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

Garvan Institute of Medical Research

Status and phase: Not yet enrolling; Phase 2

Conditions: Type 1 Diabetes Mellitus

Treatments: Drug: Tirzepatide 2.5mg weekly; Drug: Placebo injection (normal saline)

Study type: Interventional

Funder types: Other

Identifiers

NCT06820281

U1111-1316-2752

Details and patient eligibility

About

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.

Full 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.

Enrollment: 44 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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44 participants in 2 patient groups, including a placebo group

Tirzepatide 2.5mg weekly

Experimental group

Description:

Administered subcutaneously.

Treatment:

Drug: Tirzepatide 2.5mg weekly

Placebo

Placebo Comparator group

Description:

Administered subcutaneously.

Treatment:

Drug: Placebo injection (normal saline)