Inside the body with Tirzepatide

After subcutaneous administration, absolute bioavailability is about 80% and time to maximum plasma concentration ranges from 8 to 72 hours. Exposure is similar whichever of the abdomen, thigh or upper arm is the injection site.[src]

A C20 fatty diacid enables reversible albumin binding (about 99% bound) and prolongs the half-life to roughly 5 days, which supports once-weekly use. Steady-state concentrations are reached after about four weekly doses.[src][src]

Tirzepatide enhances first- and second-phase insulin secretion and lowers glucagon, both in a glucose-dependent manner. In a 28-week phase 1 study in adults with type 2 diabetes, clamp disposition index (insulin secretion combined with insulin sensitivity) rose more with tirzepatide than with placebo or semaglutide, reflecting higher insulin secretion and better insulin sensitivity. In laboratory pharmacology it mimics native GIP at the GIP receptor and is biased at the GLP-1 receptor toward cAMP signalling over beta-arrestin recruitment, which experiments in isolated mouse islets suggest may favour insulin secretion. That bias is shown only in cell lines and mouse islets; it is not proven to be the cause of the clinical effect.[src][src][src]

Tirzepatide delays gastric emptying; the delay is largest after the first dose and diminishes over time. This can alter the absorption of oral medicines taken at the same time, and the label's warning about pulmonary aspiration during general anaesthesia or deep sedation refers to this delay.[src]

GIP and GLP-1 receptors are present in brain regions involved in appetite regulation. In humans the label reports decreased calorie intake, likely mediated by effects on appetite. Animal studies show that tirzepatide distributes to and activates neurons in appetite-regulating brain regions, and in mice it lowered food intake and body weight more than a GLP-1 receptor agonist alone. The brain-distribution findings are animal data; how much of the human effect comes from direct brain action is not settled.[src][src]

In the SURPASS-3 MRI substudy (296 adults with type 2 diabetes, 52 weeks), liver fat content fell by an absolute 8.09 percentage points with the pooled higher-dose tirzepatide groups versus 3.38 with insulin degludec (estimated difference -4.71 percentage points; 95% CI -6.72 to -2.70), from a mean baseline of 15.71%. The reduction correlated with baseline liver fat and, more weakly, with weight loss and with reductions in visceral and subcutaneous abdominal fat.[src]

The label states that tirzepatide lowers body weight with greater fat mass loss than lean mass loss and decreases calorie intake. In the SURPASS-3 MRI substudy, visceral and abdominal subcutaneous adipose tissue volumes fell significantly more than with insulin degludec. In SURMOUNT-1 the mean weight change at 72 weeks was -15.0%, -19.5% and -20.9% across the three maintenance dose levels versus -3.1% with placebo.[src][src][src]

In SUMMIT (731 adults with HFpEF and obesity), the composite of cardiovascular death or worsening heart failure occurred in 9.9% with tirzepatide versus 15.3% with placebo (HR 0.62; 95% CI 0.41 to 0.95), driven by worsening heart-failure events (HR 0.54); cardiovascular deaths numbered 8 versus 5 (HR 1.58; 95% CI 0.52 to 4.83). In SURPASS-CVOT (13,165 adults in the modified intention-to-treat population with type 2 diabetes and atherosclerotic disease, versus dulaglutide), major adverse cardiovascular events occurred in 12.2% versus 13.1% (HR 0.92; 95.3% CI 0.83 to 1.01): non-inferiority was met, superiority was not shown (P=0.09).[src][src]