Tirzepatide

1. 01Skin

   Injected under the skin and absorbed slowly

   The drug is injected just under the skin. From there it seeps into the blood slowly, reaching its highest level somewhere between about 8 hours and 3 days later.

   For experts

   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]

2. 02Bloodstream

   Rides on albumin so it lasts about a week

   A fatty side chain makes the drug stick to albumin, a common blood protein. This protects it from being cleared quickly, so one injection lasts about a week.

   For experts

   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]

3. 03Pancreas

   Switches on two receptors on pancreas cells

   In the pancreas, the drug presses the GIP and GLP-1 buttons on insulin-making cells. That makes them release insulin when blood sugar is high, and it turns down glucagon, a hormone that raises blood sugar.

   For experts

   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]

4. 04Stomach

   Slows the stomach, mostly after the first injection

   The drug makes the stomach empty more slowly, so food stays around longer. This effect is strongest after the first injection and fades with time.

   For experts

   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]

5. 05Brain

   Turns down appetite signals in the brain

   GIP and GLP-1 receptors are found in parts of the brain that help control hunger. In people, the drug lowers how much they eat. Studies in animals show it reaches those brain areas and switches on nerve cells there.

   For experts

   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]

6. 06Liver

   Reduces fat stored in the liver

   In a trial of adults with type 2 diabetes, people taking tirzepatide had a bigger drop in liver fat than people taking insulin, as measured on MRI scans.

   For experts

   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]

7. 07Fat tissue

   Body weight falls, mostly as fat

   People lose weight partly because they eat less. Most of the weight lost is fat, including deep belly fat around the organs.

   For experts

   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]

8. 08Heart

   Effects on the heart in people with heart disease or heart failure

   In one trial, tirzepatide lowered the chance of a worsening-heart-failure event in people with obesity and a stiff-heart type of heart failure. In people with diabetes and heart disease, heart attacks, strokes and heart-related deaths happened about as often as with dulaglutide, another diabetes drug known to lower these events. Tirzepatide was not proven to be better.

   For experts

   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]

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