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NCT Number: NCT06820281

Acute Metabolic Effects of Tirzepatide in Type 1 Diabetes

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.

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Key information

Conditions

Type 1 Diabetes Mellitus Autoimmune Diseases Diabetes Mellitus Diabetes Mellitus, Type 1 Endocrine System Diseases Glucose Metabolism Disorders Hyperinsulinism Immune System Diseases Insulin Resistance Metabolic Diseases Nutrition Disorders Nutritional and Metabolic Diseases Overnutrition

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Victor Chang Cardiac Research Institute

Sydney, New South Wales, 2010, Australia

Location contact

Jennifer R Snaith, MD PHD

PRINCIPAL_INVESTIGATOR

Jennifer R Snaith, MD/PhD

CONTACT

[email protected]

61 2 9295 8600

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Tirzepatide 2.5mg weekly

Drug

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 injection (normal saline)

Drug

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.

Primary outcomes

  1. Whole-body insulin sensitivity

    Time frame: 6 weeks

    Change in insulin sensitivity from baseline, assessed using the hyperinsulinemic-euglycemic clamp (60 mU/m2/min)

Secondary outcomes

  1. Prandial glucagon secretion

    Time frame: 6 weeks

    Change from baseline glucagon area under the curve (AUC) during mixed meal tolerance test (MMTT)

  2. Glucagon response to hypoglycemia

    Time frame: 6 weeks

    Change from baseline glucagon AUC after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp

  3. % Time level 2 hypoglycemia

    Time frame: 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

  4. % Time level 1 hypoglycemia

    Time frame: 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

  5. Resting energy expenditure (REE)

    Time frame: 6 weeks

    Change from baseline REE as measured by indirect calorimetry

  6. Overnight growth hormone curve

    Time frame: 6 weeks

    Change from baseline growth hormone area under the curve (AUC) as measured overnight blood samples

  7. Overnight free-fatty acids (FFA) curve

    Time frame: 6 weeks

    Change from baseline FFA under the curve (AUC) as measured overnight blood samples

  8. Total daily insulin dose

    Time frame: 6 weeks

    Change from baseline total daily insulin dose as measured by pump record

  9. Total daily basal insulin dose

    Time frame: 6 weeks

    Change from baseline total daily basal insulin dose as measured by pump record

  10. Total daily bolus insulin dose

    Time frame: 6 weeks

    Change from baseline total daily bolus insulin dose as measured by pump record

  11. % Time in Range (TIR)

    Time frame: 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

  12. % Time Below Range (TBR)

    Time frame: 6 weeks

    Change from baseline %TBR (defined by % readings below 70mg/dL [3.9mmol/L]) as measured by continuous glucose monitoring

  13. % Time level 1 hyperglycemia

    Time frame: 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

  14. % Time level 2 hyperglycemia

    Time frame: 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

  15. Glycemic variability

    Time frame: 6 weeks

    Change from glycemic variability as measured by continuous glucose monitoring

  16. Gastric emptying

    Time frame: 6 weeks

    Change from baseline gastric emptying during the mixed meal tolerance test (MMTT) assessed using radiolabelled isotope and breath sampling

Other outcomes

  1. Diabetes Treatment Satisfaction

    Time frame: 6 weeks

    Change from baseline diabetes treatment satisfaction, as measured by questionnaire (DTSQ)

  2. Metanephrine response to hypoglycemia

    Time frame: 6 weeks

    Change from baseline peak metanephrine after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp

  3. Normetanephrine response to hypoglycemia

    Time frame: 6 weeks

    Change from baseline peak normetanephrine after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp

  4. Growth hormone response to hypoglycemia

    Time frame: 6 weeks

    Change from baseline peak growth hormone after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp

  5. Cortisol response to hypoglycemia

    Time frame: 6 weeks

    Change from baseline peak cortisol after glucose nadir as measured during the hyperinsulinemic hypoglycemic clamp

  6. Glucose requirement to correct hypoglycemia

    Time frame: 6 weeks

    Change from baseline glucose infusion requirement after glucose nadir to correct hypoglycemia during the hyperinsulinemic hypoglycemic clamp

  7. Body weight

    Time frame: 6 weeks

    Change from baseline body weight as measured by scale

  8. % fat free mass

    Time frame: 6 weeks

    Change from baseline % fat free mass as measured by air displacement plethysmography

  9. % fat mass

    Time frame: 6 weeks

    Change from baseline % fat mass as measured by air displacement plethysmography

  10. Lipid profile

    Time frame: 6 weeks

    Change from baseline lipid profile as measured by blood assay

  11. Systolic blood pressure

    Time frame: 6 weeks

    Change from baseline systolic blood pressure as measured by digital sphygmomanometer

  12. Diastolic blood pressure

    Time frame: 6 weeks

    Change from baseline diastolic blood pressure as measured by digital sphygmomanometer

  13. Arterial stiffness

    Time frame: 6 weeks

    Change from baseline arterial stiffness as measured by Augmentation index (AIx) by radial artery tonometry

  14. Arterial stiffness

    Time frame: 6 weeks

    Change from baseline arterial stiffness as measured by carotid femoral pulse-wave velocity (cfPWV)

  15. Prandial GLP1 secretion

    Time frame: 6 weeks

    Change from baseline GLP1 area under the curve (AUC) during mixed meal tolerance test (MMTT)

  16. Prandial GIP secretion

    Time frame: 6 weeks

    Change from baseline GIP area under the curve (AUC) during mixed meal tolerance test (MMTT)

  17. Fasting glucagon

    Time frame: 6 weeks

    Change from baseline fasting glucagon level as measured by blood assay.

  18. Fasting GLP1

    Time frame: 6 weeks

    Change from baseline fasting GLP1 as measured by blood assay

  19. Fasting GIP

    Time frame: 6 weeks

    Change from baseline fasting GIP as measured by blood assay

  20. Supraclavicular temperature profile

    Time frame: 6 weeks

    Change from baseline supraclavicular temperature profile as measured by temperature sensor

  21. Diet composition

    Time frame: 6 weeks

    Change from baseline diet composition as measured by self-reported diet diary entries

  22. Growth differentiation factor 15 (GDF15)

    Time frame: 6 weeks

    Change from baseline fasting GDF15 as measured by blood assay

  23. Fasting liver function tests

    Time frame: 6 weeks

    Change from baseline fasting liver function tests as measured by blood assay

  24. Pulse rate

    Time frame: 6 weeks

    Change from baseline pulse rate as measured by digital sphygmomanometer

  25. C-terminal telopeptide of type 1 collagen

    Time frame: 6 weeks

    Change from baseline C-terminal telopeptide of type 1 collagen (CTX) as measured by blood assay

  26. Procollagen type 1 N-terminal propeptide

    Time frame: 6 weeks

    Change from baseline procollagen type 1 N-terminal propeptide (P1NP) as measured by by blood assay

  27. HbA1c

    Time frame: 6 weeks

    Change from baseline HbA1c as measured by blood assay.

Study contacts

Contact information is provided by the study sponsor or research team.

Jennifer R Snaith, MD PHD

CONTACT

[email protected]

+61 2 9295 8600

Jerry R Greenfield, MD PHD

CONTACT

[email protected]

Sponsors and collaborators

Lead sponsor

Victor Chang Cardiac Research Institute

Other Gov

Registry information

Official study title

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

Acronym: TIRTLE2

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Feb 11, 2025
Registry last updated
May 19, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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