Clinical trial NCT06820281: Acute Metabolic Effects of Tirzepatide in Type 1 Diabetes
Official title: Acute Metabolic Effects of Tirzepatide in Type 1 Diabetes: a Phase 2 Double Blinded Placebo Controlled Clinical Trial (TIRTLE2)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Type 1 Diabetes Mellitus
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
Lead sponsor: Garvan Institute of Medical Research
Sponsor class: OTHER
First posted: 2025-02-11
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel assignment, 1:1 randomization
Primary purpose: TREATMENT

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 4 weeks of treatment with TZP. These measures will also be compared to a group of adults without diabetes (who will not receive treatment with TZP) to assess how metabolism of energy and nutrients is different in T1D compared to people without diabetes.

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 1) demonstrate that T1D is associated with insulin resistance, increased lipolysis and excessive growth hormone and prandial glucagon secretion; 2) determine whether TZP can improve whole body insulin sensitivity (main aim) and adipose insulin sensitivity, while reducing growth homrone and prandial glucagon secretion, before significant weight loss (indicating a role for TZP beyond weight management in T1D); 3) determine if TZP can maintain the glucagon response to hypoglycemia.

To address these research aims, a single comprehensive clinical trial will be performed in 20 participants with T1D, who will receive a weekly injection of TZP 2.5mg or placebo for 4 weeks. A short treatment duration was chosen to assess if TZP offers T1D-specific benefits prior to significant weight loss. Dynamic tests will also be performed in 10 participants without diabetes in a baseline only cross-sectional study (participants without diabetes will not receive treatment in the main clinical trial).

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.

Eligibility criteria: Inclusion Criteria:

* age 18-55 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

Primary outcomes:
measure: Whole-body insulin sensitivity
timeFrame: 4 weeks
Secondary outcomes:
measure: Adipose insulin sensitivity
timeFrame: 4 weeks
measure: Fasting glucagon
timeFrame: 4 weeks
measure: Prandial glucagon secretion
timeFrame: 4 weeks
measure: Glucagon response to hypoglycemia
timeFrame: 4 weeks
measure: Resting energy expenditure (REE)
timeFrame: 4 weeks
measure: Overnight growth hormone curve
timeFrame: 4 weeks
measure: Overnight free-fatty acids (FFA) curve
timeFrame: 4 weeks
measure: % fat mass
timeFrame: 4 weeks
measure: % fat free mass
timeFrame: 4 weeks
measure: Body weight
timeFrame: 4 weeks
measure: Total daily insulin dose
timeFrame: 4 weeks
measure: Total daily basal insulin dose
timeFrame: 4 weeks
measure: Total daily bolus insulin dose
timeFrame: 4 weeks
measure: % Time in Range (TIR)
timeFrame: 4 weeks
measure: % Time Below Range (TBR)
timeFrame: 4 weeks
measure: % Time level 1 hyperglycemia
timeFrame: 4 weeks
measure: % Time level 2 hyperglycemia
timeFrame: 4 weeks
measure: Glycemic variability
timeFrame: 4 weeks
measure: Arterial stiffness
timeFrame: 4 weeks
measure: Arterial stiffness
timeFrame: 4 weeks
Other outcomes:
measure: Diabetes Treatment Satisfaction
timeFrame: 4 weeks
measure: % Time level 1 hypoglycemia
timeFrame: 4 weeks
measure: % Time level 2 hypoglycemia
timeFrame: 4 weeks
measure: Adrenaline response to hypoglycemia
timeFrame: 4 weeks
measure: Growth hormone response to hypoglycemia
timeFrame: 4 weeks
measure: Cortisol response to hypoglycemia
timeFrame: 4 weeks
measure: Glucose requirement to correct hypoglycemia
timeFrame: 4 weeks
measure: Lipid profile
timeFrame: 4 weeks
measure: Systolic blood pressure
timeFrame: 4 weeks
measure: Diastolic blood pressure
timeFrame: 4 weeks
measure: Prandial GLP1 secretion
timeFrame: 4 weeks
measure: Prandial GIP secretion
timeFrame: 4 weeks
Locations:
city: Sydney
country: Australia
facility: Garvan Institute of Medical Research
state: New South Wales
Study officials:
affiliation: Garvan Institute of Medical Research
name: Jennifer R Snaith, MD PHD
role: PRINCIPAL_INVESTIGATOR
affiliation: Garvan Institute of Medical Research
name: Jerry R Greenfield, MD PHD
role: STUDY_DIRECTOR
References: