The GAPSID Study - How GLP-1 Analogues Prevent Steroid-Induced Diabetes

Imperial College London60 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

QUADRUPLE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Difference in Glucose tolerance

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).

Time frame: Through study completion, on day 7 dexamethasone and study medication

Secondary Outcomes

Difference in insulin secretion

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

Time frame: Day 6 of dexamethasone and study medication

Difference in insulin sensitivity

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

Time frame: Day 6

Difference in insulin sensitivity

This will be measured by the M/I index, calculated by the M value divided by the mean steady state insulin levels 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

Time frame: Day 6

Difference in insulin sensitivity

This will be measured by the disposition index. This will be calculated as the product of the AIRg and M value during the combined IVGTT and 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.

Time frame: Day 6

The GAPSID Study - How GLP-1 Analogues Prevent Steroid-Induced Diabetes

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts