Acute Metabolic Effects of Tirzepatide in Type 1 Diabetes

Phase 2

Not yet recruiting

• Conditions: Type 1 Diabetes Mellitus
• Interventions: Drug: Tirzepatide 2.5mg weekly; Drug: Placebo injection (normal saline)

• Registration Number: NCT06820281
• Lead Sponsor: Garvan Institute of Medical Research

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.

Study Timeline

• Status Verified: 2025-01
• Study First Submitted: 2025-02-06
• Study First Submitted QC: 2025-02-06
• Study First Posted: 2025-02-11
• Last Update Submitted: 2025-10-06
• Last Update Posted: 2025-10-08
• Study Start: 2025-12-01
• Primary Completion: 2027-12-31
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 44

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tirzepatide 2.5mg weekly	Tirzepatide 2.5mg weekly	Administered subcutaneously.
Placebo	Placebo injection (normal saline)	Administered subcutaneously.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
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
Overnight growth hormone curve	6 weeks	Change from baseline growth hormone area under the curve (AUC) as measured overnight blood samples
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
% 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
% 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
% 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
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

Trial Locations

Locations (1)

Garvan Institute of Medical Research; 🇦🇺 Sydney, New South Wales, Australia