Type 1 Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus, Type 1, Diabetes Mellitus, Autoimmune Diseases, Incretins, Physiological Effects of Drugs, Tirzepatide, Glucose Metabolism Disorders, Metabolic Diseases, Endocrine System Diseases, Overnutrition, Insulin Resistance
Brief summary
This study will examine the effects of Tirzepatide (TZP), a glucagon-like peptide 1 (GLP1) - gastric inhibitory peptide (GIP) co-agonist, on metabolism in type 1 diabetes (T1D). Research participants with T1D will undergo measures of insulin sensitivity, and hormone levels post-meal, post-hypoglycemia and during the overnight period. These measures will be performed prior to, and after 6 weeks of treatment with TZP or placebo.
Detailed description
TIRTLE2 is a phase 2 double-blinded placebo-controlled mechanistic clinical trial that extends upon the findings of TIRTLE1, a phase 2 double-blinded placebo-controlled trial (TZP 5.0mg vs placebo over 12 weeks) in T1D (trial registration: ACTRN12624000111572). TIRTLE2 is a designed to determine whether TZP can 1) improve whole body insulin sensitivity, 2) reduce prandial glucagon secretion, 3) impacts lipolysis and growth hormone secretion overnight, and 4) determine if TZP can maintain the glucagon response to hypoglycemia. The acute effects of TZP on metabolism will be assessed after 6 weeks, to limit the degree of weight loss (indicating a role for TZP on improving metabolic physiology in T1D, beyond weight management in T1D). To address these research aims, a single comprehensive clinical trial will be performed in 44 participants with T1D, who will receive a weekly injection of TZP 2.5mg or placebo for 6 weeks. A short treatment duration was chosen to assess if TZP offers T1D-specific benefits prior to significant weight loss. TIRTLE2 will employ the 'gold standard' hyperinsulinemic-euglycemic and hypoglycemic clamps, in conjunction with complementary analyses of the effects of TZP on metabolism across multiple physiological states. This mechanistic study will define mechanisms by which GLP1-GIP co-agonism may uniquely provide clinical benefits in T1D during the fasting and fed states, and during hypoglycemia.
Interventions
DRUGTirzepatide 2.5mg weekly
Tirzepatide 2.5 mg/0.5 mL solution for injection vial or pre-filled pen. Each vial/ pre-filled pen contains tirzepatide 2.5 mg in 0.5 mL solution (2.5mg in 0.6mL if Kwikpen) Tirzepatide will be administered by drawing up into a syringe, then administering by subcutaneous injection weekly by study nurses.
Placebo will be given as 0.5mL normal saline (if comparator against vial or pre-filled pen), or 0.6mL (if comparator against Mounjaro Kwikpen), drawn up into a syringe and administered by subcutaneous injection weekly by study nurses.
Sponsors
Garvan Institute of Medical Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Parallel assignment, 1:1 randomization
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* age 18-65 years * BMI ≥ 27 kg/m2 * HbA1c ≤ 9.0% * insulin delivery using an automated insulin delivery system * at least 2 years since diagnosis of type 1 diabetes
Exclusion criteria
* TZP or GLP-1 receptor agonist in last 3 months; metformin or sodium glucose co-transporter 2 (SGLT2) inhibitor in the last 6 weeks; steroids, antipsychotics, immunosuppressants in the last 6 weeks. * Hypoglycemic unawareness or severe hypoglycemia last 6 months. * History of seizure disorder. * History of weight loss surgery. * eGFR \<60 mL/min/1.73 m2. * Liver disease (known cirrhosis, LFTs \> 3x upper limit of normal). * Active malignancy. * Pregnant, breastfeeding, planning pregnancy within 6 months, or not using adequate contraception. * History of cardiovascular disease, or coronary event or stroke in last 3 months * Hemoglobin level \< 13.5 g/dL in men, \< 12.0 g/dL in women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Whole-body insulin sensitivity | 6 weeks | Change in insulin sensitivity from baseline, assessed using the hyperinsulinemic-euglycemic clamp (60 mU/m2/min) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| % Time level 2 hyperglycemia | 6 weeks | Change from baseline % time level 1 hyperglycemia (defined by glucose \> 250 mg/dL \[13.9 mmol/L\])) as measured by continuous glucose monitoring |
| % Time Below Range (TBR) | 6 weeks | Change from baseline %TBR (defined by % readings below 70mg/dL \[3.9mmol/L\]) as measured by continuous glucose monitoring |
| Prandial glucagon secretion | 6 weeks | Change from baseline glucagon area under the curve (AUC) during mixed meal tolerance test (MMTT) |
| Glucagon response to hypoglycemia | 6 weeks | Change from baseline glucagon AUC after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp |
| % Time level 2 hypoglycemia | 6 weeks | Change from baseline % time level 2 hypoglycemia (defined by glucose \< 54 mg/dL \[\<3.0 mmol/L\]) as measured by continuous glucose monitoring |
| % Time level 1 hypoglycemia | 6 weeks | Change from baseline % time level 1 hypoglycemia (defined by glucose \< 70 mg/dL \[3.9 mmol/L\] and ≥ 54 mg/dL \[3.0 mmol/L\]) as measured by continuous glucose monitoring |
| Resting energy expenditure (REE) | 6 weeks | Change from baseline REE as measured by indirect calorimetry |
| % Time level 1 hyperglycemia | 6 weeks | Change from baseline % time level 1 hyperglycemia (defined by glucose \> 180 mg/dL \[10 mmol/L\] and glucose ≤ 250 mg/dL \[13.9 mmol/L\]) as measured by continuous glucose monitoring |
| Overnight free-fatty acids (FFA) curve | 6 weeks | Change from baseline FFA under the curve (AUC) as measured overnight blood samples |
| Total daily insulin dose | 6 weeks | Change from baseline total daily insulin dose as measured by pump record |
| Total daily basal insulin dose | 6 weeks | Change from baseline total daily basal insulin dose as measured by pump record |
| Total daily bolus insulin dose | 6 weeks | Change from baseline total daily bolus insulin dose as measured by pump record |
| % Time in Range (TIR) | 6 weeks | Change from baseline %TIR (defined by % readings between 70mg/dL - 180 mg/dL \[3.9 - 10.0 mmol/L\]) as measured by continuous glucose monitoring |
| Glycemic variability | 6 weeks | Change from glycemic variability as measured by continuous glucose monitoring |
| Gastric emptying | 6 weeks | Change from baseline gastric emptying during the mixed meal tolerance test (MMTT) assessed using radiolabelled isotope and breath sampling |
| Overnight growth hormone curve | 6 weeks | Change from baseline growth hormone area under the curve (AUC) as measured overnight blood samples |
Other
| Measure | Time frame | Description |
|---|---|---|
| Fasting GIP | 6 weeks | Change from baseline fasting GIP as measured by blood assay |
| Supraclavicular temperature profile | 6 weeks | Change from baseline supraclavicular temperature profile as measured by temperature sensor |
| Diet composition | 6 weeks | Change from baseline diet composition as measured by self-reported diet diary entries |
| Growth differentiation factor 15 (GDF15) | 6 weeks | Change from baseline fasting GDF15 as measured by blood assay |
| Diabetes Treatment Satisfaction | 6 weeks | Change from baseline diabetes treatment satisfaction, as measured by questionnaire (DTSQ) |
| Pulse rate | 6 weeks | Change from baseline pulse rate as measured by digital sphygmomanometer |
| C-terminal telopeptide of type 1 collagen | 6 weeks | Change from baseline C-terminal telopeptide of type 1 collagen (CTX) as measured by blood assay |
| Procollagen type 1 N-terminal propeptide | 6 weeks | Change from baseline procollagen type 1 N-terminal propeptide (P1NP) as measured by by blood assay |
| HbA1c | 6 weeks | Change from baseline HbA1c as measured by blood assay. |
| Fasting liver function tests | 6 weeks | Change from baseline fasting liver function tests as measured by blood assay |
| Metanephrine response to hypoglycemia | 6 weeks | Change from baseline peak metanephrine after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp |
| Normetanephrine response to hypoglycemia | 6 weeks | Change from baseline peak normetanephrine after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp |
| Growth hormone response to hypoglycemia | 6 weeks | Change from baseline peak growth hormone after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp |
| Cortisol response to hypoglycemia | 6 weeks | Change from baseline peak cortisol after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp |
| Glucose requirement to correct hypoglycemia | 6 weeks | Change from baseline glucose infusion requirement after glucose nadir to correct hypoglycemia during the hyperinsulinemic hypoglycemic clamp |
| Body weight | 6 weeks | Change from baseline body weight as measured by scale |
| % fat free mass | 6 weeks | Change from baseline % fat free mass as measured by air displacement plethysmography |
| % fat mass | 6 weeks | Change from baseline % fat mass as measured by air displacement plethysmography |
| Lipid profile | 6 weeks | Change from baseline lipid profile as measured by blood assay |
| Systolic blood pressure | 6 weeks | Change from baseline systolic blood pressure as measured by digital sphygmomanometer |
| Diastolic blood pressure | 6 weeks | Change from baseline diastolic blood pressure as measured by digital sphygmomanometer |
| Arterial stiffness | 6 weeks | Change from baseline arterial stiffness as measured by Augmentation index (AIx) by radial artery tonometry |
| Prandial GLP1 secretion | 6 weeks | Change from baseline GLP1 area under the curve (AUC) during mixed meal tolerance test (MMTT) |
| Prandial GIP secretion | 6 weeks | Change from baseline GIP area under the curve (AUC) during mixed meal tolerance test (MMTT) |
| Fasting glucagon | 6 weeks | Change from baseline fasting glucagon level as measured by blood assay. |
| Fasting GLP1 | 6 weeks | Change from baseline fasting GLP1 as measured by blood assay |
Countries
Australia
Contacts
Primary ContactJennifer R Snaith, MD PHD
Backup ContactJerry R Greenfield, MD PHD
Outcome results
None listed