ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This double-blind, placebo-controlled international trial, randomized overweight and obese adults with T2D to either once-weekly subcutaneous Tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. Tirzepatide led to weight reductions of -9.6% with the 10 mg dose and -11.6% with the 15 mg dose, compared to placebo. From a mean baseline 8.0%, HbA1c reduced by –2·1% with both the 10 mg, and 15 mg dose of triszepatied compared to 0·5% reduction on placebo.

Comment: Tirzepatide is the first of a new class of drugs able to selectively bind and activate the receptors for both the intestinal hormones, glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP). GLP-1 is secreted by L cells located in the distal ileum and colon in response to nutrient ingestion. Activation of GLP-1-associated signalling pathways leads to increased insulin secretion and reduced glucagon production, enhancing glucose utilization in insulin-dependent tissues such as muscle and adipose tissue. Additionally, GLP-1 slows gastric emptying, modulates calorie intake by increasing the sense of satiety, influences cardiovascular activity, regulates natriuresis at the renal level, and has neuroprotective effects.¹

GIP is secreted by K-cells in the duodenum and upper jejunum following the oral ingestion of nutrients such as glucose, amino acids, and long-chain fatty acids. Its administration reduces β-cell apoptosis and enhances β-cell mass in animal models. GIP administration results in decreased food intake and has beneficial effects on bone mass.

Tirzepatide has a greater affinity for GIP receptors than for GLP-1 receptors. This dual agonist effect results in greater reductions in weight and glucose levels compared to a selective GLP-1 receptor agonist. It was approved for the treatment of T2D in adults in 2022 and for weight loss in 2023.

Since individuals with obesity and T2D often experience less weight reduction with anti-obesity medications than those without diabetes, the current study evaluated Tirzepatide in adults with obesity and T2D. Among those on 15 mg Tirzepatide, 51.8% achieved ≥15% weight reduction and 34.0% achieved ≥20% weight reduction, compared to 2.6% and 1.0% with placebo, respectively. The % of participants achieving an HbA1c level of <5.7% was 55% for the 10 mg dose and 50% for the 15 mg dose, compared to 2.8% with placebo. Additionally, there were decreases in waist circumference, systolic blood pressure, fasting triglycerides, and HDL-cholesterol.

We await the results of the SURPASS-PEDS study, which is evaluating Tirzepatide in children aged 10 to under 18 years with T2D inadequately controlled with metformin, basal insulin, or both, and the SURMOUNT-ADOLESCENTS-2 study, which is assessing Tirzepatide’s impact on body weight and cardiovascular risk factors in adolescents with obesity and weight-related comorbidities.

Reference: 1. Ciardullo S, Morieri ML, Daniele G, Fiorentino TV, Mezza T, Tricò D, Consoli A, Del Prato S, Giorgino F, Piro S, Solini A, Avogaro A. GLP1-GIP receptor co-agonists: a promising evolution in the treatment of type 2 diabetes. Acta Diabetol. 2024 Aug;61(8):941-950. doi:10.1007/s00592-024-02300-6.