; * Previous treatment with GC (topical, oral, injected) within 30 days or 90 days for extended-release injected GCs (e.g. Depo-Medrone); * Continuing requirement for GC treatment (e.g. for steroid replacement, chronic inflammatory or immunological condition); * Treatment with medications altering DEX pharmacokinetics (e.g. phenytoin, carbamazepine, ritonavir). * History of pancreatitis, renal disease (eGFR \<30), severe hepatic impairment, gallbladder disorders, or GI disease (e.g. IBD), heart failure, history of medullary thyroid cancer (MTC), or previous skin reactions. * History of bleeding disorders of anticoagulant therapies (exclusion from the biopsy substudy only) * History of giving blood or having taken part in another non-related study in the last three months * History of any other medical, psychological condition, or use of any medications, which, in the opinion of the investigators, would either interfere with the study or compromise the safety of the participant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Glucose tolerance | Through study completion, on day 7 dexamethasone and study medication | Glucose tolerance as measured by glucose area under the curve (AUC), in response to standardised mixed meal test (MMT) lasting for 240 minutes. This will be measured in all participants at baseline and at the end of the study medication period (after 7 days of dexamethasone and study medication). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in insulin secretion | Day 6 of dexamethasone and study medication | This will be measured by the acute insulin response to glucose based on the incremental AUC for insulin during the first 10 minutes of an IVGTT and the second phase insulin response based on incremental AUC for insulin during +10 to +60 minutes. This will be measured in a subset of patients (10 from each randomisation group), performed at baseline and on day 6 of dexamethasone and study medication |
| Difference in insulin sensitivity | Day 6 | This will be measured by the M value, based on the glucose infusion rate during the last 60 minutes of a hyperinsulinaemic-euglycaemic clamp. This will be measured in a subset of patients (10 from each randomisation group), performed at baseline and on day 6 of dexamethasone and study medication |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in post prandial gut hormones | Through study completion, on day 7 dexamethasone and study medication | Post prandial insulin and c-peptide levels will be measured during the mixed meal test, performed at baseline and after a 7-day course of DEX and treatment intervention. |
| Mean glucose and glycaemic variation by continuous glucose monitoring (CGM), using a validated blinded system (Dexcom G7). | Through study completion | A baseline recording will be made for 10 days prior to DEX. A second 10-day recording will be made covering the 7 days of DEX and for 3 days after. |
| Tissue specific changes in AMPK determined from adipose and muscle biopsies | Through study completion, on day 7 dexamethasone and study medication | This will be taken from a subset of approximately 8 individuals in each group prior to, and at the end of a 7 day course of DEX. Depending on emerging data and participant uptake, this may be subject to change. |
| Changes in anthropometrics | Through study completion, on day 7 dexamethasone and study medication | Anthropometric measurements of height and weight will be combined to report BMI kg/m2 before and after a 7-day course of DEX and treatment intervention. |
| Changes in fasting gut hormones | Through study completion, on day 7 dexamethasone and study medication | Fasting glucose will be measured at baseline and after a 7-day course of DEX and treatment intervention. |
| Changes in fasting lipid profile | Through study completion, on day 7 dexamethasone and study medication | Fasting lipid profiles will be measured at baseline and after a 7-day course of DEX and treatment intervention. |
Countries
United Kingdom
Contacts
Primary ContactKatharine Lazarus, MBChB, BSc
Outcome results
None listed