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Body journey · 7 steps

Inside the body with Orforglipron

Orforglipron is a once-a-day tablet that copies a gut hormone called GLP-1. Most drugs like it are peptides that must be injected. This one is a small, non-peptide molecule that survives being swallowed. It is approved in the US and UK for weight management. The UK has also approved it for type 2 diabetes.

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  1. 01Gut

    A tablet is absorbed through the gut

    Peptide drugs are usually broken down by stomach acid and enzymes, so they are injected. Orforglipron is a small, sturdy molecule that survives digestion and passes into the blood. About three quarters of it gets in.

    For experts +

    Orforglipron is a non-peptide small molecule, so it is not degraded by gastrointestinal proteases as peptide agonists are. Peak plasma concentration occurs 4 to 8 hours after an oral dose. Geometric mean absolute bioavailability was 77% in the label and 79.1% in a dedicated phase 1 study. Food had no clinically relevant effect on exposure.[src][src]

  2. 02Bloodstream

    Stays in the blood for more than a day

    Nearly all of the drug sticks to proteins in the blood, and the body clears it slowly. Its half-life is about one to two days, so a single tablet a day keeps a steady amount in the body.

    For experts +

    Plasma protein binding exceeds 99%, steady-state volume of distribution is about 285 L and systemic clearance is 7.15 L/h. Elimination half-life is about 29 to 49 hours, and steady state is reached after about one week of once-daily administration.[src]

  3. 03Pancreas

    Switches on GLP-1 receptors on pancreas cells

    Orforglipron fits into GLP-1 receptors, a kind of lock on the surface of cells. In the pancreas this helps the body release insulin when blood sugar is high. In a diabetes trial it lowered average blood sugar.

    For experts +

    It binds and activates the human GLP-1 receptor with high affinity (Ki about 1 nM) and is selective over other class B GPCRs. It is a partial agonist biased toward G-protein signalling over beta-arrestin recruitment, and low receptor occupancy was sufficient for a full glucose response in humanized-receptor mice (animal data). In humans, a phase 2 analysis showed improved beta-cell function markers (HOMA-B) in type 2 diabetes, and ACHIEVE-1 showed HbA1c reductions of 1.24 to 1.48 percentage points over 40 weeks against 0.41 with placebo.[src][src][src][src][src]

  4. 04Brain

    Turns down appetite signals in the brain

    GLP-1 receptors also sit in parts of the brain that control hunger. People taking it eat less, probably because they feel less hungry. Only animal studies show that the drug reaches these brain areas; in people, only the drop in eating has been measured.

    For experts +

    GLP-1 receptors are present in appetite-regulating brain regions. The label states that in animal studies orforglipron distributed to and activated neurons in these regions; in a rat model engineered to carry a sensitized GLP-1R, target engagement in the brain was consistent with peptide-based agonists (animal-only data). In humans the label reports decreased food intake, likely mediated by decreased appetite. Direct brain-receptor engagement has not been demonstrated in humans.[src][src]

  5. 05Stomach

    Slows how fast the stomach empties

    Food leaves the stomach more slowly, which can make people feel full for longer. This effect is biggest after the first dose and fades over time. It also helps explain some side effects, such as nausea.

    For experts +

    The label reports delayed gastric emptying that is largest after the first dose and diminishes over time, with the potential to affect absorption of co-administered oral drugs and a warning about pulmonary aspiration during anaesthesia or deep sedation. Gastrointestinal adverse reactions were most frequent during dose escalation and decreased over time.[src]

  6. 06Fat tissue

    Body weight goes down, mostly from fat

    With less appetite, people eat less and lose weight. In a large 72-week trial of adults with obesity but not diabetes, the highest dose group lost 11.2% of body weight on average, compared with 2.1% on placebo. More of the lost weight was fat than muscle and other lean tissue.

    For experts +

    In ATTAIN-1 (n=3,127), mean body-weight change at week 72 ranged from -7.5% to -11.2% across three doses versus -2.1% with placebo (P<0.001). In the top dose group, 54.6% lost at least 10% of body weight versus 12.9% on placebo. Waist circumference, systolic blood pressure, triglycerides and non-HDL cholesterol also improved. The label states weight loss came with greater fat-mass loss than lean-mass loss.[src][src]

  7. 07Liver

    The liver breaks it down and it leaves in stool

    The liver changes the drug into other substances, mostly using an enzyme called CYP3A4. Nearly all of it leaves the body in stool, and very little in urine.

    For experts +

    Orforglipron is metabolised primarily by hepatic CYP3A4 to oxidative metabolites that are excreted into the intestinal lumen, followed by gut-microbial metabolism of the oxadiazolone ring. About 87% of a radiolabelled dose was recovered in faeces and under 1% in urine. Exposure rose 1.7-fold and 4.6-fold in moderate and severe hepatic impairment, and strong CYP3A4 inhibitors or inducers change exposure.[src][src]

Schematic animation — real structure where marked

Gut

Step 01 of 07

AI-generated illustration · not to scale

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What is real and what is drawn

The scenes are schematic animations made for this page. Shapes, colours, speeds and sizes are chosen to explain, not to measure. Nothing is to scale.

  • Real structure: Experimental structure · cryo-EM 3.1 Å · PDB 6XOX (2020). From “Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist.” Proc Natl Acad Sci U S A 2020. RCSB PDB entry. The coordinates are experimental; the movement into place is illustrative.

Transitions between scales use short clips labelled “AI-generated illustration”. They are generated images, not recordings or simulations.

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