Acute Metabolic Effects of Tirzepatide in Type 1 Diabetes (TIRTLE2)

Acute Metabolic Effects of Tirzepatide in Type 1 Diabetes: a Phase 2 Double Blinded Placebo Controlled Clinical Trial (TIRTLE2)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Tirzepatide 2.5mg weekly; Drug: Placebo injection (normal saline)

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.

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jennifer R Snaith, MD PHD; Phone Number: +61 2 9295 8600; Email: j.snaith@victorchang.edu.au
• Study Contact Backup: Name: Jerry R Greenfield, MD PHD; Email: j.greenfield@victorchang.edu.au

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • Victor Chang Cardiac Research Institute
      • Principal Investigator: Jennifer R Snaith, MD PHD
      • Contact: Jennifer R Snaith, MD/PhD; Phone Number: 61 2 9295 8600; Email: j.snaith@victorchang.edu.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tirzepatide 2.5mg weekly; Administered subcutaneously.	Drug: Tirzepatide 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 Comparator: Placebo; Administered subcutaneously.	Drug: Placebo injection (normal saline); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole-body insulin sensitivity	Change in insulin sensitivity from baseline, assessed using the hyperinsulinemic-euglycemic clamp (60 mU/m2/min)	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prandial glucagon secretion	Change from baseline glucagon area under the curve (AUC) during mixed meal tolerance test (MMTT)	6 weeks
Glucagon response to hypoglycemia	Change from baseline glucagon AUC after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp	6 weeks
% Time level 2 hypoglycemia	Change from baseline % time level 2 hypoglycemia (defined by glucose < 54 mg/dL [<3.0 mmol/L]) as measured by continuous glucose monitoring	6 weeks
% Time level 1 hypoglycemia	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	6 weeks
Resting energy expenditure (REE)	Change from baseline REE as measured by indirect calorimetry	6 weeks
Overnight growth hormone curve	Change from baseline growth hormone area under the curve (AUC) as measured overnight blood samples	6 weeks
Overnight free-fatty acids (FFA) curve	Change from baseline FFA under the curve (AUC) as measured overnight blood samples	6 weeks
Total daily insulin dose	Change from baseline total daily insulin dose as measured by pump record	6 weeks
Total daily basal insulin dose	Change from baseline total daily basal insulin dose as measured by pump record	6 weeks
Total daily bolus insulin dose	Change from baseline total daily bolus insulin dose as measured by pump record	6 weeks
% Time in Range (TIR)	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	6 weeks
% Time Below Range (TBR)	Change from baseline %TBR (defined by % readings below 70mg/dL [3.9mmol/L]) as measured by continuous glucose monitoring	6 weeks
% Time level 1 hyperglycemia	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	6 weeks
% Time level 2 hyperglycemia	Change from baseline % time level 1 hyperglycemia (defined by glucose > 250 mg/dL [13.9 mmol/L])) as measured by continuous glucose monitoring	6 weeks
Glycemic variability	Change from glycemic variability as measured by continuous glucose monitoring	6 weeks
Gastric emptying	Change from baseline gastric emptying during the mixed meal tolerance test (MMTT) assessed using radiolabelled isotope and breath sampling	6 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diabetes Treatment Satisfaction	Change from baseline diabetes treatment satisfaction, as measured by questionnaire (DTSQ)	6 weeks
Metanephrine response to hypoglycemia	Change from baseline peak metanephrine after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp	6 weeks
Normetanephrine response to hypoglycemia	Change from baseline peak normetanephrine after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp	6 weeks
Growth hormone response to hypoglycemia	Change from baseline peak growth hormone after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp	6 weeks
Cortisol response to hypoglycemia	Change from baseline peak cortisol after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp	6 weeks
Glucose requirement to correct hypoglycemia	Change from baseline glucose infusion requirement after glucose nadir to correct hypoglycemia during the hyperinsulinemic hypoglycemic clamp	6 weeks
Body weight	Change from baseline body weight as measured by scale	6 weeks
% fat free mass	Change from baseline % fat free mass as measured by air displacement plethysmography	6 weeks
% fat mass	Change from baseline % fat mass as measured by air displacement plethysmography	6 weeks
Lipid profile	Change from baseline lipid profile as measured by blood assay	6 weeks
Systolic blood pressure	Change from baseline systolic blood pressure as measured by digital sphygmomanometer	6 weeks
Diastolic blood pressure	Change from baseline diastolic blood pressure as measured by digital sphygmomanometer	6 weeks
Arterial stiffness	Change from baseline arterial stiffness as measured by Augmentation index (AIx) by radial artery tonometry	6 weeks
Arterial stiffness	Change from baseline arterial stiffness as measured by carotid femoral pulse-wave velocity (cfPWV)	6 weeks
Prandial GLP1 secretion	Change from baseline GLP1 area under the curve (AUC) during mixed meal tolerance test (MMTT)	6 weeks
Prandial GIP secretion	Change from baseline GIP area under the curve (AUC) during mixed meal tolerance test (MMTT)	6 weeks
Fasting glucagon	Change from baseline fasting glucagon level as measured by blood assay.	6 weeks
Fasting GLP1	Change from baseline fasting GLP1 as measured by blood assay	6 weeks
Fasting GIP	Change from baseline fasting GIP as measured by blood assay	6 weeks
Supraclavicular temperature profile	Change from baseline supraclavicular temperature profile as measured by temperature sensor	6 weeks
Diet composition	Change from baseline diet composition as measured by self-reported diet diary entries	6 weeks
Growth differentiation factor 15 (GDF15)	Change from baseline fasting GDF15 as measured by blood assay	6 weeks
Fasting liver function tests	Change from baseline fasting liver function tests as measured by blood assay	6 weeks
Pulse rate	Change from baseline pulse rate as measured by digital sphygmomanometer	6 weeks
C-terminal telopeptide of type 1 collagen	Change from baseline C-terminal telopeptide of type 1 collagen (CTX) as measured by blood assay	6 weeks
Procollagen type 1 N-terminal propeptide	Change from baseline procollagen type 1 N-terminal propeptide (P1NP) as measured by by blood assay	6 weeks
HbA1c	Change from baseline HbA1c as measured by blood assay.	6 weeks

Collaborators and Investigators

• Sponsor: Victor Chang Cardiac Research Institute
• Investigators: Principal Investigator: Jennifer R Snaith, MD PHD, Victor Chang Cardiac Research Institute; Study Director: Jerry R Greenfield, MD PHD, Victor Chang Cardiac Research Institute

Publications and helpful links

General Publications

• Snaith JR, Frampton R, Samocha-Bonet D, Greenfield JR. Tirzepatide in Adults With Type 1 Diabetes: A Phase 2 Randomized Placebo-Controlled Clinical Trial. Diabetes Care. 2026 Jan 1;49(1):161-170. doi: 10.2337/dc25-2379.

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: February 6, 2025
• First Submitted That Met QC Criteria: February 6, 2025
• First Posted (Actual): February 11, 2025

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 17, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Diabetes Mellitus; Insulin Resistance; Autoimmune Diseases; Physiological Effects of Drugs; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Incretins; Overnutrition; Diabetes Mellitus, Type 1; Tirzepatide
• Additional Relevant MeSH Terms: Nutrition Disorders; Immune System Diseases; Hyperinsulinism; Nutritional and Metabolic Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Autoimmune Diseases; Insulin Resistance; Metabolic Diseases; Glucose Metabolism Disorders; Endocrine System Diseases; Overnutrition; Amino Acids, Peptides, and Proteins; Proteins; Pharmaceutical Preparations; Crystalloid Solutions; Isotonic Solutions; Solutions; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide; Saline Solution; Tirzepatide
• Other Study ID Numbers: U1111-1316-2752

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data from these analyses can be made available upon the condition of compliance with institutional review board restrictions and a data sharing agreement with the project sponsor. We encourage researchers who propose use of study data to contact the study PI.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes