What is TIRZEPATIDE?
Tirzepatide is both a GIP receptor and a GLP-1 receptor agonist, it is a modified peptide consisting of 39-amino acid and contains a C20 fatty acid diazide group. This structure provides albumin binding and prolongs the elimination half-life. Tirzepatide selectively binds to and activates both GIP and GLP-1 receptors – these receptors are the targets of the natural GIP and GLP-1 hormones. Tirzepatide reduces fasting and postprandial glucose levels, reduces food intake, and reduces body weight in patients with type 2 diabetes.
Who TIRZEPATIDE impact?
Tirzepatide is a long-acting GIP (glucose-dependent insulinotropic peptide) and GLP-1 (glucagon-like peptide-1) receptor agonist. Both receptors are present on the pancreatic α and β endocrine cells, heart, vasculature, immune cells (leukocytes), gut and kidney. GIP receptors are also present on in fat cells (adipocytes). Tirzepatide is highly selective to human GIP and GLP-1 receptors and has high affinity to both receptors.
The activity of Tirzepatide on the GIP receptor is similar to native GIP hormone. Its impact on the GLP-1 receptor is lower compared to native GLP-1 hormone. In addition, both GIP and GLP-1 receptors are expressed in the areas of the brain important to appetite regulation. Animal studies show that Tirzepatide distributes to and activates neurons in brain regions involved in regulation of appetite and food intake.
Animal studies show that Tirzepatide can modulate fat utilization through the GIP receptor. In human adipocytes cultured in vitro, Tirzepatide acts on GIP receptors to regulate glucose uptake and modulate lipid uptake and lipolysis.
Appetite regulation and energy metabolism
Tirzepatide lowers body weight and body fat mass. The mechanisms associated with body weight and body fat mass reduction involve decreased food intake through the regulation of appetite. Clinical studies show that Tirzepatide reduces energy intake and appetite by increasing feelings of satiety and fullness, and decreasing feelings of hunger.
Tirzepatide significantly reduced the amount of free choice of lunch, dinner, and total daily food intake and calorie intake compared to placebo in obese patients. Based on a retrospective assessment using a visual analog scale (VAS), tirzepatide significantly reduced overall appetite compared to placebo over an 18-week period.
Tirzepatide reduced hunger and future food intake as early as the first week of treatment and increased satiety from the third week onwards. Tirzepatide significantly reduced cravings for fast food, fatty foods, sweets, carbohydrates, and starchy foods in obese individuals compared to placebo, while cravings for vegetables and fruits remained unchanged.
Glucose control
Tirzepatid improves glucose control in patients with Type 2 Diabetes by reducing fasting and postprandial glucose levels through various mechanisms.
Pharmacodynamic effects
Insulin secretion
Tirzepatide increases pancreatic β-cell glucose sensitivity. It enhances first- and second-phase insulin secretion in a glucose dependent manner. In a hyperglycaemic clamp study in patients with Type 2 Diabetes, tirzepatide was compared to placebo and the selective GLP-1 receptor agonist semaglutide 1 mg for insulin secretion. Tirzepatide 15 mg enhanced the first and second-phase insulin secretion rate by 466 % and 302 % from baseline, respectively. There was no change in first- and second-phase insulin secretion rate for placebo.
Insulin sensitivity
Tirzepatide improves insulin sensitivity. Tirzepatide 15 mg increased whole-body insulin sensitivity by 63%. This was determined by the M-value (an indicator of glucose uptake into tissues, measured by a study method in which blood glucose and insulin levels are kept constant). No change in M-value was observed in the placebo group.
Tirzepatide reduces body weight in overweight and obese patients with Type 2 Diabetes, which may contribute to improved insulin sensitivity. Reduction in food intake with Tirzepatide leads to a decrease in body weight. The decrease in body weight is mainly due to a decrease in fat mass.
Glucagon concentration
Tirzepatide reduced the fasting and postprandial glucagon concentrations in a glucose dependent manner. Tirzepatide 15 mg reduced fasting glucagon concentration by 28 % and glucagon AUC after a mixed meal by 43 %, compared with no change for placebo.
Gastric emptying
Tirzepatide delays gastric emptying which may slow post meal glucose absorption and can lead to a beneficial effect on postprandial glycaemia. Tirzepatide induced delay in gastric emptying diminishes over time.
Clinical efficacy and safety
Type 2 diabetes mellitus
The safety and efficacy of Tirzepatide were evaluated in five global randomised, controlled, phase 3 studies (SURPASS 1-5) assessing glycaemic control as the primary objective.
The studies involved 6 263 treated patients with type 2 diabetes (4 199 treated with Tirzepatide). The secondary objectives included body weight, percentage of patients achieving weight reduction targets, fasting serum glucose (FSG) and percentage of patients reaching target HbA1c.
All five phase 3 studies assessed tirzepatide 5 mg, 10 mg and 15 mg. All patients treated with tirzepatide started with 2.5 mg for 4 weeks. Then the dose of tirzepatide was increased by 2.5 mg every 4 weeks until they reached their assigned dose. Across all studies, treatment with Tirzepatide demonstrated sustained, statistically significant and clinically meaningful reductions from baseline in HbA1c as the primary objective compared to either placebo or active control treatment (semaglutide, insulin degludec and insulin glargine) for up to 1 year. In 1 study these effects were sustained for up to 2 years.
Statistically significant and clinically meaningful reductions from baseline in body weight were also demonstrated.
Results from the phase 3 studies are presented below based on the on-treatment data without rescue therapy in the modified intent-to-treat population consisting of all randomly assigned patients who were exposed to at least 1 dose of study treatment, excluding patients discontinuing study treatment due to inadvertent enrolment.