Orforglipron

Why this record breaks our model

Every other weight-loss compound in this library is injected. Orforglipron is a tablet, and it is not a peptide at all: it is a small molecule that happens to fit the GLP-1 receptor. Both facts matter for how you track it: there is no vial, no reconstitution, no concentration, no beyond-use window, and no injection site to rotate.

What it does

The same three things as semaglutide: reduces appetite through GLP-1 receptors in the brain, slows gastric emptying so meals stay filling, and improves glucose-dependent insulin secretion.

The difference is chemistry. A peptide is a chain of amino acids and digestion pulls it apart, which is why peptide GLP-1 drugs are injected and why the oral semaglutide tablet needs an absorption enhancer plus a fasted morning, a maximum of four ounces of water, and a thirty-minute lockout before anything else goes in your mouth.

Orforglipron needs none of that. Once daily, with or without food, any time of day, swallowed whole. That is the whole commercial argument for the drug and it is a real advantage in adherence terms.

The titration

Six steps: 0.8 mg, 2.5 mg, 5.5 mg, 9 mg, 14.5 mg, and 17.2 mg maximum. Each step is held for at least 30 days, and a strength exists at every rung so there is no splitting or improvising. Reaching the top dose therefore takes about five months by the label's own schedule.

The interaction burden is the differentiated content

Orforglipron is cleared by CYP3A4, the liver enzyme responsible for metabolising an enormous share of prescription drugs. That gives it a set of instructions no injectable in this library has:

• Maximum 9 mg with a strong CYP3A4 inhibitor.
• Avoid strong CYP3A4 inducers.
• Simvastatin capped at 20 mg per day.
• Oral contraceptive users add a barrier method for 30 days after starting and after each escalation.

Note the last one carefully, because it is close to but not the same as the tirzepatide instruction, which is four weeks after initiation and four weeks after each escalation. And semaglutide injection carries no contraceptive warning at all. Three drugs in the same class with three different answers is exactly why a class-level rule of thumb is dangerous here.

Efficacy, with the harms column attached

The BMJ network meta-analysis, 262 trials and 99,791 participants, puts orforglipron at about 9.9% weight loss at one year, with moderate-to-high certainty. That is behind tirzepatide at 14.9% and CagriSema at 14.8%, and ahead of a lot of what came before.

The same analysis names orforglipron among the agents with the highest adverse-event discontinuation, in a risk-ratio band of 1.9 to 4.2, with a fatigue risk ratio of 3.4. Trial-reported gastrointestinal effects are substantial: nausea 35% against 10% on placebo, diarrhoea 25% against 11%, vomiting 24% against 4%, constipation 24% against 9%.

Reading the efficacy number without the harms column is how people end up surprised.

Boxed warning

Thyroid C-cell tumours, in line with the class. Contraindicated with a personal or family history of medullary thyroid carcinoma, or with Multiple Endocrine Neoplasia syndrome type 2.

What we do not publish

Three items appeared in our first pass and did not survive fact-checking: a specific alopecia rate, a specific adverse-event discontinuation rate, and a statement that orforglipron is not pharmacologically active in rodents and did not produce tumours in them. All three would need re-verifying against label sections 5.1 and 6.1 before we would print them, and we do not print numbers we cannot re-find.