GLP-1 and Incretin Drugs, Explained

GLP-1 drugs started out as a small, specialized treatment for diabetes. Today they are some of the most talked-about medicines in the world. The names add up fast: Ozempic, Wegovy, Mounjaro, Zepbound, and a growing list of drugs still being tested, with names like retatrutide and CagriSema. This guide sets the brand names aside and explains the basics: how these drugs work in the body, how the different versions really differ, what the studies have found, and what we know about the risks. It is for learning only. It includes no dosing information, and no help with getting these drugs.

The incretin system

Let’s start with a curious fact about how the body works, called the incretin effect (the way the gut tells the body to release insulin after you eat). When you swallow sugar, your body releases far more insulin than it does when the same amount of sugar is put straight into a vein. In healthy people, this gut-driven response is responsible for about 50-70% of the insulin you release after a meal. In people with type 2 diabetes, that response is clearly weaker.

Two gut hormones drive this effect. GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) are both released from cells lining your intestines after you eat. Modern incretin drugs are built to copy or adjust these hormones, sometimes along with two related signals, glucagon and amylin.

GLP-1 acts on the insulin-making cells in the pancreas (the beta cells). Its effects are worth listing, because they explain both the benefits and the side effects of this whole group of drugs: it tells the body to release insulin, it lowers glucagon (a hormone that raises blood sugar), it slows how fast the stomach empties, and it acts on the parts of the brain that control hunger and feeling full. One important safety detail: GLP-1’s insulin push is glucose-dependent, meaning it only nudges insulin up when blood sugar is already high. That is why GLP-1 drugs are fairly unlikely to cause low blood sugar (hypoglycemia) compared with older diabetes drugs.

GIP also helps the body release insulin, and here the science holds a real, unsettled debate worth being honest about. Both turning the GIP receptor on (called agonism) and blocking it (called antagonism) seem to help with weight loss when paired with GLP-1 activity. Tirzepatide turns the GIP receptor fully on, while MariTide (a drug Amgen is still testing) blocks the GIP receptor and turns on GLP-1 at the same time. This contradiction was the topic of a 2025 back-and-forth exchange in the journal Diabetes, and it has not been resolved.

Two more hormones round out the group. Glucagon normally raises blood sugar, but switching its receptor on also burns more energy and helps clear fat from the liver. That is why GLP-1/glucagon drugs and triple drugs target it, while balancing it against GLP-1’s blood-sugar-lowering. Amylin is released along with insulin. It helps you feel full and slows how fast the stomach empties. We already know it works in people, because an approved version called pramlintide exists.

The drug generations

It helps to picture these drugs in generations, sorted by which receptors they act on:

First-generation GLP-1: liraglutide (Victoza, Saxenda), a daily injection.
Second-generation GLP-1: semaglutide (Ozempic, Wegovy, Rybelsus), a weekly injection plus a pill form. An oral version (Wegovy 25 mg) was approved in late December 2025.
Dual incretin (GIP + GLP-1): tirzepatide (Mounjaro, Zepbound), weekly.
GLP-1/glucagon duals: survodutide, mazdutide, and pemvidutide — still being tested in the US. Mazdutide is approved in China for weight management and type 2 diabetes.
Triple agonist (GIP + GLP-1 + glucagon): retatrutide, in phase 3 trials.
Amylin combination: cagrilintide plus semaglutide (CagriSema), still being tested and not FDA-approved as of this writing.

What the trials show: weight and glucose

The data on how well these drugs work comes from large, carefully run studies (randomized controlled trials), and the numbers have gone up with each generation.

Liraglutide in the SCALE trial (56 weeks, 3,731 participants without diabetes) led to an average loss of about 8.4 kg, versus 2.8 kg on a placebo (a dummy treatment with no active drug).

Semaglutide in STEP-1 (68 weeks, 1,961 participants without diabetes) led to an average drop of 14.9%, versus 2.4% on placebo, with 86% of participants losing at least 5% of their body weight. The oral 25 mg form, studied in OASIS-4, showed about 16.6% versus 2.7% when looking only at people who took it as directed, and about 14% under a more cautious way of counting that includes everyone regardless of how closely they stuck to it.

Tirzepatide in SURMOUNT-1 (72 weeks) led to drops of 16.0%, 21.4%, and 22.5% at its three doses, versus 2.4% on placebo. In SURMOUNT-5, which pitted the two drugs directly against each other, tirzepatide reached 20.2% versus semaglutide’s 13.7% — though this was paid for by the maker and was open-label (everyone knew which drug they were getting), which is worth keeping in mind.

The drugs still being tested go further, but they rest on weaker evidence so far. Retatrutide in a phase 2 trial (48 weeks, 338 participants) reached about 22-24% at its higher doses — promising, but phase 2 is an early stage compared with the approved drugs. CagriSema in REDEFINE-1 reached 20.4% versus 3.0% on placebo (counting everyone), or 22.7% among those who took it as directed. Survodutide, aimed at liver disease (MASH), improved the disease without making scarring worse in 47%, 62%, and 43% of participants across its three doses, versus 14% on placebo — a result that does not climb steadily with the dose, meaning the highest dose did not give the best response.

What the trials show: cardiovascular outcomes

Some of the strongest evidence for this group of drugs is about the heart, not just weight.

LEADER (liraglutide, in people with type 2 diabetes at high heart risk, 9,340 participants) found about a 13% drop in major heart problems.
SUSTAIN-6 (semaglutide) found a hazard ratio of 0.74 (a hazard ratio below 1 means fewer events on the drug). But because this was a safety study done before approval, the better-than-placebo signal was a side finding, not the main thing the trial set out to prove.
SELECT (semaglutide in people with obesity and known heart disease but without diabetes, 17,604 participants) found a hazard ratio of 0.80 — the first time a drug showed a heart benefit in obesity without diabetes.
SURPASS-CVOT (tirzepatide versus dulaglutide) compared one active drug against another to show it was at least as good, with a hazard ratio of 0.92.

The honest read: GLP-1’s heart benefit is strong and has been shown again and again against placebo. Tirzepatide’s heart data, on the other hand, came from a comparison against another active drug — so the takeaway is “at least as good as a proven medication,” not a fresh case of beating placebo.

Side effects and risks

The most common side effects involve the stomach and gut: nausea, vomiting, diarrhea, and constipation. They depend on the dose, are usually mild to moderate, often fade over time, and are the top reason people stop. Raising the dose slowly is the standard way to keep them in check.

A few more serious risks deserve attention:

Thyroid C-cell tumors (boxed warning): This warning is based on studies in rodents; it has not been proven to cause this in people. These drugs should not be used by anyone with a personal or family history of medullary thyroid cancer or MEN2 (a genetic condition that raises the risk of certain tumors). Reassuringly, a large 2025 study in people found no extra thyroid-tumor risk.
Pancreatitis (inflammation of the pancreas): Labels say to stop the drug if this is suspected.
Gallbladder disease: Slightly more common, mostly a result of losing weight quickly.
NAION (non-arteritic anterior ischemic optic neuropathy, a type of sudden vision loss from reduced blood flow to the optic nerve): A new and debated eye signal. A 2024 study and a Danish-Norwegian study (combined adjusted hazard ratio 2.81) reported a link, but the actual risk is small (on the order of a few extra cases per 10,000 person-years), the studies looked backward at existing records, and it has not been proven that the drug is the cause. Read this one cautiously.
Other items on the label: slowed stomach emptying (which matters for anesthesia and the risk of breathing food into the lungs), a faster heart rate, loss of muscle when weight comes off quickly, and weight coming back after stopping.

The approved versus compounded landscape

Through 2024 the FDA listed these drugs as in short supply, which for a time let compounding pharmacies (pharmacies that mix up their own versions of a drug) make copies. That window has closed. The tirzepatide shortage was resolved in December 2024 and the semaglutide injection shortage in February 2025; the FDA’s leeway for compounders ended on a staggered timeline through mid-2025. Compounding pharmacies (whether state-licensed 503A pharmacies or registered 503B outsourcing facilities) are now barred from making what are “essentially copies” of these approved drugs.

In 2026 the FDA went a step further. On April 30, 2026, it proposed permanently removing semaglutide, tirzepatide, and liraglutide from the 503B bulk-substance list (the list of raw ingredients those facilities are allowed to use), having found no clinical need for them, with public comment open through late June 2026. As of this writing that is a proposed rule, not a final one.

The FDA has also publicly raised concerns about unapproved or “research-grade” GLP-1 products: dosing mistakes from measuring out the material yourself, unverified salt forms (semaglutide sodium or acetate are not the approved active ingredient), and fake or illegally imported ingredients. These concerns matter directly to anyone trying to judge whether a product is any good. Our how to read a COA guide explains what a certificate of analysis can and cannot tell you, and our reconstitution and handling page covers the real-world dangers the FDA points to around measuring out product yourself.

One note for athletes: GLP-1 receptor agonists are not on the World Anti-Doping Agency’s 2026 Prohibited List, but they are on WADA’s Monitoring Program, and tests to detect them are being actively developed. “Monitored,” not “cleared,” is the accurate status.

Bottom line

The incretin drugs are one of the best-studied groups of medicines in modern metabolic medicine, with weight, blood-sugar, and (for several of them) heart benefits shown again and again in large studies. The science is also still moving: the question of switching GIP on versus blocking it is genuinely unsettled, the triple drugs and amylin combinations rest on earlier-stage data, and risk signals like NAION are still being studied. Two practical facts frame where things stand right now — the compounding route has mostly closed, and the FDA has been clear about the quality and safety risks of unapproved versions. None of this is medical advice or a suggestion to use, get, or self-measure these drugs; it is a map of what the published evidence supports today.

Sources

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